WorldWideScience

Sample records for intestinal th17 cells

  1. TLR5 mediates CD172α(+) intestinal lamina propria dendritic cell induction of Th17 cells.

    Science.gov (United States)

    Liu, Han; Chen, Feidi; Wu, Wei; Cao, Anthony T; Xue, Xiaochang; Yao, Suxia; Evans-Marin, Heather L; Li, Yan-Qing; Cong, Yingzi

    2016-02-24

    Multiple mechanisms exist in regulation of host responses to massive challenges from microbiota to maintain immune homeostasis in the intestines. Among these is the enriched Th17 cells in the intestines, which regulates intestinal homeostasis through induction of antimicrobial peptides and secretory IgA among others. However, the means by which Th17 cells develop in response to microbiota is still not completely understood. Although both TLR5 and CD172α(+) lamina propria dendritic cells (LPDC) have been shown to promote Th17 cell development, it is still unclear whether TLR5 mediates the CD172α(+)LPDC induction of Th17 cells. By using a microbiota antigen-specific T cell reporter mouse system, we demonstrated that microbiota antigen-specific T cells developed into Th17 cells in the intestinal LP, but not in the spleen when transferred into TCRβxδ(-/-) mice. LPDCs expressed high levels of TLR5, and most CD172α(+)LPDCs also co-expressed TLR5. LPDCs produced high levels of IL-23, IL-6 and TGFβ when stimulated with commensal flagellin and promoted Th17 cell development when cultured with full-length CBir1 flagellin but not CBir1 peptide. Wild-type CD172α(+), but not CD172α(-), LPDCs induced Th17 cells, whereas TLR5-deficient LPDC did not induce Th17 cells. Our data thereby demonstrated that TLR5 mediates CD172α(+)LPDC induction of Th17 cells in the intestines.

  2. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation.

    Science.gov (United States)

    Goto, Yoshiyuki; Panea, Casandra; Nakato, Gaku; Cebula, Anna; Lee, Carolyn; Diez, Marta Galan; Laufer, Terri M; Ignatowicz, Leszek; Ivanov, Ivaylo I

    2014-04-17

    How commensal microbiota contributes to immune cell homeostasis at barrier surfaces is poorly understood. Lamina propria (LP) T helper 17 (Th17) cells participate in mucosal protection and are induced by commensal segmented filamentous bacteria (SFB). Here we show that MHCII-dependent antigen presentation of SFB antigens by intestinal dendritic cells (DCs) is crucial for Th17 cell induction. Expression of MHCII on CD11c(+) cells was necessary and sufficient for SFB-induced Th17 cell differentiation. Most SFB-induced Th17 cells recognized SFB in an MHCII-dependent manner. SFB primed and induced Th17 cells locally in the LP and Th17 cell induction occurred normally in mice lacking secondary lymphoid organs. The importance of other innate cells was unveiled by the finding that MHCII deficiency in group 3 innate lymphoid cells (ILCs) resulted in an increase in SFB-independent Th17 cell differentiation. Our results outline the complex role of DCs and ILCs in the regulation of intestinal Th17 cell homeostasis.

  3. Small intestinal eosinophils regulate Th17 cells by producing IL-1 receptor antagonist.

    Science.gov (United States)

    Sugawara, Reiko; Lee, Eun-Jung; Jang, Min Seong; Jeun, Eun-Ji; Hong, Chun-Pyo; Kim, Jung-Hwan; Park, Areum; Yun, Chang Ho; Hong, Sung-Wook; Kim, You-Me; Seoh, Ju-Young; Jung, YunJae; Surh, Charles D; Miyasaka, Masayuki; Yang, Bo-Gie; Jang, Myoung Ho

    2016-04-04

    Eosinophils play proinflammatory roles in helminth infections and allergic diseases. Under steady-state conditions, eosinophils are abundantly found in the small intestinal lamina propria, but their physiological function is largely unexplored. In this study, we found that small intestinal eosinophils down-regulate Th17 cells. Th17 cells in the small intestine were markedly increased in the ΔdblGATA-1 mice lacking eosinophils, and an inverse correlation was observed between the number of eosinophils and that of Th17 cells in the small intestine of wild-type mice. In addition, small intestinal eosinophils suppressed the in vitro differentiation of Th17 cells, as well as IL-17 production by small intestinal CD4(+)T cells. Unlike other small intestinal immune cells or circulating eosinophils, we found that small intestinal eosinophils have a unique ability to constitutively secrete high levels of IL-1 receptor antagonist (IL-1Ra), a natural inhibitor of IL-1β. Moreover, small intestinal eosinophils isolated from IL-1Ra-deficient mice failed to suppress Th17 cells. Collectively, our results demonstrate that small intestinal eosinophils play a pivotal role in the maintenance of intestinal homeostasis by regulating Th17 cells via production of IL-1Ra.

  4. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens.

    Science.gov (United States)

    Yang, Yi; Torchinsky, Miriam B; Gobert, Michael; Xiong, Huizhong; Xu, Mo; Linehan, Jonathan L; Alonzo, Francis; Ng, Charles; Chen, Alessandra; Lin, Xiyao; Sczesnak, Andrew; Liao, Jia-Jun; Torres, Victor J; Jenkins, Marc K; Lafaille, Juan J; Littman, Dan R

    2014-06-05

    T-helper-17 (TH17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis. They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota. Segmented filamentous bacteria (SFB) are sufficient to induce TH17 cells and to promote TH17-dependent autoimmune disease in animal models. However, the specificity of TH17 cells, the mechanism of their induction by distinct bacteria, and the means by which they foster tissue-specific inflammation remain unknown. Here we show that the T-cell antigen receptor (TCR) repertoire of intestinal TH17 cells in SFB-colonized mice has minimal overlap with that of other intestinal CD4(+) T cells and that most TH17 cells, but not other T cells, recognize antigens encoded by SFB. T cells with antigen receptors specific for SFB-encoded peptides differentiated into RORγt-expressing TH17 cells, even if SFB-colonized mice also harboured a strong TH1 cell inducer, Listeria monocytogenes, in their intestine. The match of T-cell effector function with antigen specificity is thus determined by the type of bacteria that produce the antigen. These findings have significant implications for understanding how commensal microbiota contribute to organ-specific autoimmunity and for developing novel mucosal vaccines.

  5. Induction of Th17 cells by segmented filamentous bacteria in the murine intestine.

    Science.gov (United States)

    Farkas, Adam M; Panea, Casandra; Goto, Yoshiyuki; Nakato, Gaku; Galan-Diez, Marta; Narushima, Seiko; Honda, Kenya; Ivanov, Ivaylo I

    2015-06-01

    Segmented filamentous bacteria (SFB) are Gram-positive, anaerobic, spore-forming commensals that reside in the gut of many animal species. Described more than forty years ago, SFB have recently gained interest due to their unique ability to modulate the host immune system through induction of IgA and Th17 cells. Here, we describe a collection of methods to detect and quantify SFB and SFB adhesion in intestinal mucosa, as well as SFB-specific CD4 T cells in the lamina propria. In addition, we describe methods for purification of SFB from fecal material of SFB-monoassociated gnotobiotic mice. Using these methods we examine the kinetics of SFB colonization and Th17 cell induction. We also show that SFB colonize unevenly the intestinal mucosa and that SFB adherence occurs predominantly in the terminal ileum and correlates with an increased proportion of SFB-specific Th17 cells.

  6. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving ILC3

    Science.gov (United States)

    Withers, David R.; Hepworth, Matthew R.; Wang, Xinxin; Mackley, Emma C.; Halford, Emily E.; Dutton, Emma E.; Marriott, Clare L.; Brucklacher-Waldert, Verena; Veldhoen, Marc; Kelsen, Judith; Baldassano, Robert N.; Sonnenberg, Gregory F.

    2016-01-01

    RAR-related orphan receptor γt (ROR-γt) directs differentiation of pro-inflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases1–3. However, ROR-γt-dependent group 3 innate lymphoid cells (ILC3s) provide essential immunity and tissue protection in the intestine4–11, suggesting that targeting ROR-γt could also result in impaired host defense to infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 cells but not ILC3s in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Transient genetic deletion of ROR-γt in mature ILC3s also did not impair cytokine responses in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation, and reduced the frequencies of TH17 cells but not ILC3s isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell versus ILC3 responses, and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation. PMID:26878233

  7. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation.

    Science.gov (United States)

    Wang, Jian; Li, Fengqi; Wei, Haiming; Lian, Zhe-Xiong; Sun, Rui; Tian, Zhigang

    2014-11-17

    Influenza in humans is often accompanied by gastroenteritis-like symptoms such as diarrhea, but the underlying mechanism is not yet understood. We explored the occurrence of gastroenteritis-like symptoms using a mouse model of respiratory influenza infection. We found that respiratory influenza infection caused intestinal injury when lung injury occurred, which was not due to direct intestinal viral infection. Influenza infection altered the intestinal microbiota composition, which was mediated by IFN-γ produced by lung-derived CCR9(+)CD4(+) T cells recruited into the small intestine. Th17 cells markedly increased in the small intestine after PR8 infection, and neutralizing IL-17A reduced intestinal injury. Moreover, antibiotic depletion of intestinal microbiota reduced IL-17A production and attenuated influenza-caused intestinal injury. Further study showed that the alteration of intestinal microbiota significantly stimulated IL-15 production from intestinal epithelial cells, which subsequently promoted Th17 cell polarization in the small intestine in situ. Thus, our findings provide new insights into an undescribed mechanism by which respiratory influenza infection causes intestinal disease.

  8. Induced Treg Cells Augment the Th17-Mediated Intestinal Inflammatory Response in a CTLA4-Dependent Manner.

    Directory of Open Access Journals (Sweden)

    Nobumasa Watanabe

    Full Text Available Th17 cells and Foxp3+ regulatory T cells (Tregs are thought to promote and suppress inflammatory responses, respectively. However, whether they counteract each other or synergize in regulating immune reactions remains controversial. To determine their interactions, we describe the results of experiments employing mouse models of intestinal inflammation by transferring antigen-specific Th cells (Th1, Th2, and Th17 differentiated in vitro followed by the administration of the cognate antigen via enema. We show that cotransfer of induced Tregs (iTregs suppressed Th1- and Th2-mediated colon inflammation. In contrast, colon inflammation induced by transfer of Th17 cells, was augmented by the cotransfer of iTregs. Furthermore, oral delivery of antigen potentiated Th17-mediated colon inflammation. Administration of a blocking antibody against cytotoxic T lymphocyte-associated antigen 4 (CTLA4 abrogated the effects of cotransfer of iTregs, while the injection of a soluble recombinant immunoglobulin (Ig fusion protein, CTLA4-Ig substituted for the cotransfer of iTregs. These results suggest that antigen-specific activation of iTregs in a local environment stimulates the Th17-mediated inflammatory response in a CTLA4-dependent manner.

  9. Mesenteric lymph nodes contribute to proinflammatory Th17-cell generation during inflammation of the small intestine in mice.

    Science.gov (United States)

    Kawabe, Takeshi; Suzuki, Nobu; Yamaki, Satoshi; Sun, Shu-Lan; Asao, Atsuko; Okuyama, Yuko; So, Takanori; Iwakura, Yoichiro; Ishii, Naoto

    2016-05-01

    cells of the small intestine, including Th17 cells, are critically involved in host protection from microbial infection, and also contribute to the pathogenesis of small bowel inflammatory disorders. Accumulating evidence suggests that mesenteric lymph nodes (MLNs) play important roles in gut-tropic T-cell generation, although it is still unclear if MLNs are involved in the pathogenesis of small intestine inflammation. To address this issue, we analyzed the roles of both MLNs and Peyer's patches (PPs) by evaluating MLN- or PP-deficient mice in an experimental model of small intestine inflammation, induced by CD3-specific mAb injection. Interestingly, MLNs, but not PPs, were essential for the pathogenesis of intestinal inflammation, in particular the accumulation and infiltration of CD4(+) T-cell populations, including Th17 cells, from the blood. In addition, CD4(+) T-cell accumulation was dependent on the function of the α4 β7 integrin. Furthermore, MLN removal led to a significantly reduced number of peripheral α4 β7 (+) CD4(+) effector memory T cells under normal conditions, suggesting that MLNs may play a role in maintaining the number of gut-tropic CD4(+) effector memory T cells circulating in the blood. Taken together, the present study highlights the important role of MLNs in contributing to the pathogenesis of small intestine inflammation.

  10. Ulmus davidiana var. japonica Nakai upregulates eosinophils and suppresses Th1 and Th17 cells in the small intestine.

    Directory of Open Access Journals (Sweden)

    Han-Sung Lee

    Full Text Available The bark of Ulmus davidiana var. japonica Nakai (Ulmaceae has been used in traditional Korean medicine for chronic inflammation in the gastrointestinal tract. Here we investigated the frequency and cytokine profile of the major immune cells in the small intestinal lamina propria (SI LP, spleen, and mesenteric lymph nodes (MLNs of mice treated orally with Ulmus davidiana var. japonica Nakai bark water extract (UDE to address the immunomodulatory role of this herb in intestinal homeostasis. B6 mice were given 5g/kg UDE once daily for 14 days. They were then sacrificed, and cells were isolated from the spleen, MLNs, and SI LP. The proportion of B versus T lymphocytes, CD4(+ versus CD8(+ T lymphocytes, Th1 and Th17 cells, and Foxp3(+ regulatory T cells in the spleen, MLNs, and SI LP were analyzed. The frequency of antigen-presenting cells (APCs, including dendritic cells, macrophages, and eosinophils in the SI LP and the expression of costimulatory molecules on APCs were also evaluated. The numbers and frequencies of Th1 and Th17 cells in the SI LP were significantly reduced in the UDE-treated mice compared with PBS controls. In addition, the proportion of IL-4-producing eosinophils in the SI LP was significantly elevated in the UDE-treated mice compared with controls. Taken together, these data indicate that UDE up-regulates the number and frequency of SI LP eosinophils, which can down-regulate the Th1 and Th17 responses via IL-4 secretion and contribute to intestinal homeostasis.

  11. Role of Th17 Cells and Intestinal Flora in Pathogenesis of Inflammatory Bowel Disease%Th17细胞和肠道菌群在炎症性肠病发病中的作用

    Institute of Scientific and Technical Information of China (English)

    芦泽兰; 乔宇琪; 冉志华

    2015-01-01

    炎症性肠病(IBD)是一种自身免疫性疾病,发病机制尚未明确,目前认为是由宿主基因、肠道微生物以及生活环境等因素综合作用,引发机体异常免疫应答所致。近年来,Th17细胞与 IBD 的关系成为研究热点,且越来越多的研究表明,肠道菌群对 Th17细胞及其相关细胞因子的调节与 IBD 发病密切相关。本文就 Th17细胞和肠道菌群在 IBD 发病中的作用作一综述。%Inflammatory bowel disease(IBD)is an autoimmune disease and its etiology has not yet been clarified. Dysregulated immune responses resulted from complex interactions among genetic factors,intestinal flora and environmental cues have been considered as the etiology of IBD. Recently,the relationship between Th17 cells and IBD has become a hotspot of study,and more and more studies showed that Th17 cells and their related cytokines regulated by intestinal flora contributed to the pathogenesis of IBD. This article reviewed the role of Th17 cells and intestinal flora in the pathogenesis of IBD.

  12. Purinergic Signaling as a Regulator of Th17 Cell Plasticity

    Science.gov (United States)

    Fernández, Dominique; Flores-Santibáñez, Felipe; Neira, Jocelyn; Osorio-Barrios, Francisco; Tejón, Gabriela; Nuñez, Sarah; Hidalgo, Yessia; Fuenzalida, Maria Jose; Meza, Daniel; Ureta, Gonzalo; Lladser, Alvaro; Pacheco, Rodrigo; Acuña-Castillo, Claudio; Guixé, Victoria; Quintana, Francisco J.; Bono, Maria Rosa; Rosemblatt, Mario; Sauma, Daniela

    2016-01-01

    T helper type 17 (Th17) lymphocytes, characterized by the production of interleukin-17 and other pro-inflammatory cytokines, are present in intestinal lamina propria and have been described as important players driving intestinal inflammation. Recent evidence, supporting the notion of a functional and phenotypic instability of Th17 cells, has shown that Th17 differentiate into type 1 regulatory (Tr1) T cells during the resolution of intestinal inflammation. Moreover, it has been suggested that the expression of CD39 ectonucleotidase endows Th17 cells with immunosuppressive properties. However, the exact role of CD39 ectonucleotidase in Th17 cells has not been studied in the context of intestinal inflammation. Here we show that Th17 cells expressing CD39 ectonucleotidase can hydrolyze ATP and survive to ATP-induced cell death. Moreover, in vitro-generated Th17 cells expressing the CD39 ectonucleotidase produce IL-10 and are less pathogenic than CD39 negative Th17 cells in a model of experimental colitis in Rag-/- mice. Remarkably, we show that CD39 activity regulates the conversion of Th17 cells to IL-10-producing cells in vitro, which is abrogated in the presence of ATP and the CD39-specific inhibitor ARL67156. All these data suggest that CD39 expression by Th17 cells allows the depletion of ATP and is crucial for IL-10 production and survival during the resolution of intestinal inflammation. PMID:27322617

  13. Purinergic Signaling as a Regulator of Th17 Cell Plasticity.

    Directory of Open Access Journals (Sweden)

    Dominique Fernández

    Full Text Available T helper type 17 (Th17 lymphocytes, characterized by the production of interleukin-17 and other pro-inflammatory cytokines, are present in intestinal lamina propria and have been described as important players driving intestinal inflammation. Recent evidence, supporting the notion of a functional and phenotypic instability of Th17 cells, has shown that Th17 differentiate into type 1 regulatory (Tr1 T cells during the resolution of intestinal inflammation. Moreover, it has been suggested that the expression of CD39 ectonucleotidase endows Th17 cells with immunosuppressive properties. However, the exact role of CD39 ectonucleotidase in Th17 cells has not been studied in the context of intestinal inflammation. Here we show that Th17 cells expressing CD39 ectonucleotidase can hydrolyze ATP and survive to ATP-induced cell death. Moreover, in vitro-generated Th17 cells expressing the CD39 ectonucleotidase produce IL-10 and are less pathogenic than CD39 negative Th17 cells in a model of experimental colitis in Rag-/- mice. Remarkably, we show that CD39 activity regulates the conversion of Th17 cells to IL-10-producing cells in vitro, which is abrogated in the presence of ATP and the CD39-specific inhibitor ARL67156. All these data suggest that CD39 expression by Th17 cells allows the depletion of ATP and is crucial for IL-10 production and survival during the resolution of intestinal inflammation.

  14. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells.

    Science.gov (United States)

    Withers, David R; Hepworth, Matthew R; Wang, Xinxin; Mackley, Emma C; Halford, Emily E; Dutton, Emma E; Marriott, Clare L; Brucklacher-Waldert, Verena; Veldhoen, Marc; Kelsen, Judith; Baldassano, Robert N; Sonnenberg, Gregory F

    2016-03-01

    RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.

  15. Increased Th17-inducing activity of CD14+ CD163 low myeloid cells in intestinal lamina propria of patients with Crohn's disease.

    Science.gov (United States)

    Ogino, Takayuki; Nishimura, Junichi; Barman, Soumik; Kayama, Hisako; Uematsu, Satoshi; Okuzaki, Daisuke; Osawa, Hideki; Haraguchi, Naotsugu; Uemura, Mamoru; Hata, Taishi; Takemasa, Ichiro; Mizushima, Tsunekazu; Yamamoto, Hirofumi; Takeda, Kiyoshi; Doki, Yuichiro; Mori, Masaki

    2013-12-01

    Abnormal activity of innate immune cells and T-helper (Th) 17 cells has been implicated in the pathogenesis of autoimmune and inflammatory diseases, including Crohn's disease (CD). Intestinal innate immune (myeloid) cells have been found to induce development of Th17 cells in mice, but it is not clear if this occurs in humans or in patients with CD. We investigated whether human intestinal lamina propria cells (LPCs) induce development of Th17 cells and whether these have a role in the pathogenesis of CD. Normal intestinal mucosa samples were collected from patients with colorectal cancer and noninflamed and inflamed regions of mucosa were collected from patients with CD. LPCs were isolated by enzymatic digestion and analyzed for expression of HLA-DR, lineage markers CD14 and CD163 using flow cytometry. Among HLA-DR(high) Lin(-) cells, we identified a subset of CD14(+) CD163(low) cells in intestinal LPCs; this subset expressed Toll-like receptor (TLR) 2, TLR4, and TLR5 mRNAs and produced interleukin (IL)-6, IL-1β, and tumor necrosis factor in response to lipopolysaccharide. In vitro co-culture with naïve T cells revealed that CD14(+) CD163(low) cells induced development of Th17 cells. CD14(+) CD163(low) cells from inflamed regions of mucosa of patients with CD expressed high levels of IL-6, IL-23p19, and tumor necrosis factor mRNAs, and strongly induced Th17 cells. CD14(+) CD163(low) cells from the noninflamed mucosa of patients with CD also had increased abilities to induce Th17 cells compared with those from normal intestinal mucosa. CD14(+) CD163(low) cells in intestinal LPCs from normal intestinal mucosa induce differentiation of naive T cells into Th17 cells; this activity is increased in mucosal samples from patients with CD. These findings show how intestinal myeloid cell types could contribute to pathogenesis of CD and possibly other Th17-associated diseases. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. The function of T helper type 17 cell in intestinal mucosal immunity%Th17细胞在肠黏膜免疫中的作用

    Institute of Scientific and Technical Information of China (English)

    徐瑞

    2011-01-01

    肠黏膜是人体最大的淋巴器官,它与呼吸道黏膜、泌尿生殖道黏膜等一起构成机体的第一道防御体系.肠黏膜经常抵御细菌、病毒、食物抗原、非甾体类抗炎药等的侵袭,若肠黏膜免疫系统遭受破坏,机体发生感染性疾病、自身免疫性疾病等.因此,肠黏膜免疫功能正常对机体的健康非常重要.Th17细胞是近年来发现的一类不同于Th1和Th2细胞的T细胞亚群,它的发现颠覆了传统的Th1/Th2模式.Th17细胞在肠道自身免疫性疾病、组织炎症和各类病原菌的感染中均起重要作用,是肠黏膜免疫的重要组成成分.该文对Th17细胞的分化及Th17细胞在肠黏膜屏障、肠道自身免疫性疾病和感染性疾病中的作用作一概述.%The intestinal mucosa is the biggest lymph organ in human body, which consists of the first line of defensive system with the respiratory mucosa and urinary mucosa. The intestinal mucosa is responsible to defend bacteria, viruses, dietary pathogens, non-steroid anti-inflammatory drug and so on. If the intestinal mucosal immune system is destroyed, the human will suffer many diseases such as infectious diseases,autoimmune diseases. Therefore, it plays an important part in physical health. T helper type 17 (Th17) cells different from Th1 cells and Th2 cells are a distinct lineage of T cells. The discovery of Th17 cells has ruined the constitutional pattern of Th1/Th2. Th17 cells, which are important parts of intestinal mucosal immune system,play critical roles in intestinal autoimmune diseases, tissue inflammation and the infection of various pathogenic bacteria. This paper will review the differentiation of Th17 cell and its function in intestinal mucosal barrier,intestinal autoimmune diseases and intestinal infectious diseases.

  17. Maintenance of intestinal Th17 cells and reduced microbial translocation in SIV-infected rhesus macaques treated with interleukin (IL-21.

    Directory of Open Access Journals (Sweden)

    Suresh Pallikkuth

    Full Text Available In pathogenic HIV and SIV infections of humans and rhesus macaques (RMs, preferential depletion of CD4⁺ Th17 cells correlates with mucosal immune dysfunction and disease progression. Interleukin (IL-21 promotes differentiation of Th17 cells, long-term maintenance of functional CD8⁺ T cells, and differentiation of memory B cells and antibody-secreting plasma cells. We hypothesized that administration of IL-21 will improve mucosal function in the context of pathogenic HIV/SIV infections. To test this hypothesis, we infected 12 RMs with SIV(mac239 and at day 14 post-infection treated six of them with rhesus rIL-21-IgFc. IL-21-treatment was safe and did not increase plasma viral load or systemic immune activation. Compared to untreated animals, IL-21-treated RMs showed (i higher expression of perforin and granzyme B in total and SIV-specific CD8⁺ T cells and (ii higher levels of intestinal Th17 cells. Remarkably, increased levels of Th17 cells were associated with reduced levels of intestinal T cell proliferation, microbial translocation and systemic activation/inflammation in the chronic infection. In conclusion, IL-21-treatment in SIV-infected RMs improved mucosal immune function through enhanced preservation of Th17 cells. Further preclinical studies of IL-21 may be warranted to test its potential use during chronic infection in conjunction with antiretroviral therapy.

  18. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.

    Science.gov (United States)

    Leppkes, Moritz; Becker, Christoph; Ivanov, Ivaylo I; Hirth, Sebastian; Wirtz, Stefan; Neufert, Clemens; Pouly, Sandrine; Murphy, Andrew J; Valenzuela, David M; Yancopoulos, George D; Becher, Burkhard; Littman, Dan R; Neurath, Markus F

    2009-01-01

    IL-17-producing CD4(+) T-helper cells (Th17) contribute to chronic autoimmune inflammation in the brain, and levels of Th17-derived cytokines increase in patients with colitis, suggesting a role in pathogenesis. We analyzed the roles of Th17 cells and the transcription factor retinoic acid receptor-related organ receptor (ROR)gamma, which regulates Th17 differentiation, in chronic intestinal inflammation. Using an adoptive transfer model of colitis, we compared the colitogenic potential of wild-type, interleukin-17A (IL-17A)-, IL-17F-, IL-22-, and RORgamma-deficient CD4(+)CD25(-) T cells in RAG1-null mice. Adoptive transfer of IL-17A-, IL-17F-, or IL-22-deficient T lymphocytes into RAG1-null mice caused severe colitis that was indistinguishable from that caused by wild-type cells. In contrast, transfer of RORgamma-null T cells failed to increase mucosal IL-17 cytokine levels and did not induce colitis. Treatment with IL-17A was able to restore colitis after transfer of RORgamma-null T cells, indicating a crucial role for Th17 cells in pathogenesis. Treatment of RAG1 mice that received IL-17F-null (but not wild-type) T cells with a neutralizing anti-IL-17A antibody significantly suppressed disease, indicating redundant biological effects of IL-17A and IL-17F. We have identified a crucial role of RORgamma-expressing Th17 cells in chronic intestinal inflammation. RORgamma controls IL-17A and IL-17F production, and these cytokines have a redundant but highly pathogenic role in gut inflammation. Reagents that target RORgamma or a combination of anti-IL-17A and anti-IL-17F might be developed as therapeutics for chronic colitis.

  19. Th17 Cells in Immunity and Autoimmunity

    Directory of Open Access Journals (Sweden)

    Simone Kennedy Bedoya

    2013-01-01

    Full Text Available Th17 and IL-17 play important roles in the clearance of extracellular bacterial and fungal infections. However, strong evidence also implicates the Th17 lineage in several autoimmune disorders including multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and asthma. The Th17 subset has also been connected with type I diabetes, although whether it plays a role in the pathogenicity of or protection from the disease remains a controversial issue. In this review we have provided a comprehensive overview of Th17 pathogenicity and function, including novel evidence for a protective role of Th17 cells in conjunction with the microbiota gut flora in T1D onset and progression.

  20. Rebamipide prevents peripheral arthritis and intestinal inflammation by reciprocally regulating Th17/Treg cell imbalance in mice with curdlan-induced spondyloarthritis.

    Science.gov (United States)

    Min, Hong-Ki; Kim, Jae-Kyung; Lee, Seon-Yeong; Kim, Eun-Kyung; Lee, Seung Hoon; Lee, Jennifer; Kwok, Seung-Ki; Cho, Mi-La; Park, Sung-Hwan

    2016-06-27

    Spondyloarthritis (SpA) usually manifests as arthritis of the axial and peripheral joints but can also result in extra-articular manifestations such as inflammatory bowel disease. Proinflammatory cytokine interleukin-17 (IL-17) plays a crucial role in the pathogenesis of SpA. Rebamipide inhibits signal transducer and activator of transcription 3 that controls IL-17 production and Th17 cell differentiation. This study examined the effect of rebamipide on SpA development. SKG ZAP-70(W163C) mice were immunized with curdlan to induce SpA features. The mice were then intraperitoneally injected with rebamipide or vehicle 3 times a week for 14 weeks and their clinical scores were evaluated. Histological scores of the paw and spine and the length of the gut were measured at sacrifice. Immunohistochemical staining of IL-17 and tumor necrosis factor-α (TNF-α) was performed using tissue samples isolated from the axial joints, peripheral joints, and gut. Spleen tissue samples were isolated from both rebamipide- or vehicle-treated mice with SpA at 14 weeks after curdlan injection to determine the effect of rebamipide on Th17 and regulatory T (Treg) cell differentiation. Rebamipide decreased the clinical and histological scores of the peripheral joints. The total length of the gut was preserved in rebamipide-treated mice. IL-17 and TNF-α expression in the spine, peripheral joints, and gut was lower in rebamipide-treated mice than in control mice. Th17 cell differentiation was suppressed whereas Treg cell differentiation was upregulated in the spleen of rebamipide-treated mice. Rebamipide exerted beneficial effects in mice with SpA by preventing peripheral arthritis and intestinal inflammation and by regulating Th17/Treg cell imbalance, suggesting that it can be used as a potential therapeutic agent for treating arthritis to SpA patients.

  1. More stories on Th17 cells

    Institute of Scientific and Technical Information of China (English)

    Alexandra S Basso; Hilde Cheroutre; Daniel Mucida

    2009-01-01

    For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. The Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4+ T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4+ T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Thl or Th2 cells. The Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Thl, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Thl7 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-β or TGF-β plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.

  2. Lactobacillus rhamnosus GG supernatant promotes intestinal barrier function, balances Treg and TH17 cells and ameliorates hepatic injury in a mouse model of chronic-binge alcohol feeding.

    Science.gov (United States)

    Chen, Rui-Cong; Xu, Lan-Man; Du, Shan-Jie; Huang, Si-Si; Wu, He; Dong, Jia-Jia; Huang, Jian-Rong; Wang, Xiao-Dong; Feng, Wen-Ke; Chen, Yong-Ping

    2016-01-22

    Impaired intestinal barrier function plays a critical role in alcohol-induced hepatic injury, and the subsequent excessive absorbed endotoxin and bacterial translocation activate the immune response that aggravates the liver injury. Lactobacillus rhamnosus GG supernatant (LGG-s) has been suggested to improve intestinal barrier function and alleviate the liver injury induced by chronic and binge alcohol consumption, but the underlying mechanisms are still not clear. In this study, chronic-binge alcohol fed model was used to determine the effects of LGG-s on the prevention of alcoholic liver disease in C57BL/6 mice and investigate underlying mechanisms. Mice were fed Lieber-DeCarli diet containing 5% alcohol for 10 days, and one dose of alcohol was gavaged on Day 11. In one group, LGG-s was supplemented along with alcohol. Control mice were fed isocaloric diet. Nine hours later the mice were sacrificed for analysis. Chronic-binge alcohol exposure induced an elevation in liver enzymes, steatosis and morphology changes, while LGG-s supplementation attenuated these changes. Treatment with LGG-s significantly improved intestinal barrier function reflected by increased mRNA expression of tight junction (TJ) proteins and villus-crypt histology in ileum, and decreased Escherichia coli (E. coli) protein level in liver. Importantly, flow cytometry analysis showed that alcohol reduced Treg cell population while increased TH17 cell population as well as IL-17 secretion, which was reversed by LGG-s administration. In conclusion, our findings indicate that LGG-s is effective in preventing chronic-binge alcohol exposure-induced liver injury and shed a light on the importance of the balance of Treg and TH17 cells in the role of LGG-s application.

  3. Th17 cells and tumor%Th17细胞与肿瘤

    Institute of Scientific and Technical Information of China (English)

    何宋兵; 郑丁铖; 汪良; 李德春

    2011-01-01

    Th17细胞是一类CD4+效应T细胞.研究发现Th17细胞及其相关细胞因子存在于许多肿瘤中,并在炎症相关性肿瘤中发挥重要作用,但对Th17细胞在肿瘤微环境中的分化表达、免疫调控机制及功能效应仍不明确.%Th17 cells are CD4 + effector T cells.Many studies have confirmed that Th17 cells and their related cytokines exist in many kinds of tumors,and play critical roles in inflammation related tumors.But the expression and differentiation in tumor microenvironment,the immune regulation mechanisms and functional effects of Th17 cells remains controversial.

  4. Inflammatory Th1 and Th17 in the Intestine Are Each Driven by Functionally Specialized Dendritic Cells with Distinct Requirements for MyD88

    Directory of Open Access Journals (Sweden)

    Jie Liang

    2016-10-01

    Full Text Available Normal dynamics between microbiota and dendritic cells (DCs support modest numbers of T cells, yet these do not cause inflammation. The DCs that induce inflammatory T cells and the signals that drive this process remain unclear. Here, we demonstrate that small intestine DCs lacking the signaling attenuator A20 induce inflammatory T cells and that the signals perceived and antigen-presenting cell (APC functions are unique for different DC subsets. Thus, although CD103+CD11b− DCs exclusively instruct IFNγ+ T cells, CD103+CD11b+ DCs exclusively instruct IL-17+ T cells. Surprisingly, APC functions of both DC subsets are upregulated in a MyD88-independent fashion. In contrast, CD103−CD11b+ DCs instruct both IFNγ+ and IL-17+ T cells, and only the IL-17-inducing APC functions require MyD88. In disease pathogenesis, both CD103−CD11b+ and CD103+CD11b+ DCs expand pathologic Th17 cells. Thus, in disease pathogenesis, specific DCs instruct specific inflammatory T cells.

  5. The requirements for natural Th17 cell development are distinct from those of conventional Th17 cells

    OpenAIRE

    Kim, Jiyeon S.; Smith-Garvin, Jennifer E; Koretzky, Gary A.; Jordan, Martha S.

    2011-01-01

    CD4+ T helper 17 (Th17) cells play a critical role in the adaptive immune response against extracellular pathogens. Most studies to date have focused on understanding the differentiation of Th17 cells from naive CD4+ T cells in peripheral effector sites. However, Th17 cells are present in the thymus. In this study, we demonstrate that a population of Th17 cells, natural Th17 cells (nTh17 cells), which acquire effector function during development in the thymus before peripheral antigen exposur...

  6. Intestinal Monocyte-Derived Macrophages Control Commensal-Specific Th17 Responses

    Directory of Open Access Journals (Sweden)

    Casandra Panea

    2015-08-01

    Full Text Available Generation of different CD4 T cell responses to commensal and pathogenic bacteria is crucial for maintaining a healthy gut environment, but the associated cellular mechanisms are poorly understood. Dendritic cells (DCs and macrophages (Mfs integrate microbial signals and direct adaptive immunity. Although the role of DCs in initiating T cell responses is well appreciated, how Mfs contribute to the generation of CD4 T cell responses to intestinal microbes is unclear. Th17 cells are critical for mucosal immune protection and at steady state are induced by commensal bacteria, such as segmented filamentous bacteria (SFB. Here, we examined the roles of mucosal DCs and Mfs in Th17 induction by SFB in vivo. We show that Mfs, and not conventional CD103+ DCs, are essential for the generation of SFB-specific Th17 responses. Thus, Mfs drive mucosal T cell responses to certain commensal bacteria.

  7. Th17 cells and colorectal cancer%Th17细胞与结直肠癌

    Institute of Scientific and Technical Information of China (English)

    周倩; 金弢; 连晓媛; 张治针

    2016-01-01

    Under normal condition,T helper 17 (Th17) cells play an important role in keeping intestinal immune homeostasis and resisting to external pathogenic microorganisms invasion.However,recent studies show that Th17 cells' abnormal differentiation and activation and their secreted cytokines (IL-17,IL-22,IL-21,IL-26) have an important role in the development of colorectal cancer.This article focuses on reviewing the role of Th17 cells and their secreted cytokines in the development and advance of colorectal cancer,and summarizes their potential mechanism,which will bring some new ideas for the prevention and treatment of colorectal cancer.%正常情况下,肠道内辅助性T细胞17(Th17)在维持肠内免疫稳态和抵抗外界病原微生物侵入方面起着重要的作用.然而近来研究发现Th17细胞异常分化、激活、增殖及其分泌的细胞因子(IL-17、IL-22、IL-21、IL-26)是导致结直肠癌发生发展的重要因素.故本文着重对Th17细胞及其分泌的细胞因子在结直肠癌发生发展中所起的作用进行综述并总结了其潜在的机制,为结直肠癌的防治提供新思路.

  8. Reconstitution of intestinal CD4 and Th17 T cells in antiretroviral therapy suppressed HIV-infected subjects: implication for residual immune activation from the results of a clinical trial.

    Directory of Open Access Journals (Sweden)

    Gabriella d'Ettorre

    Full Text Available INTRODUCTION: During HIV infection the severe depletion of intestinal CD4+ T-cells is associated with microbial translocation, systemic immune activation, and disease progression. This study examined intestinal and peripheral CD4+ T-cell subsets reconstitution under combined antiretroviral therapy (cART, and systemic immune activation markers. METHODS: This longitudinal single-arm pilot study evaluates CD4+ T cells, including Th1 and Th17, in gut and blood and soluble markers for inflammation in HIV-infected individuals before (M0 and after eight (M8 months of cART. From January 2010 to December 2011, 10 HIV-1 naïve patients were screened and 9 enrolled. Blood and gut CD4+ T-cells subsets and cellular immune activation were determined by flow-cytometry and plasma soluble CD14 by ELISA. CD4+ Th17 cells were detected in gut biopsies by immunohistochemistry. Microbial translocation was measured by limulus-amebocyte-lysate assay to detect bacterial lipopolysaccharide (LPS and PCR Real Time to detect plasma bacterial 16S rDNA. RESULTS: Eight months of cART increased intestinal CD4+ and Th17 cells and reduced levels of T-cell activation and proliferation. The magnitude of intestinal CD4+ T-cell reconstitution correlated with the reduction of plasma LPS. Importantly, the magnitude of Th17 cells reconstitution correlated directly with blood CD4+ T-cell recovery. CONCLUSION: Short-term antiretroviral therapy resulted in a significant increase in the levels of total and Th17 CD4+ T-cells in the gut mucosa and in decline of T-cell activation. The observation that pre-treatment levels of CD4+ and of CD8+ T-cell activation are predictors of the magnitude of Th17 cell reconstitution following cART provides further rationale for an early initiation of cART in HIV-infected individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT02097381.

  9. Leukotrienes induce the migration of Th17 cells.

    Science.gov (United States)

    Lee, Wonyong; Su Kim, Hyeong; Lee, Gap Ryol

    2015-01-01

    Th17 cell trafficking in response to leukotriene signaling is poorly understood. Here we showed that Th17 cells express high levels of leukotriene B4 receptor 1 (LTB4R1) and cysteinyl leukotriene receptor 1 (CysLTR1). Th17 cells migrated under the guidance of leukotriene B4 and D4. The migration of Th17 cells was more efficient than that of Th1 and Th2 cells, and it was blocked by specific inhibitors of LTB4R1 or CysLTR1. Studies in an animal model of experimental autoimmune encephalomyelitis revealed that treatment with montelukast alleviated disease symptoms and inhibited the recruitment of Th17 cells to the central nervous system. Thus, leukotrienes may act as chemoattractants for Th17 cells.

  10. Role of Th17 cells in common liver diseases

    Directory of Open Access Journals (Sweden)

    WEI Linlin

    2013-06-01

    Full Text Available In recent years, it has been found that T helper type 17 (Th17 cells are a new subset of CD4+ Th cells. Th17 cells play an important role in the onset and development of many liver diseases and have become the research focus in immunology. This paper summarizes the studies on the relationship between Th17 cells and various liver diseases in order to provide a new idea for the study and treatment of liver diseases.

  11. Th17 cells in neuromyelitis optica spectrum disorder: a review.

    Science.gov (United States)

    Lin, Jie; Li, Xiang; Xia, Junhui

    2016-12-01

    Neuromyelitis optica spectrum disorder (NMOSD) has been identified as a central nervous system (CNS) autoimmune inflammatory disorder, which has been recognized as a B cell-mediated humoral immune disease. However, cases have been reported indicating that some of the neuromyelitis optica (NMO) patients have been resistant to B cell-related treatments. Recently, more and more evidence has shown that T cell-mediated immunity may take part in the pathogenesis of NMOSD, especially in the Th17 phenotype. In our PUBMED search, we used the following keywords: Th17 cell, Th17 cell-related cytokines, T cells, B cells, B cell-related productions, NMO, NMOSD, recurrent/bilateral optic neuritis, recurrent transverse myelitis and longitudinally extensive transverse myelitis. We systemically reviewed the role of Th17 cells and Th17 cell-related cytokines in NMOSD. We found that Th17 cells and Th17-related cytokines, such as IL-6, IL-1β, IL-17, IL-21, IL-22, IL-23 and TGF-β, are not only directly involved in the pathogenesis but also collaborated with B cells and B cell-related antibody production to induce CNS lesions. Th17 cell-related therapy has also been reviewed in this article, and the data suggested that Th17 may be a new therapeutic target of NMOSD.

  12. Th17细胞与肺部疾病%Th17 cell and pulmonary diseases

    Institute of Scientific and Technical Information of China (English)

    孙燕; 解卫平

    2011-01-01

    Th17细胞是新近发现的CD4+T细胞亚群,因主要分泌白介素17而命名.白介素17是具有强大的招募中性粒细胞功能的前炎性细胞因子,可促进多种细胞释放炎性因子.Th17细胞在增强炎症反应的同时也提高了机体的防御能力,与肺部感染、气道慢性炎性疾病等密切相关.本文就此作一简要综述.%Th17 cell is a newly discovered subtype of CD4+ T cells. It can secret interleukin-17 (IL-17) which determines its denomination. IL-17 is a kind of proinflammatory cytokine that can strongly recruit neutrophils and promote many kinds of cells to release inflammatory cytokines. Th17 cell can strengthen inflammatory responses, and moreover, it enhances the body's defense ability. It has a close relation with pulmonary infections, chronic inflammatory disorder of the airway and so on. This review makes a summing-up for it.

  13. Th17细胞与银屑病%Th17 cells and psoriasis

    Institute of Scientific and Technical Information of China (English)

    陈丽娜; 苏玉文; 陆前进

    2016-01-01

    银屑病是一种常见的自身免疫性皮肤病,主要累及皮肤,部分患者累及关节,具有慢性、易复发等特征.Th17细胞是CD4+T淋巴细胞的一种亚型,以分泌IL-17为主要特征,近年来大量研究发现其在银屑病的发生发展中起重要作用,而且与其相关的药物在银屑病的治疗中也取得了一定的疗效.本文主要对Th17细胞在银屑病发病机制中的作用及以其为治疗靶点的药物做简要介绍.%Psoriasis is a common autoimmune disease and mainly affects skin,joints,or both.Psoriasis is also a chronic relapsing disorder that can cause physical and psychological burdens to patients.Currently it is widely accepted that the immune system is involved in the development of psoriasis.Th17 cells,a subtype of CD4 +T lymphocytes,are characterized by its ability to secrete proinflammatory cytokine IL-17.Recent studies indicate that Th17 cells play a predominant role in the pathogenesis of psoriasis and other immune-mediated inflammatory diseases.Moreover,targeted therapies have been developed and approved for the treatment of moderate-to-severe plaque psoriasis or psoriatic arthritis.This review summarizes the role of Th17 cells in the pathogenesis of psoriasis and several therapeutic biologics targeting this pathway in psoriasis.

  14. Th17 cell development: from the cradle to the grave.

    Science.gov (United States)

    Zúñiga, Luis A; Jain, Renu; Haines, Christopher; Cua, Daniel J

    2013-03-01

    T cells surviving the clonal selection process emigrate from the thymus to the periphery as immature naive T cells. In the periphery, upon activation under specific cytokine milieus, naive T cells adopt specific effector phenotypes, e.g. T-helper 1 (Th1), Th2, or Th17, and acquire diverse functions to control a myriad of pathogens, tissue injuries, and other immunological insults. Interleukin-23 (IL-23) is one of the key cytokines that shapes the development and function of Th17 cells with characteristic expression of retinoic acid receptor-related orphan receptor γ-t (RORγt), IL-17, IL-22, and granulocyte macrophage colony-stimulating factor (GM-CSF). More recently, emerging data suggest that IL-23 also promotes development of 'natural Th17' (nTh17) cells that arise from the thymus, analogous to natural regulatory T cells (nTreg). We are just beginning to understand the unique thymic developmental path of nTh17 cells, which are distinct from antigen-experienced memory Th17 cells. In this review, we explore the differentiation and function of inducible, natural, and memory Th17 subsets, which encompass a broad range of immune functions while maintaining tissue hemostasis, and highlight the participation of IL-23 during the life cycle of Th17 cells. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

  15. Th17 cells in the pathogenesis of multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Marek Juszczak

    2009-10-01

    Full Text Available Th17 cells are a recently described subset of T helper lymphocytes characterized by the production of IL-17 (IL-17A. Since their discovery in 2003, studies on Th17 cells have become increasingly popular among immunologists and they have emerged as key players in the pathogenesis of multiple sclerosis (MS and other autoimmune disorders traditionally attributed to Th1 cells. Murine Th17 lymphocytes differentiate from naive CD4 cells in a specific cytokine environment, which includes TGF- and IL-6 or IL-21, whereas human Th17 cell development requires TGF-, IL-1, and IL-2 in combination with IL-6, IL-21, or IL-23. Th17-related response is additionally enhanced by osteopontin, TNF, and PGE2 and suppressed by IL-25, IL-27, IL-35, and IL-10. Apart from their main cytokine, Th17 cells can also express IL-17F, IL-21, IL-22, TNF, CCL20, and, in humans, IL-26. All of these mediators may contribute to the proinflammatory action of Th17 .cells both in the clearance of various pathogens and in autoimmunity. At least some of these functions are exerted through the induction of neutrophil-recruiting chemokines (CXCL1, CXCL2, CXCL8 by IL-17. Accumulating evidence from studies on mice and humans indicates an important role of Th17 cells in mediating autoimmune neuroinflammation. This has led some immunologists to question the previously exhibited importance of Th1 cells in MS pathology. However, more recent data suggest that both these T-cell subsets are capable of inducing and promoting the disease. Further investigation is required to clarify the role of Th17 cells in the pathogenesis of MS since some of the Th17-related molecules appear as attractive targets for future therapeutic strategies

  16. Harnessing the Therapeutic Potential of Th17 Cells.

    Science.gov (United States)

    Bystrom, Jonas; Taher, Taher E; Muhyaddin, M Sherwan; Clanchy, Felix I; Mangat, Pamela; Jawad, Ali S; Williams, Richard O; Mageed, Rizgar A

    2015-01-01

    Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases.

  17. Harnessing the Therapeutic Potential of Th17 Cells

    Directory of Open Access Journals (Sweden)

    Jonas Bystrom

    2015-01-01

    Full Text Available Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ. In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases.

  18. Interleukin-23 and Th17 Cells in the Control of Gut Inflammation

    Directory of Open Access Journals (Sweden)

    Ivan Monteleone

    2009-01-01

    Full Text Available Crohn's Disease and Ulcerative Colitis, the major forms of inflammatory bowel diseases (IBDs in humans, have been traditionally associated with exaggerated and poorly controlled T helper (Th type 1 or Th2 cell response, respectively. More recent studies have, however, shown that IBDs are also characterized by a sustained production of cytokines made by a distinct lineage of Th cells, termed Th17 cells. The demonstration that Th17-related cytokines cause pathology in many organs, including the gut, and that expansion and maintenance of Th17 cell responses require the activity of IL-23, a cytokine made in excess in the gut of IBD patients has contributed to elucidate new pathways of intestinal tissue damage as well as to design new therapeutic strategies. In this review, we discuss the available data supporting the role of the IL-23/Th17 axis in the modulation of intestinal tissue inflammation.

  19. Protective role of Th17 cells in pulmonary infection.

    Science.gov (United States)

    Rathore, Jitendra Singh; Wang, Yan

    2016-03-18

    Th17 cells are characterized as preferential producer of interleukins including IL-17A, IL-17F, IL-21 and IL-22. Corresponding receptors of these cytokines are expressed on number of cell types found in the mucosa, including epithelial cells and fibroblasts which constitute the prime targets of the Th17-associated cytokines. Binding of IL-17 family members to their corresponding receptors lead to modulation of antimicrobial functions of target cells including alveolar epithelial cells. Stimulated alveolar epithelial cells produce antimicrobial peptides and are involved in granulepoesis, neutrophil recruitment and tissue repair. Mucosal immunity mediated by Th17 cells is protective against numerous pulmonary pathogens including extracellular bacterial and fungal pathogens. This review focuses on the protective role of Th17 cells during pulmonary infection, highlighting subset differentiation, effector cytokines production, followed by study of the binding of these cytokines to their corresponding receptors, the subsequent signaling pathway they engender and their effector role in host defense.

  20. Plasticity of Th17 Cells in Autoimmune Kidney Diseases.

    Science.gov (United States)

    Krebs, Christian F; Turner, Jan-Eric; Paust, Hans-Joachim; Kapffer, Sonja; Koyro, Tobias; Krohn, Sonja; Ufer, Friederike; Friese, Manuel A; Flavell, Richard A; Stockinger, Brigitta; Steinmetz, Oliver M; Stahl, Rolf A K; Huber, Samuel; Panzer, Ulf

    2016-07-15

    The ability of CD4(+) T cells to differentiate into pathogenic Th1 and Th17 or protective T regulatory cells plays a pivotal role in the pathogenesis of autoimmune diseases. Recent data suggest that CD4(+) T cell subsets display a considerable plasticity. This plasticity seems to be a critical factor for their pathogenicity, but also for the potential transition of pathogenic effector T cells toward a more tolerogenic phenotype. The aim of the current study was to analyze the plasticity of Th17 cells in a mouse model of acute crescentic glomerulonephritis and in a mouse chronic model of lupus nephritis. By transferring in vitro generated, highly purified Th17 cells and by using IL-17A fate reporter mice, we demonstrate that Th17 cells fail to acquire substantial expression of the Th1 and Th2 signature cytokines IFN-γ and IL-13, respectively, or the T regulatory transcription factor Foxp3 throughout the course of renal inflammation. In an attempt to therapeutically break the stability of the Th17 phenotype in acute glomerulonephritis, we subjected nephritic mice to CD3-specific Ab treatment. Indeed, this treatment induced an immunoregulatory phenotype in Th17 cells, which was marked by high expression of IL-10 and attenuated renal tissue damage in acute glomerulonephritis. In summary, we show that Th17 cells display a minimum of plasticity in acute and chronic experimental glomerulonephritis and introduce anti-CD3 treatment as a tool to induce a regulatory phenotype in Th17 cells in the kidney that may be therapeutically exploited.

  1. Regulation of TH17 Cells and Associated Cytokines in Wound Healing, Tissue Regeneration, and Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Leonie Brockmann

    2017-05-01

    Full Text Available Wound healing is a crucial process which protects our body against permanent damage and invasive infectious agents. Upon tissue damage, inflammation is an early event which is orchestrated by a multitude of innate and adaptive immune cell subsets including TH17 cells. TH17 cells and TH17 cell associated cytokines can impact wound healing positively by clearing pathogens and modulating mucosal surfaces and epithelial cells. Injury of the gut mucosa can cause fast expansion of TH17 cells and their induction from naïve T cells through Interleukin (IL-6, TGF-β, and IL-1β signaling. TH17 cells produce various cytokines, such as tumor necrosis factor (TNF-α, IL-17, and IL-22, which can promote cell survival and proliferation and thus tissue regeneration in several organs including the skin, the intestine, and the liver. However, TH17 cells are also potentially pathogenic if not tightly controlled. Failure of these control mechanisms can result in chronic inflammatory conditions, such as Inflammatory Bowel Disease (IBD, and can ultimately promote carcinogenesis. Therefore, there are several mechanisms which control TH17 cells. One control mechanism is the regulation of TH17 cells via regulatory T cells and IL-10. This mechanism is especially important in the intestine to terminate immune responses and maintain homeostasis. Furthermore, TH17 cells have the potential to convert from a pro-inflammatory phenotype to an anti-inflammatory phenotype by changing their cytokine profile and acquiring IL-10 production, thereby limiting their own pathological potential. Finally, IL-22, a signature cytokine of TH17 cells, can be controlled by an endogenous soluble inhibitory receptor, Interleukin 22 binding protein (IL-22BP. During tissue injury, the production of IL-22 by TH17 cells is upregulated in order to promote tissue regeneration. To limit the regenerative program, which could promote carcinogenesis, IL-22BP is upregulated during the later phase of

  2. RNA干扰抑制IL-23表达对感染后内脏高敏感小鼠肠黏膜固有层DC活化Th17细胞功能的影响%Effect of IL-23 RNA Interference on Activation of Th17 Cells Induced by Dendritic Cells from Intestinal Lamina Propria in Postinfectious Visceral Hypersensitivity Mice

    Institute of Scientific and Technical Information of China (English)

    汪之沫; 王文峰; 龙艳芹; 汪欢; 钱伟; 侯晓华

    2012-01-01

    visceral hypersensin'vity mice, DCs from intestinal lamina propria might secrete IL-23 to activate Thl7 cells and thus maintaining the activation of intestinal mucosal immune system after recovery from intestinal infection.%前期研究发现感染后内脏高敏感小鼠肠黏膜固有层树突细胞(DC)诱导活化Th17细胞与肠道感染消退后肠黏膜免疫系统的持续激活有关.推测DC可能系通过分泌白细胞介素-23 (IL-23)活化Th17细胞.目的:应用RNA干扰技术抑制DC分泌IL-23,探讨感染后内脏高敏感小鼠肠黏膜固有层DC活化Th17细胞的机制.方法:建立旋毛虫感染后内脏高敏感小鼠模型,以免疫磁珠分选肠黏膜固有层DC和脾脏CD4+T细胞.构建、鉴定小鼠IL-23小发夹RNA(shRNA)干扰质粒,以脂质体法转染DC(A组)以抑制IL-23表达,同时设置转染空脂质体的DC(B组)和转染无关序列shRNA干扰质粒的DC(C组)作为对照.各组DC与CD4+T细胞共培养120 h,以单独培养的CD4+T细胞(D组)作为对照.以ELISA方法检测DC转染前后培养上清液中的IL-23水平,以及DC与CD4+T细胞共培养上清液和CD4+T细胞单独培养上清液中的IL-17水平.结果:A组DC培养上清液中的IL-23水平较转染前显著降低(P<0.05),B、C两组转染前后IL-23水平无明显变化.A、B、C组DC与CD4+T细胞共培养上清液中的IL-17水平均较D组显著增高(P<0.05),其中A组显著低于B、C两组(P<0.05),B、C组间差异无统计学意义.结论:感染后内脏高敏感小鼠肠黏膜固有层DC可能通过分泌IL-23活化Th17细胞,参与维持肠道感染消退后肠黏膜免疫系统的持续激活.

  3. Th17 Cells in Autoimmune and Infectious Diseases

    Directory of Open Access Journals (Sweden)

    José Francisco Zambrano-Zaragoza

    2014-01-01

    Full Text Available The view of CD4 T-cell-mediated immunity as a balance between distinct lineages of Th1 and Th2 cells has changed dramatically. Identification of the IL-17 family of cytokines and of the fact that IL-23 mediates the expansion of IL-17-producing T cells uncovered a new subset of Th cells designated Th17 cells, which have emerged as a third independent T-cell subset that may play an essential role in protection against certain extracellular pathogens. Moreover, Th17 cells have been extensively analyzed because of their strong association with inflammatory disorders and autoimmune diseases. Also, they appear to be critical for controlling these disorders. Similar to Th1 and Th2 cells, Th17 cells require specific cytokines and transcription factors for their differentiation. Th17 cells have been characterized as one of the major pathogenic Th cell populations underlying the development of many autoimmune diseases, and they are enhanced and stabilized by IL-23. The characteristics of Th17 cells, cytokines, and their sources, as well as their role in infectious and autoimmune diseases, are discussed in this review.

  4. Th17 Cells as Potential Probiotic Therapeutic Targets in Inflammatory Bowel Diseases.

    Science.gov (United States)

    Owaga, Eddy; Hsieh, Rong-Hong; Mugendi, Beatrice; Masuku, Sakhile; Shih, Chun-Kuang; Chang, Jung-Su

    2015-09-01

    Inflammatory bowel diseases (IBD) are characterized by wasting and chronic intestinal inflammation triggered by various cytokine-mediated pathways. In recent years, it was shown that T helper 17 (Th17) cells are involved in the pathogenesis of IBD, which makes them an attractive therapeutic target. Th17 cells preferentially produce interleukin (IL)-17A-F as signature cytokines. The role of the interplay between host genetics and intestinal microbiota in the pathogenesis of IBD was demonstrated. Probiotics are live microorganisms that when orally ingested in adequate amounts, confer a health benefit to the host by modulating the enteric flora or by stimulating the local immune system. Several studies indicated the effectiveness of probiotics in preventing and treating IBD (ulcerative colitis, and Crohn's disease). Furthermore, there is mounting evidence of probiotics selectively targeting the Th17 lineage in the prevention and management of inflammatory and autoimmune diseases such as IBD. This review highlights critical roles of Th17 cells in the pathogenesis of IBD and the rationale for using probiotics as a novel therapeutic approach for IBD through manipulation of Th17 cells. The potential molecular mechanisms by which probiotics modulate Th17 cells differentiation and production are also discussed.

  5. Aggregatibacter actinomycetemcomitans induces Th17 cells in atherosclerotic lesions.

    Science.gov (United States)

    Jia, Ru; Hashizume-Takizawa, Tomomi; Du, Yuan; Yamamoto, Masafumi; Kurita-Ochiai, Tomoko

    2015-04-01

    Th17 cells have been linked to the pathogenesis of several chronic inflammatory and autoimmune diseases. However, the role of Th17 cells and IL-17 in atherosclerosis remains poorly understood. We previously reported that Aggregatibacter actinomycetemcomitans (Aa) bacteremia accelerated atherosclerosis accompanied by inflammation in apolipoprotein E-deficient spontaneously hyperlipidemic (Apoe(shl)) mice. In this study, we investigated whether Aa promotes the Th17 inducing pathway in Aa-challenged Apoe(shl) mice. Mice were intravenously injected with live Aa HK1651 or vehicles. Time-course analysis of splenic IL-17(+)CD4(+) cell frequencies, the proximal aorta lesion area, serum IL-17, IL-6, TGF-β and IL-1β levels, the mRNA expression of Th17-related molecules such as IL-1β, IL-6, IL17RA, STAT3, IL-21, IL-23, TGF-β and RORγt, Th17-related microRNA levels and the levels of AIM-2, Mincle and NLRP3 were examined. Challenge with Aa time dependently induced tropism of Th17 cells in the spleen and increase in atheromatous lesions in the aortic sinus of Apoe(shl) mice. Serum IL-17, IL-6, TGF-β and IL-1β levels were significantly enhanced by Aa. The gene expression of IL-1β, IL-6, IL-17RA, IL-21, IL-23, TGF-β, STAT3, RORγt, AIM-2, Mincle and NLRP3 was also time dependently stimulated in the aorta of Aa-challenged mice. Furthermore, Aa challenge significantly increased the expression of miR-146b and miR-155 in the aorta. Based on the results, it seems that Aa stimulates Th17 induction that affects the progression of Aa-accelerated atherosclerosis.

  6. TH17 Cell Induction and Effects of IL-17A and IL-17F Blockade in Experimental Colitis

    DEFF Research Database (Denmark)

    Wedebye Schmidt, Esben Gjerløff; Larsen, Hjalte List; Kristensen, Nanna Ny

    2013-01-01

    T helper (TH) 17 cells are believed to play a pivotal role in development of inflammatory bowel disease, and their contribution to intestinal inflammation has been studied in various models of colitis. TH17 cells produce a range of cytokines, some of which are potential targets for immunotherapy...

  7. Cellular and Molecular Dynamics of Th17 Differentiation and its Developmental Plasticity in the Intestinal Immune Response

    Science.gov (United States)

    Bhaumik, Suniti; Basu, Rajatava

    2017-01-01

    After emerging from the thymus, naive CD4 T cells circulate through secondary lymphoid tissues, including gut-associated lymphoid tissue of the intestine. The activation of naïve CD4 T cells by antigen-presenting cells offering cognate antigen initiate differentiation programs that lead to the development of highly specialized T helper (Th) cell lineages. Although initially believed that developmental programing of effector T cells such as T helper 1 (Th1) or T helper 2 (Th2) resulted in irreversible commitment to a fixed fate, subsequent studies have demonstrated greater flexibility, or plasticity, in effector T cell stability than originally conceived. This is particularly so for the Th17 subset, differentiation of which is a highly dynamic process with overlapping developmental axes with inducible regulatory T (iTreg), T helper 22 (Th22), and Th1 cells. Accordingly, intermediary stages of Th17cells are found in various tissues, which co-express lineage-specific transcription factor(s) or cytokine(s) of developmentally related CD4 T cell subsets. A highly specialized tissue like that of the intestine, which harbors the largest immune compartment of the body, adds several layers of complexity to the intricate process of Th differentiation. Due to constant exposure to millions of commensal microbes and periodic exposure to pathogens, the intestinal mucosa maintains a delicate balance between regulatory and effector T cells. It is becoming increasingly clear that equilibrium between tolerogenic and inflammatory axes is maintained in the intestine by shuttling the flexible genetic programming of a developing CD4 T cell along the developmental axis of iTreg, Th17, Th22, and Th1 subsets. Currently, Th17 plasticity remains an unresolved concern in the field of clinical research as targeting Th17cells to cure immune-mediated disease might also target its related subsets. In this review, we discuss the expanding sphere of Th17 plasticity through its shared

  8. Platelet-Activating Factor Induces Th17 Cell Differentiation

    Directory of Open Access Journals (Sweden)

    Anne-Marie Drolet

    2011-01-01

    Full Text Available Th17 cells have been implicated in a number of inflammatory and autoimmune diseases. The phospholipid mediator platelet-activating factor (PAF is found in increased concentrations in inflammatory lesions and has been shown to induce IL-6 production. We investigated whether PAF could affect the development of Th17 cells. Picomolar concentrations of PAF induced IL-23, IL-6, and IL-1β expression in monocyte-derived Langerhans cells (LCs and in keratinocytes. Moreover, when LC were pretreated with PAF and then cocultured with anti-CD3- and anti-CD28-activated T cells, the latter developed a Th17 phenotype, with a significant increase in the expression of the transcriptional regulator RORγt and enhanced expression of IL-17, IL-21, and IL-22. PAF-induced Th17 development was prevented by the PAF receptor antagonist WEB2086 and by neutralizing antibodies to IL-23 and IL-6R. This may constitute a previously unknown stimulus for the development and persistence of inflammatory processes that could be amenable to pharmacologic intervention.

  9. The obesity-related pathology and Th17 cells.

    Science.gov (United States)

    Endo, Yusuke; Yokote, Koutaro; Nakayama, Toshinori

    2017-04-01

    Chronic inflammation associated with obesity plays a major role in the development of metabolic diseases, cancer, and autoimmune diseases. Among Th subsets, Th17 cells are involved in the pathogenesis of autoimmune disorders such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Accumulating data suggest that reciprocal interactions between the metabolic systems and immune system play pivotal roles in the pathogenesis of obesity-associated diseases. We herein outline the developing principles in the control of T cell differentiation and function via their cellular metabolism. Also discussed are recent findings that changes in the intracellular metabolism, including fatty acid metabolism, affect the Th17 cell function in obese individuals. Finally, we will also highlight the unique molecular mechanism involved in the activation of retinoid-related orphan receptor-gamma-t (RORγt) by intracellular metabolism and discuss a new therapeutic approach for treating autoimmune disorders through the inhibition of RORγt.

  10. Evidence of a role for Th17 cells in the breach of immune tolerance in arthritis

    OpenAIRE

    Yu, Xinhua; Ibrahim, Saleh M.

    2011-01-01

    Th17 cells are thought to play a pathogenic role in various autoimmune diseases. Cytokines secreted by Th17 cells like IL-17, IL-17F and IL-22 have the capacity to mediate a massive inflammatory response. These proinflammatroy cytokines are likely to mediate the pathogenic potential of Th17 cells. Recent evidence suggests a role for Th17 cells in the breach of immune tolerance. This might shed some new light on the pathogenic role of Th17 cells in autoimmunity.

  11. Th17 cells express interleukin-10 receptor and are controlled by Foxp3− and Foxp3+ regulatory CD4+ T cells in an interleukin-10 dependent manner

    Science.gov (United States)

    Huber, Samuel; Gagliani, Nicola; Esplugues, Enric; O’Connor, William; Huber, Francis J.; Chaudhry, Ashutosh; Kamanaka, Masahito; Kobayashi, Yasushi; Booth, Carmen J.; Rudensky, Alexander Y.; Battaglia, Manuela; Roncarolo, Maria Grazia; Flavell, Richard A.

    2011-01-01

    Summary T helper 17 (Th17) cells are important for host defense against extra-cellular microorganisms. However they are also implicated in autoimmune and chronic inflammatory diseases, and as such need to be tightly regulated. The mechanisms that directly control committed pathogenic Th17 cells in vivo remain unclear. We showed here that IL-17A-producing CD4+ T cells expressed interleukin-10 receptor α (IL-10Rα) in vivo. Importantly, T cell specific blockade of IL-10 signaling led to a selective increase of IL-17A+IFN-γ− (Th17), and IL-17A+IFN-γ+ (Th17+Th1) CD4+ T cells during intestinal inflammation in the small intestine. CD4+ Foxp3− IL-10 producing (Tr1) cells and Foxp3+ regulatory (Treg) were able to control Th17 and Th17+Th1 cells in an IL-10-dependent manner in vivo. Lastly, IL-10 treatment of mice with established colitis decreased Th17 and Th17+Th1 cells frequencies via direct signaling in T cells. Thus IL-10 signaling directly suppresses Th17 and Th17+Th1 cells. PMID:21511184

  12. Feedback mechanisms between M2 macrophages and Th17 cells in colorectal cancer patients.

    Science.gov (United States)

    Mao, Hui; Pan, Fei; Guo, Hongxia; Bu, Fangfang; Xin, Tong; Chen, Shukun; Guo, Yajun

    2016-09-01

    IL-17 and IL-22 are linked to the development of intestinal inflammation and colorectal cancer (CRC). However, the maintenance of IL-17 and IL-22 production, as well as the cell type (Th17) that mediates these cytokines in CRC patients, remains unknown. To examine this, untreated CRC patients and healthy controls were recruited in this study. We first observed that CRC patients contained significantly elevated levels of IL-17- and IL-22-producing CD4(+) T cells. The vast majority of IL-22-expressing CD4(+) T cells also expressed IL-17. We then found that the production of both IL-17 and IL-22 required support from autologous monocytes, since the depletion of monocytes significantly downregulated IL-17 and IL-22 secretion. Naive T cells from CRC patients did not secrete IL-17 or IL-22 initially, but long-term coculture with autologous monocytes significantly upregulated IL-17 and IL-22 production in an IL-6-dependent manner. Blockade of IL-6 significantly reduced the levels of both IL-17 and IL-22. We then observed that CD163(+) M2 macrophages were the main contributor of IL-6. Interestingly, incubation of monocytes with CCR4(+)CCR6(+) Th17 cells resulted in significantly higher levels of CD163(+) macrophages as well as higher IL-6 secretion, than incubation with non-Th17 CD4(+) T cells. Together, our study discovered a positive feedback mechanism between Th17 and M2 macrophages in CRC patients.

  13. Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells.

    Science.gov (United States)

    Kofler, David M; Marson, Alexander; Dominguez-Villar, Margarita; Xiao, Sheng; Kuchroo, Vijay K; Hafler, David A

    2014-06-01

    Prostaglandin E2 (PGE2) promotes Th17 expansion while otherwise inhibiting other CD4+ T cell subsets. Here, we identified a PGE2-dependent pathway that induces pathogenic Th17 cells in autoimmune disease and is regulated by the transcription factor RORC. Compared with other CD4+ cell types from healthy subjects, there is a surprising lack of the prostaglandin receptor EP2 on Th17 cells; therefore, we examined the hypothesis that RORγt, which is highly expressed in Th17 cells, mediates EP2 downregulation. Chromatin immunoprecipitation followed by DNA sequencing revealed that RORγt binds directly to Ptger2 (the gene encoding EP2 receptor) in Th17 cells isolated from WT mice. In Th17 cells isolated from humans, RORC repressed EP2 by directly silencing PTGER2 transcription, and knock down of RORC restored EP2 expression in Th17 cells. Compared with Th17 cells from healthy individuals, Th17 cells from patients with MS exhibited reduced RORC binding to the PTGER2 promoter region, resulting in higher EP2 levels and increased expression of IFN-γ and GM-CSF. Finally, overexpression of EP2 in Th17 cells from healthy individuals induced a specific program of inflammatory gene transcription that produced a pathogenic Th17 cell phenotype. These findings reveal that RORC directly regulates the effects of PGE2 on Th17 cells, and dysfunction of this pathway induces a pathogenic Th17 cell phenotype.

  14. TGF-β converts Th1 cells into Th17 cells through stimulation of Runx1 expression.

    Science.gov (United States)

    Liu, Hou-Pu; Cao, Anthony T; Feng, Ting; Li, Qingjie; Zhang, Wenbo; Yao, Suxia; Dann, Sara M; Elson, Charles O; Cong, Yingzi

    2015-04-01

    Differentiated CD4(+) T cells preserve plasticity under various conditions. However, the stability of Th1 cells is unclear, as is whether Th1 cells can convert into Th17 cells and thereby contribute to the generation of IFN-γ(+) IL-17(+) CD4(+) T cells, the number of which correlates with severity of colitis. We investigated whether IFN-γ(+) Th1 cells can convert into Th17 cells under intestinal inflammation and the mechanisms involved. IFN-γ(Thy1.1+) Th1 cells were generated by culturing naïve CD4(+) T cells from IFN-γ(Thy1.1) CBir1 TCR-Tg reporter mice, whose TCR is specific for an immunodominant microbiota antigen, CBir1 flagellin, under Th1 polarizing conditions. IFN-γ(Thy1.1+) Th1 cells induced colitis in Rag(-/-) mice after adoptive transfer and converted into IL-17(+) Th17, but not Foxp3(+) Treg cells in the inflamed intestines. TGF-β and IL-6, but not IL-1β and IL-23, regulated Th1 conversion into Th17 cells. TGF-β induction of transcriptional factor Runx1 is crucial for the conversion, since silencing Runx1 by siRNA inhibited Th1 conversion into Th17 cells. Furthermore, TGF-β enhanced histone H3K9 acetylation but inhibited H3K9 trimethylation of Runx1- and ROR-γt-binding sites on il-17 or rorc gene in Th1 cells. We conclude that Th1 cells convert into Th17 cells under inflammatory conditions in intestines, which is possibly mediated by TGF-β induction of Runx1.

  15. Antagonizing arachidonic acid-derived eicosanoids reduces inflammatory Th17 and Th1 cell-mediated inflammation and colitis severity.

    Science.gov (United States)

    Monk, Jennifer M; Turk, Harmony F; Fan, Yang-Yi; Callaway, Evelyn; Weeks, Brad; Yang, Peiying; McMurray, David N; Chapkin, Robert S

    2014-01-01

    During colitis, activation of two inflammatory T cell subsets, Th17 and Th1 cells, promotes ongoing intestinal inflammatory responses. n-6 polyunsaturated fatty acid- (PUFA-) derived eicosanoids, such as prostaglandin E2 (PGE2), promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2 levels. We utilized two genetic mouse models, which differentially antagonize PGE2 levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Fat-1 mice contain the ω3 desaturase gene from C. elegans and synthesize n-3 PUFA de novo, thereby reducing the biosynthesis of n-6 PUFA-derived eicosanoids. In contrast, Fads1 Null mice contain a disrupted Δ5 desaturase gene and produce lower levels of n-6 PUFA-derived eicosanoids. Compared to Wt littermates, Fat-1 and Fads1 Null mice exhibited a similar colitic phenotype characterized by reduced colonic mucosal inflammatory eicosanoid levels and mRNA expression of Th17 cell markers (IL-17A, RORγτ, and IL-23), decreased percentages of Th17 cells and, improved colon injury scores (P ≤ 0.05). Thus, during colitis, similar outcomes were obtained in two genetically distinct models, both of which antagonize PGE2 levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation.

  16. Antagonizing Arachidonic Acid-Derived Eicosanoids Reduces Inflammatory Th17 and Th1 Cell-Mediated Inflammation and Colitis Severity

    Directory of Open Access Journals (Sweden)

    Jennifer M. Monk

    2014-01-01

    Full Text Available During colitis, activation of two inflammatory T cell subsets, Th17 and Th1 cells, promotes ongoing intestinal inflammatory responses. n-6 polyunsaturated fatty acid- (PUFA- derived eicosanoids, such as prostaglandin E2 (PGE2, promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2 levels. We utilized two genetic mouse models, which differentially antagonize PGE2 levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS- induced colitis. Fat-1 mice contain the ω3 desaturase gene from C. elegans and synthesize n-3 PUFA de novo, thereby reducing the biosynthesis of n-6 PUFA-derived eicosanoids. In contrast, Fads1 Null mice contain a disrupted Δ5 desaturase gene and produce lower levels of n-6 PUFA-derived eicosanoids. Compared to Wt littermates, Fat-1 and Fads1 Null mice exhibited a similar colitic phenotype characterized by reduced colonic mucosal inflammatory eicosanoid levels and mRNA expression of Th17 cell markers (IL-17A, RORγτ, and IL-23, decreased percentages of Th17 cells and, improved colon injury scores (P≤0.05. Thus, during colitis, similar outcomes were obtained in two genetically distinct models, both of which antagonize PGE2 levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation.

  17. In vitro differentiation of human Th-17 CD4+ T cells

    OpenAIRE

    sprotocols

    2015-01-01

    Human CD4+ Th-17 cells produce inflammatory cytokines and have been implicated in the development of several inflammatory pathologies. The transcription factor RORgammaT is though to establish Th-17 cell differentiation. Expression of IL-17A is a hallmark of Th-17 cells.

  18. Th17/Treg cell expression in children with primary nephritic syndrome and the effects of ox-LDL on Th17/Treg cells.

    Science.gov (United States)

    Li, Y Y; Wei, S G; Zhao, X; Jia, Y Z; Zhang, Y F; Sun, S Z

    2016-06-10

    To investigate the role of T-helper cells/Treg (Th17/Treg) and morbidity factors related to primary nephritic syndrome (PNS) in children, as well as the influence of ox-low density lipoprotein (ox-LDL) on Th17/Treg expression in children with PNS. To clarify the pathogenesis of PNS in children, 50 children with PNS treated in our hospital were enrolled in the study group. Additionally, 20 healthy children who came to our hospital for physical examination during the same period were enrolled in the control group. Th17 and Treg cells in children belonging to the two groups were detected by flow cytometry; the numbers of Th17/Treg cells in peripheral blood mononuclear cells at different concentrations of ox-LDL were detected simultaneously. Ox-LDL can affect the number of Th17/Treg cells in peripheral blood mononuclear cells, and both cell types decreased with increasing concentration of ox-LDL, with the numbers being significantly lower in the control group. However, the decrease in the number of Th17 cells was statistically insignificant (P > 0.05), whereas the decrease in Treg cells was more obvious and statistically significant (P Treg cells was stronger than that on Th17 cells. We concluded that the imbalance of Th17/Treg cells influenced by high and low ox-LDL concentrations in children with PNS might be the immunological basis of the disease.

  19. CD103+ Dendritic Cells Control Th17 Cell Function in the Lung

    Directory of Open Access Journals (Sweden)

    Teresa Zelante

    2015-09-01

    Full Text Available Th17 cells express diverse functional programs while retaining their Th17 identity, in some cases exhibiting a stem-cell-like phenotype. Whereas the importance of Th17 cell regulation in autoimmune and infectious diseases is firmly established, the signaling pathways controlling their plasticity are undefined. Using a mouse model of invasive pulmonary aspergillosis, we found that lung CD103+ dendritic cells (DCs would produce IL-2, dependent on NFAT signaling, leading to an optimally protective Th17 response. The absence of IL-2 in DCs caused unrestrained production of IL-23 and fatal hyperinflammation, which was characterized by strong Th17 polarization and the emergence of a Th17 stem-cell-like population. Although several cell types may be affected by deficient IL-2 production in DCs, our findings identify the balance between IL-2 and IL-23 productions by lung DCs as an important regulator of the local inflammatory response to infection.

  20. Chemokine receptor CCR7 regulates the intestinal TH1/TH17/Treg balance during Crohn's-like murine ileitis.

    Science.gov (United States)

    McNamee, Eóin N; Masterson, Joanne C; Veny, Marisol; Collins, Colm B; Jedlicka, Paul; Byrne, Fergus R; Ng, Gordon Y; Rivera-Nieves, Jesús

    2015-06-01

    The regulation of T cell and DC retention and lymphatic egress within and from the intestine is critical for intestinal immunosurveillance; however, the cellular processes that orchestrate this balance during IBD remain poorly defined. With the use of a mouse model of TNF-driven Crohn's-like ileitis (TNF(Δ) (ARE)), we examined the role of CCR7 in the control of intestinal T cell and DC retention/egress during experimental CD. We observed that the frequency of CCR7-expressing TH1/TH17 effector lymphocytes increased during active disease in TNF(Δ) (ARE) mice and that ΔARE/CCR7(-/-) mice developed exacerbated ileitis and multiorgan inflammation, with a marked polarization and ileal retention of TH1 effector CD4(+) T cells. Furthermore, adoptive transfer of ΔARE/CCR7(-/-) effector CD4(+) into lymphopenic hosts resulted in ileo-colitis, whereas those transferred with ΔARE/CCR7(+/+) CD4(+) T cells developed ileitis. ΔARE/CCR7(-/-) mice had an acellular draining MLN, decreased CD103(+) DC, and decreased expression of RALDH enzymes and of CD4(+)CD25(+)FoxP3(+) Tregs. Lastly, a mAb against CCR7 exacerbated ileitis in TNF(Δ) (ARE) mice, phenocopying the effects of congenital CCR7 deficiency. Our data underscore a critical role for the lymphoid chemokine receptor CCR7 in orchestrating immune cell traffic and TH1 versus TH17 bias during chronic murine ileitis.

  1. TH17 cells in human recurrent pregnancy loss and pre-eclampsia.

    Science.gov (United States)

    Fu, Binqing; Tian, Zhigang; Wei, Haiming

    2014-11-01

    T helper 17 (TH17) cells have been identified as a new lineage of helper T cells and have been shown to be important in host defense against extracellular infectious agents, autoimmune disease and chronic inflammatory diseases. Recently, TH17 cells have also been shown to participate in successful pregnancy, as well as in the pathogenesis of diseases of pregnancy, such as recurrent spontaneous abortion (RSA) and pre-eclampsia (PE). Here, we review our current knowledge of TH17 cells in human RSA and PE. We also discuss how the local uterine microenvironment affects the differentiation of TH17 cells and the mechanisms that regulate TH17 cells during pregnancy. Research into TH17 cells will not only advance our understanding of TH17-related pregnancy complications, but will also facilitate the design of novel therapies for reproductive diseases.

  2. Preferential recruitment of Th17 cells to cervical cancer via CCR6-CCL20 pathway.

    Science.gov (United States)

    Yu, Qing; Lou, Xiang-ming; He, Yan

    2015-01-01

    Our previous studies suggest that Th17 cells accumulate within tumor tissues and correlate with recurrence of cervical cancer patients. However, the source of the increased tumor-infiltrating Th17 cells remains poorly understood. We investigated the prevalence, phenotype and trafficking property of Th17 cells in patients with cervical cancer. Our results showed that Th17 cells highly aggregated within tumor tissues in an activated phenotype with markedly increased expression of CCR6. Correspondingly, level of CCL20 in the tumor tissues was significantly higher than that in non-tumor and normal control tissues, and strongly positively associated with Th17 cells. Further, in vitro migration assay showed CCL20 had effective chemotaxis to circulating Th17 cells. In conclusion, Th17 cells are recruited into tumor tissues preferentially through CCR6-CCL20 pathway, which can serve as a novel therapeutic target for cervical cancer.

  3. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation.

    Science.gov (United States)

    Gagliani, Nicola; Amezcua Vesely, Maria Carolina; Iseppon, Andrea; Brockmann, Leonie; Xu, Hao; Palm, Noah W; de Zoete, Marcel R; Licona-Limón, Paula; Paiva, Ricardo S; Ching, Travers; Weaver, Casey; Zi, Xiaoyuan; Pan, Xinghua; Fan, Rong; Garmire, Lana X; Cotton, Matthew J; Drier, Yotam; Bernstein, Bradley; Geginat, Jens; Stockinger, Brigitta; Esplugues, Enric; Huber, Samuel; Flavell, Richard A

    2015-07-09

    Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The Th17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A) and plasticity (they can start expressing cytokines typical of other lineages) upon in vitro re-stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion Th17 cells ex vivo during immune responses. Thus, it is unknown whether Th17 cell plasticity merely reflects change in expression of a few cytokines, or if Th17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation. Furthermore, although Th17 cell instability/plasticity has been associated with pathogenicity, it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic Th17 cells could adopt an anti-inflammatory fate. Here we used two new fate-mapping mouse models to track Th17 cells during immune responses to show that CD4(+) T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. The transdifferentiation of Th17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion Th17 cells also revealed a role for canonical TGF-β signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, Th17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that Th17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases.

  4. Altered Th17 cells and Th17/regulatory T-cell ratios indicate the subsequent conversion from undifferentiated connective tissue disease to definitive systemic autoimmune disorders.

    Science.gov (United States)

    Szodoray, Peter; Nakken, Britt; Barath, Sandor; Csipo, Istvan; Nagy, Gabor; El-Hage, Fadi; Osnes, Liv T; Szegedi, Gyula; Bodolay, Edit

    2013-12-01

    A shift in the balance between Th17-cells and regulatory T-cells (Treg) is an important feature of systemic autoimmune diseases (SAID), and may also contribute to their development. Hereby, we assessed the distribution of peripheral Th17 and Treg-cells in patients with undifferentiated connective tissue disease (UCTD), the forerunner of SAIDs and followed these parameters during the development towards definitive SAIDs. Fifty-one UCTD patients were investigated and followed-up for 3 years. Flow cytometry was used to identify and follow three cell-populations: Th17-cells (CD4+IL-17+ T-cells), natural regulatory T-cells (CD4(+)CD25(bright)FoxP3(+); nTregs) and IL-10 producing Type-1 regulatory T-cells (CD4+IL-10+ T-cells; Tr1). Altogether 37.3% of these patients progressed into SAIDs. Th17-cells were increased in UCTD vs. controls, which further increased in those, whom developed SAIDs eventually. The Th17/nTreg ratio gradually increased from controls through UCTD patients, reaching the highest values in SAID-progressed patients. Regarding the Th17/Tr1 ratios, a similar tendency was observed moreover Th17/Tr1 could distinguish between UCTD patients with, or without subsequent SAID progression in a very early UCTD stage. Various immunoserological markers showed association with Th17 and Th17/nTreg at baseline, indicating the consecutive development of a distinct SAID. The derailed Th17/Treg balance may contribute to disease progression therefore could function as a prognostic marker.

  5. Basophil-derived IL-6 regulates TH17 cell differentiation and CD4 T cell immunity

    Science.gov (United States)

    Yuk, Chae Min; Park, Hyeung Ju; Kwon, Bo-In; Lah, Sang Joon; Chang, Jun; Kim, Ji-Young; Lee, Kyung-Mi; Park, Su-Hyung; Hong, Seokchan; Lee, Seung-Hyo

    2017-01-01

    Basophils are rare, circulating granulocytes proposed to be involved in T helper (TH) type 2 immunity, mainly through secretion of interleukin (IL)-4. In addition to IL-4, basophils produce IL-6 and tumor necrosis factor (TNF)-α in response to immunoglobulin E (IgE) crosslinking. Differentiation of TH17 cells requires IL-6 and transforming growth factor (TGF)-β, but whether basophils play a significant role in TH17 induction is unknown. Here we show a role for basophils in TH17 cell development by using in vitro T cell differentiation and in vivo TH17-mediated inflammation models. Bone marrow derived-basophils (BMBs) and splenic basophils produce significant amounts of IL-6 as well as IL-4 following stimulation with IgE crosslink or cholera toxin (CT). In addition, through IL-6 secretion, BMBs cooperate with dendritic cells to promote TH17 cell differentiation. In the TH17 lung inflammation model, basophils are recruited to the inflamed lungs following CT challenge, and TH17 responses are significantly reduced in the absence of basophils or IL-6. Furthermore, reconstitution with wild-type, but not IL-6-deficient, basophils restored CT-mediated lung inflammation. Lastly, basophil-deficient mice showed reduced phenotypes of TH17-dependent experimental autoimmune encephalomyelitis. Therefore, our results indicate that basophils are an important inducer of TH17 cell differentiation, which is dependent on IL-6 secretion. PMID:28134325

  6. Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Zhan-Ju Liu; Praveen K Yadav; Jing-Ling Su; Jun-Shan Wang; Ke Fei

    2009-01-01

    The etiopathology of inflammatory bowel disease (IBD) remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflammation. IBD including Crohn's disease (CD) and ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Th1mediated inflammatory disorder while UC is regarded as a Th2like disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Th1 or Th2 cells, and several cytokines [e.g. interleukin (IL)-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Th1/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.

  7. IL-21在Th17细胞炎症反应中的作用%Effects of IL-21 in Th17 cell maintenance

    Institute of Scientific and Technical Information of China (English)

    刘巍; 田文单; Sally A.Huber

    2011-01-01

    Th17细胞是新近发现的T淋巴细胞亚群.作为不同于Th1、Th2的细胞亚群,已经被证实在自身免疫病、感染、炎症等疾病中发挥重要作用.IL-21作为Th17细胞的自分泌调节因子,在Th17细胞功能的维持、抑制Th1、调节性T细胞(Treg)分化等方面发挥关键作用.Th17细胞能够自分泌产生IL-21,从而促进自身分化过程.IL-21在Th17细胞维持中的作用及潜在机制的揭示,必将为Th17细胞致病机制的探索提供新思路.%Th17 cell has recently been identified as an IL-17-producing CD4+ Th cell, and its functions and regulatory mechanisms in immune responses have been studied extensively. Functional studies have provided evidence that Th17 cells are important for the modulation of autoimmune responses and inflammation.Murine Th17 cell differentiation is promoted by the coordinated functions of distinct cytokines including TGFp,IL-6,IL-21 and IL-23, whereas IL-2,IL-4,IFNγ and IL-27 inhibit Th17 cell differentiation. Th17 cell could produce IL-21 ,thus promotes auto-differentiation. IL-21 is the new target in Th17 cell-mediated diseases.

  8. Research Advances on Th17 Cell and Tumor%Th17细胞与肿瘤的研究进展

    Institute of Scientific and Technical Information of China (English)

    彭峰

    2011-01-01

    Th17细胞是近些年来才被发现确立的Th细胞亚群,主要的功能是促进炎症发展,并参与多种自身免疫性疾病的发生.现在发现Th17细胞与肿瘤也有一定的关系,研究主要集中在Th17细胞水平与肿瘤相关性、相关细胞因子的作用、Th17细胞对肿瘤作用等方面,但是研究的结果还不能明确说明Th17细胞在肿瘤中的确切作用,还需要深入地研究来验证.现就Th17细胞与肿瘤的研究进展予以综述.%Th17 cell is a newly discovered Th cell subpopulation. It mainly functions to promote inflammation and participate in the occurrences of multiple autoimmune disorders. Th17 cell is found to be also associated with tumor. The current studies forus mainly on cellular association of Th17 cell with tumor,effects of cytokines , and efferts of Th17 cell on tumor. The definitive role of Th17 cell in tumor has been unclear and yet to be further investigated. This article reviews the research advances on Th17 cell and tumor.

  9. TH17, TH22 and Treg cells are enriched in the healthy human cecum.

    Directory of Open Access Journals (Sweden)

    Martin J Wolff

    Full Text Available There is increasing evidence that dysregulation of CD4(+ T cell populations leads to intestinal inflammation, but the regional distribution of these populations throughout the intestinal tract in healthy individuals remains unclear. Here, we show that T(H17, T(H22 and T(Reg cells are enriched in the healthy human cecum compared to the terminal ileum and sigmoid colon, whereas T(H1 and T(H2 cells do not significantly vary by location. Transcriptional profiling analysis of paired pinch biopsies from different regions of the intestine identified significant differences in the metabolic state of the terminal ileum, cecum, and sigmoid colon. An increased proportion of T(H17 cells was positively associated with expression of resistin (RETN and negatively associated with expression of trefoil factor 1 (TFF1. These results suggest that CD4(+ T helper cells that are important in maintaining mucosal barrier function may be enriched in the cecum as a result of metabolic differences of the surrounding microenvironment.

  10. The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis.

    Science.gov (United States)

    Kotake, Shigeru; Yago, Toru; Kobashigawa, Tsuyoshi; Nanke, Yuki

    2017-07-10

    Helper T (Th) cells play an important role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). It has been revealed that Th17 cells can shift to Th1 cells (i.e., "nonclassic Th1 cells"), which are reported to be more pathogenic than Th17 cells per se. Thus, the association of Th cells in the pathogenesis of autoimmune disease has become more complicated. We recently reported using peripheral blood from untreated and early-onset RA patients that the ratio of CD161+Th1 cells (i.e., Th17-derived Th1 cells to CD161+Th17 cells) is elevated and that levels of interferon-γ (IFNγ)+Th17 cells are inversely correlated with levels of anti-CCP antibodies. Here, we review the plasticity of Th17 cells in the pathogenesis of RA, suggesting possible implications for novel therapies.

  11. The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Shigeru Kotake

    2017-07-01

    Full Text Available Helper T (Th cells play an important role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA. It has been revealed that Th17 cells can shift to Th1 cells (i.e., “nonclassic Th1 cells”, which are reported to be more pathogenic than Th17 cells per se. Thus, the association of Th cells in the pathogenesis of autoimmune disease has become more complicated. We recently reported using peripheral blood from untreated and early-onset RA patients that the ratio of CD161+Th1 cells (i.e., Th17-derived Th1 cells to CD161+Th17 cells is elevated and that levels of interferon-γ (IFNγ+Th17 cells are inversely correlated with levels of anti-CCP antibodies. Here, we review the plasticity of Th17 cells in the pathogenesis of RA, suggesting possible implications for novel therapies.

  12. Correlation between Th17 cells and Crohn' s disease%Th17细胞与克罗恩病的相关性研究进展

    Institute of Scientific and Technical Information of China (English)

    刘颂; 任建安

    2011-01-01

    Th17细胞是近年来新发现的一种T细胞亚群.研究发现,Th17细胞与克罗恩病等免疫性疾病关系密切,IL-23/Th17轴及Th17分泌的多种细胞因子在炎性介质反应性肠病中具有重要作用.本文就Th17细胞与克罗恩病的相关性研究做一全面综述.%As a novel T cell population,Th17 cells are demonstrated to play an important role in autoimmune diseases,including Crohn' s disease.Several recent studies indicate the specific contributions of IL-23/Th17 axis and cytokines secreted by Th17 cells to the inflammatory bowel disease.This article is dedicated to describe the correlation between Th17 cells and Crohn' s disease.

  13. Downregulation of Th17 cells and the related cytokines with treatment in Kawasaki disease.

    Science.gov (United States)

    Rasouli, Manoochehr; Heidari, Behzad; Kalani, Mehdi

    2014-11-01

    Given the inflammatory nature of Kawasaki disease (KD) and the pro-inflammatory properties of Th17, this study aimed to determine the frequency of Th17 cells and the levels of corresponding cytokines in acute phase of KD and to evaluate their alterations one and eight weeks after treatment. Th17 and the related cytokine levels were measured in 21 KD patients and 42 positive and negative controls, using flow cytometry and ELISA, respectively. Th17, IL-17, IL-22 and IL-23 were significantly higher (P0.05) with the positive controls. Furthermore, Th17, IL-17, IL-22 and IL-23 were significantly higher in patients before treatment than those one and eight weeks after. Considering the downregulation of Th17 and its related cytokines with aspirin and intravenous immunoglobulin therapy implies the probable role of Th17 in KD pathogenesis.

  14. Disturbed Th17/Treg Balance in Patients with Non-small Cell Lung Cancer.

    Science.gov (United States)

    Duan, Min-Chao; Han, Wei; Jin, Pei-Wen; Wei, Yu-Ping; Wei, Qiu; Zhang, Liang-Ming; Li, Jun-Chen

    2015-12-01

    The fine balance of T help-17 (Th17)/regulatory T(Treg) cells is crucial for maintenance of immune homeostasis. However, there is little information concerning the role played in non-small cell lung cancer (NSCLC) by Th17/Treg cells. The objective of this study was to investigate the variation of Th17 and Treg cells in the peripheral blood of patients with NSCLC. Blood samples were collected from 19 patients with NSCLC and 19 healthy donors. Samples were processed to detect CD4(+)IL-17(+) Th17 cells and CD4(+)CD25(+)Foxp3(+) Treg cells by flow cytometry, and related gene expressions were assessed by real-time quantitative polymerase chain reaction. The concentrations of interleukin (IL)-1β, IL-6, IL-10, IL-17, IL-23, and transforming growth factor-beta (TGF-β1) were also measured by enzyme-linked immunosorbent assay analysis (ELISA). The frequency of circulating Th17 cells and Treg cells was increased in samples derived from patients with NSCLC, accompanied by the upregulation of Foxp3 and RORγt. However, a negative correlation between Treg cells and Th17 cells was found in patients with NSCLC. Additionally, the Th17/Treg ratio and the related cytokines were also significantly higher in patients with NSCLC than in healthy controls. Furthermore, the frequency of Th17 cells was positively correlated with IL-1β, IL-6, and IL-23 in patients with NSCLC, and the frequency of Treg cells was positively correlated with TGF-β1 and IL-10. More importantly, the Th17/Treg ratio was positively correlated with the CEA concentrations in patients with NSCLC. Our data indicated that Th17 and Treg subset are involved in the immunopathology of NSCLC. Distinct cytokine environment might play a key role in the differentiation of the Th17 and Treg cells in NSCLC. Reconstituting an adequate balance between Th17 and Treg may be beneficial in the treatment of NSCLC.

  15. Inhibition of Th17 Cell Differentiation as a Treatment for Multiple Sclerosis

    Science.gov (United States)

    2013-10-01

    0736 TITLE: Inhibition of Th17 Cell Differentiation as a Treatment for Multiple Sclerosis PRINCIPAL INVESTIGATOR: Annalisa D’Andrea, PhD...29September2013 4. TITLE AND SUBTITLE Inhibition of Th17 Cell Differentiation as a Treatment for Multiple Sclerosis 5a. CONTRACT NUMBER 5b...were not able to screen compounds. Additionally, experiments aimed to reproduce data showing an association of miR-326 with Th17 cells failed to

  16. Role of Th9 cells and Th17 cells in the pathogenesis of malignant ascites简

    Institute of Scientific and Technical Information of China (English)

    Xian-Wen; Yang; Hai-Xing; Jiang; Xiao-Li; Huang; Shi-Jia; Ma; Shan-Yu; Qin

    2015-01-01

    Objective: To assess the role of Th9 and Th17 cells in malignant ascites(MA).Methods: MA from 30 hepatic carcinoma patients and benign ascites from 30 cirrhotic patients were collected. Corresponding peripheral blood samples from these hepatic carcinoma and cirrhotic patients as well as 30 healthy subjects were collected. The frequency of Th9 and Th17 cells was tested by flow cytometry. Serum levels of interleukin(IL)-9 and IL-17 were examined by ELISA.Results: The observed frequency of Th9 and Th17 cells, and the IL-9 and IL-17 serum levels were significantly higher in MA patients than those in cirrhotic patients and healthy control samples(P < 0.05). Moreover, the Th9 cells demonstrated positive correlation with Th17 cells as well as IL-9 in MA patients; however, this positive correlation was not observed in the cirrhotic patients or healthy control samples. The frequency of Th9 and Th17 cells was distinctly higher in MA patients presenting with stage III or IV malignancy and with lymph node or distant metastasis than those in patients in stage I or II and without distant metastasis(P < 0.05).Conclusions: The increased frequency of Th9 and Th17 cells in MA patients suggests that these two T cell subsets play a synergistic role in MA pathogenesis. This study also demonstrated that Th9 and Th17 cells may perform their biological functions in conjunction with IL-9 production.

  17. Interleukin-7 and -15 maintain pathogenic memory Th17 cells in autoimmunity.

    Science.gov (United States)

    Chen, Yihe; Chauhan, Sunil K; Tan, Xuhua; Dana, Reza

    2017-02-01

    Th17 cells are principal mediators of many autoimmune conditions. Recently, memory Th17 cells have been revealed as crucial in mediating the chronicity of various refractory autoimmune disorders; however, the underlying mechanisms maintaining memory Th17 cells have remained elusive. Here, using a preclinical model of ocular autoimmune disease we show that both IL-7 and IL-15 are critical for maintaining pathogenic memory Th17 cells. Neutralization of these cytokines leads to substantial reduction of memory Th17 cells; both IL-7 and IL-15 provide survival signals via activating STAT5, and IL-15 provides additional proliferation signals via activating both STAT5 and Akt. Topical neutralization of ocular IL-7 or IL-15 effectively reduces memory Th17 cells at the inflammatory site and draining lymphoid tissues, while topical neutralization of IL-17 alone, the major pathogenic cytokine secreted by Th17 cells, does not diminish memory Th17 cells at the draining lymphoid tissues. Our results suggest that the effective removal of pathogenic memory Th17 cells via abolishing environmental IL-7 or IL-15 is likely to be a novel strategy in the treatment of autoimmune diseases.

  18. Th17细胞与肾小球疾病的研究进展%Research progress of Th17 cells and glomerulonephritis

    Institute of Scientific and Technical Information of China (English)

    周乐天; 刘伏友

    2013-01-01

    Th17细胞是近年来被发现的一种不同于Th1和Th2细胞的Th细胞亚群,它具有独立的分化和调节机制.Th17的分化及分泌的IL-17A(IL-17)主要受TGF-β,IL-6,IL-23和孤儿核受体(orphan nuclear receptor,RORγt)调控.IL-17A调节前炎症因子和趋化因子,并介导中性粒细胞的招募.Th17细胞参与多种肾小球疾病的发病过程.特异性针对Th17细胞或IL-17A的治疗可能成为治疗肾小球肾炎的新靶点.%Thelper (Th) 17 cells are a kind of Th cell subset,and are distinct from the Th1 and Th2 cells and produce interleukin-17A (IL-17A,IL-17).Th17 cells have a mechanism of independent differentiation and developmental regulation.The differentiation and cytokine secretion of Th17 cells are regulated by TGF-β,IL-6,IL-23 and orphan nuclear receptor (RORγt).IL-17A induces pro-inflammatory cytokines and chemokines,mediating neutrophil recruitment.Increasing evidence implicated involvement of Th17 cells in anti-glomerular basement membrane disease,lupus nephritis and pauciimmune glomerulonephritis.In this review,we discussed the discovery of Th17 subset,its properties,its relationship with other Th subsets and involvement of Th17 cells in glomerulonephritis.

  19. Elevated Frequencies of Circulating Th22 Cell in Addition to Th17 Cell and Th17/Th1 Cell in Patients with Acute Coronary Syndrome

    OpenAIRE

    Lei Zhang; Ting Wang; Xiao-qi Wang; Rui-zhi Du; Kai-ning Zhang; Xin-guang Liu; Dao-xin Ma; Shuang Yu; Guo-hai Su; Zhen-hua Li; Yu-qing Guan; Nai-li Du

    2013-01-01

    BACKGROUND: Atherosclerosis is a chronic inflammatory disease mediated by immune cells. Th22 cells are CD4(+) T cells that secret IL-22 but not IL-17 or IFN-γ and are implicated in the pathogenesis of inflammatory disease. The roles of Th22 cells in the pathophysiologic procedures of acute coronary syndrome (ACS) remain unclear. The purpose of this study is to investigate the profile of Th22, Th17 and Th17/Th1 cells in ACS patients, including unstable angina (UA) and acute myocardial infarcti...

  20. [Th17 cells, a novel proinflammatory effector CD4 T cell population].

    Science.gov (United States)

    Leung-Theung-Long, Stéphane; Guerder, Sylvie

    2008-11-01

    After more than 20 years of hegemony, the Th1-Th2 paradigm was recently shaken by the discovery of a novel population of CD4 effector T cells, the Th17 cells. Th17 effector cells produce IL-17 and IL-22 and thus have pro-inflammatory properties notably favoring neutrophils recruitment and thus control of extracellular bacteria mainly at the epithelium surface. Th17 cells appear also as the major inducer of organ specific autoimmune pathologies such as EAE or rheumatoid arthritis, a function previously attributed to Th1 effector cells. The discovery of Th17 cells further supports the notion that effector CD4 T cells responses are diverse in vivo and that fine tuning of these different effector cells is critical to maintain tissue integrity.

  1. Th17 cells are long lived and retain a stem cell-like molecular signature.

    Science.gov (United States)

    Muranski, Pawel; Borman, Zachary A; Kerkar, Sid P; Klebanoff, Christopher A; Ji, Yun; Sanchez-Perez, Luis; Sukumar, Madhusudhanan; Reger, Robert N; Yu, Zhiya; Kern, Steven J; Roychoudhuri, Rahul; Ferreyra, Gabriela A; Shen, Wei; Durum, Scott K; Feigenbaum, Lionel; Palmer, Douglas C; Antony, Paul A; Chan, Chi-Chao; Laurence, Arian; Danner, Robert L; Gattinoni, Luca; Restifo, Nicholas P

    2011-12-23

    Th17 cells have been described as short lived, but this view is at odds with their capacity to trigger protracted damage to normal and transformed tissues. We report that Th17 cells, despite displaying low expression of CD27 and other phenotypic markers of terminal differentiation, efficiently eradicated tumors and caused autoimmunity, were long lived, and maintained a core molecular signature resembling early memory CD8(+) cells with stem cell-like properties. In addition, we found that Th17 cells had high expression of Tcf7, a direct target of the Wnt and β-catenin signaling axis, and accumulated β-catenin, a feature observed in stem cells. In vivo, Th17 cells gave rise to Th1-like effector cell progeny and also self-renewed and persisted as IL-17A-secreting cells. Multipotency was required for Th17 cell-mediated tumor eradication because effector cells deficient in IFN-γ or IL-17A had impaired activity. Thus, Th17 cells are not always short lived and are a less-differentiated subset capable of superior persistence and functionality.

  2. Identity crisis of Th17 cells: many forms, many functions, many questions.

    Science.gov (United States)

    Sundrud, Mark S; Trivigno, Catherine

    2013-11-15

    Th17 cells are a subset of CD4(+) effector T cells characterized by expression of the IL-17-family cytokines, IL-17A and IL-17F. Since their discovery nearly a decade ago, Th17 cells have been implicated in the regulation of dozens of immune-mediated inflammatory diseases and cancer. However, attempts to clarify the development and function of Th17 cells in human health and disease have generated as many questions as answers. On one hand, cytokine expression in Th17 cells appears to be remarkably dynamic and is subject to extensive regulation (both positive and negative) in tissue microenvironments. On the other hand, accumulating evidence suggests that the human Th17 subset is a heterogeneous population composed of several distinct pro- and anti-inflammatory subsets. Clearly, Th17 cells as originally conceived no longer neatly fit the long-standing paradigm of stable and irrepressible effector T cell function. Here we review current concepts surrounding human Th17 cells, with an emphasis on their plasticity, heterogeneity, and their many, tissue-specific functions. In spite of the challenges ahead, a comprehensive understanding of Th17 cells and their relationship to human disease is key to ongoing efforts to develop safer and more selective anti-inflammatory medicines.

  3. The role of Th17 cells in anti-cancer immunity

    Directory of Open Access Journals (Sweden)

    Iwona Hus

    2010-05-01

    Full Text Available Th17 cells are a newly identified population of CD4 Th cells characterized by interleukin 17 production and are therefore named “Th17”. Interleukin 17 (IL-17; IL-17A is one of the key cytokines for the activation, recruitment, and migration of neutrophils, so Th17 cells have been suggested to play an important role in responses against extracellular bacteria and fungi, in which granulocyte infiltration is highly protective. Among the other cytokines secreted by Th17 cells are IL-22, IL-26, IL-6, and TNF-α. Th17 cells are considered to be involved in the pathogenesis of various inflammatory, autoimmune, and allergic diseases. Th17 cells were found in both mouse and human tumors; however, their role in the tumor microenvironment is still poorly understood IL-17, as a pleiotropic cytokine, may suppress or promote tumor growth since it was shown that it stimulated tumor growth by inducing tumor vascularization or enhancing inflammation, but some other studies revealed also opposite roles for Th17 cells in human tumors. It seems that Th17 cells may play distinct roles in cancer depending of tumor immunogenicity, the stage of development, and the impact of inflammation and angiogenesis on tumor pathogenesis.

  4. Th17 Cells in Type 1 Diabetes: Role in the Pathogenesis and Regulation by Gut Microbiome

    Directory of Open Access Journals (Sweden)

    Yangyang Li

    2015-01-01

    Full Text Available Type 1 diabetes (T1D is an autoimmune disease which is characterized by progressive destruction of insulin producing pancreatic islet β cells. The risk of developing T1D is determined by both genetic and environmental factors. A growing body of evidence supports an important role of T helper type 17 (Th17 cells along with impaired T regulatory (Treg cells in the development of T1D in animal models and humans. Alteration of gut microbiota has been implicated to be responsible for the imbalance between Th17 and Treg cells. However, there is controversy concerning a pathogenic versus protective role of Th17 cells in murine models of diabetes in the context of influence of gut microbiota. In this review we will summarize current knowledge about Th17 cells and gut microbiota involved in T1D and propose Th17 targeted therapy in children with islet autoimmunity to prevent progression to overt diabetes.

  5. Th17 effector cells support B cell responses outside of germinal centres.

    Directory of Open Access Journals (Sweden)

    Agapitos Patakas

    Full Text Available Th17 cells are pro-inflammatory CD4⁺T cells, which are important in immune responses against fungal pathogens and extracellular bacteria and have also been implicated in various autoimmune syndromes. However, their role in supporting B cell responses in these scenarios remains unclear, representing a significant lapse in our understanding of the role Th17 play in vaccine responses and the regulation of autoimmunity. We employed T cell and B cell receptor transgenic mice specific for model antigens, and adoptive transfer approaches that allowed the tracking of cognate B and T cells in situ and ex vivo using immunological methods. We have found that T cells activated under Th17 polarising conditions have a greater capacity to provide cognate B cell help compared with Th1 polarised populations, supporting higher expansion of antigen specific B cells and enhanced antibody titres. This advantage is associated with the increased persistence of Th17 polarised cells in areas of the lymph nodes where they can provide help (i.e. the B cell follicles. Also the Th17 cells are characterised by their higher expression of ICOS, a costimulatory molecule important for B cell help. Surprisingly, contrary to published reports, Th17 cells were not detected inside germinal centres, although they were found in close proximity to cognate B cells in the follicle early in the genesis of the humoral immune response. These data indicate that, Th17 cells have a more significant role earlier in the initiation/development of the germinal centre response and/or germinal centre-independent events, consistent with their early effector status.

  6. Photo(chemotherapy reduces circulating Th17 cells and restores circulating regulatory T cells in psoriasis.

    Directory of Open Access Journals (Sweden)

    Takuya Furuhashi

    Full Text Available BACKGROUND: Photo(chemotherapy is widely used to treat psoriasis, the pathogenesis of which might be caused by an imbalance of Th17 cells/regulatory T cells (Treg. In the present study, we evaluated the effects of photo(chemotherapy on the Th17/Treg balance and Treg function. METHODS: Peripheral blood was obtained from psoriasis patients treated with bath-psoralen ultraviolet A (UVA, n = 50 or narrowband ultraviolet B (UVB, n = 18, and age-matched healthy volunteers (n = 20. CD3(+CD4(+IL-17A(+ or CD4(+CD25(+Foxp3(+cells were analyzed to estimate Th17 or Treg number by fluorescence-activated cell sorting. Moreover, CD4(+ CD25(- T cells from patients treated with PUVA(n = 14 were incubated in CFSE and activated with or without CD4(+ CD25(+T cells, and the suppressive function of CD4(+ CD25(+T cells were analyzed. RESULTS: Photo(chemotherapy significantly reduced Th17 levels from 5.66 ± 3.15% to 2.96 ± 2.89% in patients with increased Th17 (Th17/CD4>3.01% [mean+SD of controls]. In contrast, photo(chemotherapy significantly increased Treg levels from 2.77 ± 0.75 to 3.40 ± 1.88% in patients with less than 4.07% Treg level, defined as the mean of controls. Furthermore, while Treg suppressed the CD4(+CD25(- T cell proliferation to a greater extent in controls (Treg Functional Ratio 94.4 ± 4.28% than in patients (70.3±25.1%, PUVA significantly increased Treg Functional Ratio to 88.1 ± 6.47%. Th17 levels in severe patients (>30 PASI were significantly higher as compared to controls. Th17 levels that were left after treatment in the patients not achieving PASI 50 (3.78 ± 4.18% were significantly higher than those in the patients achieving PASI 75 (1.83±1.87%. Treg levels in patients achieving PASI 90 (4.89 ± 1.70% were significantly higher than those in the patients not achieving PASI 90 (3.90 ± 1.66%. Treg levels prior to treatment with Th17 high decreased group (5.16 ± 2.20% was significantly higher than that with Th17 high increased group

  7. Sarcoidosis Th17 Cells are ESAT-6 Antigen Specific but Demonstrate Reduced IFN-γ Expression

    Science.gov (United States)

    Richmond, Bradley W.; Ploetze, Kristen; Isom, Joan; Chambers-Harris, Isfahan; Braun, Nicole A.; Taylor, Thyneice; Abraham, Susamma; Mageto, Yolanda; Culver, Dan A.; Oswald-Richter, Kyra A.; Drake, Wonder P.

    2013-01-01

    Rationale Sarcoidosis is a granulomatous disease of unknown etiology. Many patients with sarcoidosis demonstrate antigen-specific immunity to mycobacterial virulence factors. Th-17 cells are crucial to the immune response in granulomatous inflammation, and have recently been shown to be present in greater numbers in the peripheral blood and bronchoalveolar lavage (BAL) fluid (BALF) of sarcoidosis patients than healthy controls. It is unclear whether Th-17 cells in sarcoidosis are specific for mycobacterial antigens, or whether they have similar functionality to control Th-17 cells. Methods Flow cytometry was used to determine the numbers of Th-17 cells present in the peripheral blood and BALF of patients with sarcoidosis, the percentage of Th-17 cells that were specific to the mycobacterial virulence factor ESAT-6, and as well as to assess IFN-γ expression in Th-17 cells following polyclonal stimulation. Results Patients with sarcoidosis had greater numbers of Th-17 cells in the peripheral blood and BALF than controls and produced significantly more extracellular IL-17A (p=0.03 and p=0.02, respectively). ESAT-6 specific Th-17 cells were present in both peripheral blood and BALF of sarcoidosis patients (psarcoidosis patients produced less IFN-γ than healthy controls. Conclusions Patients with sarcoidosis have mycobacterial antigen-specific Th-17 cells peripherally and in sites of active sarcoidosis involvement. Despite the Th1 immunophenotype of sarcoidosis immunology, the Th-17 cells have reduced IFN-γ expression, compared to healthy controls. This reduction in immunity may contribute to sarcoidosis pathogenesis. PMID:23073617

  8. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis.

    Science.gov (United States)

    Komatsu, Noriko; Okamoto, Kazuo; Sawa, Shinichiro; Nakashima, Tomoki; Oh-hora, Masatsugu; Kodama, Tatsuhiko; Tanaka, Sakae; Bluestone, Jeffrey A; Takayanagi, Hiroshi

    2014-01-01

    Autoimmune diseases often result from an imbalance between regulatory T (Treg) cells and interleukin-17 (IL-17)-producing T helper (TH17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of Treg cells, but the stability of Foxp3 has been under debate. Here we show that TH17 cells originating from Foxp3(+) T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25(lo)Foxp3(+)CD4(+) T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into TH17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 TH17) cells accumulated in inflamed joints. The conversion of Foxp3(+)CD4(+) T cells to TH17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 TH17 cells were more potent osteoclastogenic T cells than were naive CD4(+) T cell-derived TH17 cells. Notably, exFoxp3 TH17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-κB ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25(lo)Foxp3(+)CD4(+) T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17(+)Foxp3(+) T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3(+) T cells contribute to the pathogenesis of RA. These findings establish the pathological importance of Foxp3 instability in the generation of pathogenic TH17 cells in autoimmunity.

  9. Tregs promote the differentiation of Th17 cells in silica-induced lung fibrosis in mice.

    Directory of Open Access Journals (Sweden)

    Laiyu Song

    Full Text Available BACKGROUND: Silicosis is an occupational lung disease caused by inhalation of silica dust and characterized by lung inflammation and fibrosis. Previous study showed that Tregs regulate the process of silicosis by modulating the maintenance of immune homeostasis in the lung. Th17 cells share reciprocal developmental pathway with Tregs and play a pivotal role in the immunopathogenesis of many lung diseases by recruiting and activating neutrophils, but the regulatory function of Tregs on Th17 response in silica induced lung fibrosis remains to be explored. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the role of Th17 and IL-17 in the development of silicosis and their interaction with Tregs, Treg-depleted mice model was generated and exposed to silica to establish experimental model of silica-induced lung fibrosis. Here we showed that silica increased Th17 response in lung fibrosis. Tregs depletion enhanced the neutrophils accumulation and attenuated Th17 response in silica induced lung fibrosis. Both mRNA and protein results showed that Tregs exerted its modulatory function on Th17 cells and IL-17 by regulating TGF-β1 and IL-1β. CONCLUSION/SIGNIFICANCE: Our study suggested that Tregs could promote Th17 cells differentiation by regulating TGF-β1 and IL-1β in silica induced lung fibrosis of mice, which further the understanding of the progress of silicosis and provide a new insight in the regulatory mechanism of Th17 by Tregs in lung inflammation.

  10. Role of Th17 Cells in Immunity Against Pulmonary Infection%Th17细胞在肺部感染免疫中的作用

    Institute of Scientific and Technical Information of China (English)

    王慧芳; 王斯; 吴发玲; 施小妹

    2009-01-01

    Th17 (T helper 17 cel1), a newly discovered subpopulation of T lymphocytes, was confirmed to play a critical role in inflammatory and autoimmune diseases. This subpopulation produces several proinflammatory cytokines including a novel interleukin named as IL-17. The cytokines produced by Th17 cells differed from those by and Th1 and Th2 cells, and exhibits antagonistic effects among them. Th17 cells are probably effective to resist infections caused by extracellular bacteria. This paper discussed the cytokines produced by th17 cells and the function of cytokins in immunity against pulmonary infection.%Th17细胞是近年来发现的一种新的效应T细胞亚群,在自身免疫性疾病和感染中发挥重要的作用,其分泌产生几种致炎细胞因子,包括新发现的细胞因子白细胞介素 17.Th17产生的细胞因子与Thl、Th2不同并且与其相互对抗.Th17细胞很可能对防御胞外病原菌的感染及自身免疫性疾病产生影响.综述了Th17细胞产生的细胞因子及其在肺部感染免疫中的作用相关方面的进展.

  11. Aberrant Circulating Th17 Cells in Patients with B-Cell Non-Hodgkin's Lymphoma.

    Science.gov (United States)

    Lu, Ting; Yu, Shuang; Liu, Yan; Yin, Congcong; Ye, Jingjing; Liu, Zhi; Ma, Daoxin; Ji, Chunyan

    2016-01-01

    Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of neoplasm in which 90% are B-cell lymphomas and 10% T-cell lymphomas. Although T-helper 17 (Th17) cells have been implicated to be essential in the pathogenesis of autoimmune and inflammatory diseases, its role in B-cell non-Hodgkin's lymphoma (B-NHL) remains unknown. In this study, we observed a significantly decreased frequency of Th17 cells in peripheral blood from B-NHL patients compared with healthy individuals, accompanied with increased Th1 cells. IL-17AF plasma levels were remarkably decreased in B-NHL patients, accompanied with undetectable IL-17FF and unchangeable IL-17AA. Moreover, Th17 and Th1 cells became normalized after one or two cycles of chemotherapy. Interestingly, in B-NHL, circulating Th17 cells frequencies were significantly higher in relapsed patients than those in untreated patients or normal individuals. Meanwhile, there was no statistical difference regarding the frequencies of Th1 cells between relapsed and untreated patients. Taken these data together, circulating Th17 subset immune response may be associated with the response of patients to treatment and with different stages of disease.

  12. Correlation between Th17 Cells and Human Tumors%Th17细胞与人类肿瘤的关系研究进展

    Institute of Scientific and Technical Information of China (English)

    徐秀娟; 马守宝

    2011-01-01

    辅助性T细胞17是新发现的一种CD4+效应T细胞亚群,具有独特的分化发育机制,在转化生长因子-β(transforminggrowth factor beta,TGF-β)、IL-6、IL-23等多种因子及特异性转录因子孤儿核受体(Orphan nuclear receptor,RORγt)的参与下,初始CD4+细胞分化发育为Th17细胞,活化的Th17细胞通过分泌IL-17、IL-21、IL-22等细胞因子导致炎症和疾病的发生.Th17细胞在感染性疾病、自身免疫病以及移植排斥反应中发挥重要的作用,但在肿瘤免疫中的作用却知之甚少.目前已在人类多种恶性肿瘤组织及外周血中检测到Th17细胞及其细胞因子的存在,关于Th17细胞在肿瘤发生发展中的作用,究竟是促进肿瘤还是抑制肿瘤仍存在较多争议,是近年来肿瘤免疫研究的热点.Th17细胞在肿瘤中的表达及作用机制的研究,为特异性靶向Th17细胞的抗肿瘤治疗提供理论依据.%T helper17 cells ( Th17 cell ) have been recently identified as part of the CD4+ T helper cell lineage.It has a unique mechanism of differentiation and development.With the participation of several cytokines, such as transforming growth factor beta ( TGF-β ), interleukin 6, and interleukin 23, and the orphan nuclear receptor ( RORγt ) of specific transcription factors, the initial CD4+ cells differentiate and develop into Th17 cells.The activated Th17 cells can trigger inflammations and diseases by secreting the cytokines, including interleukin 17, interleukin 21, and interleukin 22.Th17 cells play an important role in infectious diseases, autoimmune diseases and graft rejection reactions.However, the role of these cells in tumor immunity is unknown.Th17 cells and their cytokines have recently been found in several human malignancies and peripheral blood smears.Concerning the role of Th17 cells in the onset and progression of tumors, whether they facilitate or inhibit tumor growth remains controversial.Over the past few years, it has become the

  13. MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression

    Science.gov (United States)

    Hu, Ruozhen; Huffaker, Thomas B.; Kagele, Dominique A.; Runtsch, Marah C.; Bake, Erin; Chaudhuri, Aadel A.; Round, June L.; O’Connell, Ryan M.

    2013-01-01

    Th17 cells are central to the pathogenesis of autoimmune disease, and recently specific noncoding microRNAs (miRNAs) have been shown to regulate their development. However, it remains unclear if miRNAs are also involved in modulating Th17 cell effector functions. Consequently, we examined the role of miR-155 in differentiated Th17 cells during their induction of Experimental Autoimmune Encephalomyelitis (EAE). Using adoptive transfer experiments, we found that highly purified, MOG antigen-specific Th17 cells lacking miR-155 were defective in their capacity to cause EAE. Gene expression profiling of purified miR-155−/− IL-17F+ Th17 cells identified a subset of effector genes that are dependent upon miR-155 for their proper expression through a mechanism involving repression of the transcription factor Ets1. Among the genes reduced in the absence of miR-155 was IL-23R, resulting in miR-155−/− Th17 cells being hypo-responsive to IL-23. Taken together, our study demonstrates a critical role for miR-155 in Th17 cells as they unleash autoimmune inflammation, and finds that this occurs through a signaling network involving miR-155, Ets1 and the clinically relevant IL-23-IL-23R pathway. PMID:23686497

  14. Th17 cells demonstrate stable cytokine production in a proallergic environment.

    Science.gov (United States)

    Glosson-Byers, Nicole L; Sehra, Sarita; Stritesky, Gretta L; Yu, Qing; Awe, Olufolakemi; Pham, Duy; Bruns, Heather A; Kaplan, Mark H

    2014-09-15

    Th17 cells are critical for the clearance of extracellular bacteria and fungi, but also contribute to the pathology of autoimmune diseases and allergic inflammation. After exposure to an appropriate cytokine environment, Th17 cells can acquire a Th1-like phenotype, but less is known about their ability to adopt Th2 and Th9 effector programs. To explore this in more detail, we used an IL-17F lineage tracer mouse strain that allows tracking of cells that formerly expressed IL-17F. In vitro-derived Th17 cells adopted signature cytokine and transcription factor expression when cultured under Th1-, Th2-, or Th9-polarizing conditions. In contrast, using two models of allergic airway disease, Th17 cells from the lungs of diseased mice did not adopt Th1, Th2, or Th9 effector programs, but remained stable IL-17 secretors. Although in vitro-derived Th17 cells expressed IL-4Rα, those induced in vivo during allergic airway disease did not, possibly rendering them unresponsive to IL-4-induced signals. However, in vitro-derived, Ag-specific Th17 cells transferred in vivo to OVA and aluminum hydroxide-sensitized mice also maintained IL-17 secretion and did not produce alternative cytokines upon subsequent OVA challenge. Thus, although Th17 cells can adopt new phenotypes in response to some inflammatory environments, our data suggest that in allergic inflammation, Th17 cells are comparatively stable and retain the potential to produce IL-17. This might reflect a cytokine environment that promotes Th17 stability, and allow a broader immune response at tissue barriers that are susceptible to allergic inflammation.

  15. TH17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26

    KAUST Repository

    Meller, Stephan

    2015-07-13

    Interleukin 17-producing helper T cells (TH 17 cells) have a major role in protection against infections and in mediating autoimmune diseases, yet the mechanisms involved are incompletely understood. We found that interleukin 26 (IL-26), a human TH17 cell-derived cytokine, is a cationic amphipathic protein that kills extracellular bacteria via membrane-pore formation. Furthermore, TH17 cell-derived IL-26 formed complexes with bacterial DNA and self-DNA released by dying bacteria and host cells. The resulting IL-26-DNA complexes triggered the production of type I interferon by plasmacytoid dendritic cells via activation of Toll-like receptor 9, but independently of the IL-26 receptor. These findings provide insights into the potent antimicrobial and proinflammatory function of TH17 cells by showing that IL-26 is a natural human antimicrobial that promotes immune sensing of bacterial and host cell death. © 2015 Nature America, Inc.

  16. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells

    OpenAIRE

    Guedan, Sonia; Chen, Xi; Madar, Aviv; Carpenito, Carmine; McGettigan, Shannon E.; Frigault, Matthew J.; Lee, Jihyun; Posey, Avery D.; Scholler, John; Scholler, Nathalie; Bonneau, Richard; June, Carl H.

    2014-01-01

    ICOS-based CARs program bipolar TH17/TH1 cells with augmented effector function and in vivo persistence.The expression of selected CAR endodomains can program T cells for their subsequent differentiation fates and effector functions.

  17. Paeoniflorin Ameliorates Experimental Autoimmune Encephalomyelitis via Inhibition of Dendritic Cell Function and Th17 Cell Differentiation

    Science.gov (United States)

    Zhang, Han; Qi, Yuanyuan; Yuan, Yuanyang; Cai, Li; Xu, Haiyan; Zhang, Lili; Su, Bing; Nie, Hong

    2017-01-01

    Paeoniflorin (PF) is a monoterpene glycoside and exhibits multiple effects, including anti-inflammation and immunoregulation. To date, the effect of PF on multiple sclerosis (MS) has not been investigated. In this study, we investigated the effect of PF in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. After administered with PF, the onset and clinical symptoms of EAE mice were significantly ameliorated, and the number of Th17 cells infiltrated in central nervous system (CNS) and spleen was also dramatically decreased. Instead of inhibiting the differentiation of Th17 cells directly, PF influenced Th17 cells via suppressing the expression of costimulatory molecules and the production of interlukin-6 (IL-6) of dendritic cells (DCs) in vivo and in vitro, which may be attributable to the inhibition of IKK/NF-κB and JNK signaling pathway. When naïve CD4+ T cells were co-cultured with PF-treated dendritic cells under Th17-polarizing condition, the percentage of Th17 cells and the phosphorylation of STAT3 were decreased, as well as the mRNA levels of IL-17, RORα, and RORγt. Our study provided insights into the role of PF as a unique therapeutic agent for the treatment of multiple sclerosis and illustrated the underlying mechanism of PF from a new perspective. PMID:28165507

  18. Highly polarized Th17 cells induce EAE via a T-bet independent mechanism.

    Science.gov (United States)

    Grifka-Walk, Heather M; Lalor, Stephen J; Segal, Benjamin M

    2013-11-01

    In the MOG35-55 induced EAE model, autoreactive Th17 cells that accumulate in the central nervous system acquire Th1 characteristics via a T-bet dependent mechanism. It remains to be determined whether Th17 plasticity and encephalitogenicity are causally related to each other. Here, we show that IL-23 polarized T-bet(-/-) Th17 cells are unimpaired in either activation or proliferation, and induce higher quantities of the chemokines RANTES and CXCL2 than WT Th17 cells. Unlike their WT counterparts, T-bet(-/-) Th17 cells retain an IL-17(hi) IFN-γ(neg-lo) cytokine profile following adoptive transfer into syngeneic hosts. This population of highly polarized Th17 effectors is capable of mediating EAE, albeit with a milder clinical course. It has previously been reported that the signature Th1 and Th17 effector cytokines, IFN-γ and IL-17, are dispensable for the development of autoimmune demyelinating disease. The current study demonstrates that the "master regulator" transcription factor, T-bet, is also not universally required for encephalitogenicity. Our results contribute to a growing body of data showing heterogeneity of myelin-reactive T cells and the independent mechanisms they employ to inflict damage to central nervous system tissues, complicating the search for therapeutic targets relevant across the spectrum of individuals with multiple sclerosis.

  19. Targeting Th17 Cells with Small Molecules and Small Interference RNA.

    Science.gov (United States)

    Lin, Hui; Song, Pingfang; Zhao, Yi; Xue, Li-Jia; Liu, Yi; Chu, Cong-Qiu

    2015-01-01

    T helper 17 (Th17) cells play a central role in inflammatory and autoimmune diseases via the production of proinflammatory cytokines interleukin- (IL-) 17, IL-17F, and IL-22. Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA) and Crohn's disease. Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine. Retinoic acid-related orphan receptor gamma t (RORγt) which acts as the master transcription factor of Th17 differentiation has been an attractive pharmacologic target for the treatment of Th17-mediated autoimmune disease. Recent progress in technology of chemical screen and engineering nucleic acid enable two new classes of therapeutics targeting RORγt. Chemical screen technology identified several small molecule specific inhibitors of RORγt from a small molecule library. Systematic evolution of ligands by exponential enrichment (SELEX) technology enabled target specific aptamers to be isolated from a random sequence oligonucleotide library. In this review, we highlight the development and therapeutic potential of small molecules inhibiting Th17 cells by targeting RORγt and aptamer mediated CD4(+) T cell specific delivery of small interference RNA against RORγt gene expression to inhibit pathogenic effector functions of Th17 lineage.

  20. Targeting Th17 Cells with Small Molecules and Small Interference RNA

    Directory of Open Access Journals (Sweden)

    Hui Lin

    2015-01-01

    Full Text Available T helper 17 (Th17 cells play a central role in inflammatory and autoimmune diseases via the production of proinflammatory cytokines interleukin- (IL- 17, IL-17F, and IL-22. Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA and Crohn’s disease. Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine. Retinoic acid-related orphan receptor gamma t (RORγt which acts as the master transcription factor of Th17 differentiation has been an attractive pharmacologic target for the treatment of Th17-mediated autoimmune disease. Recent progress in technology of chemical screen and engineering nucleic acid enable two new classes of therapeutics targeting RORγt. Chemical screen technology identified several small molecule specific inhibitors of RORγt from a small molecule library. Systematic evolution of ligands by exponential enrichment (SELEX technology enabled target specific aptamers to be isolated from a random sequence oligonucleotide library. In this review, we highlight the development and therapeutic potential of small molecules inhibiting Th17 cells by targeting RORγt and aptamer mediated CD4+ T cell specific delivery of small interference RNA against RORγt gene expression to inhibit pathogenic effector functions of Th17 lineage.

  1. Th17 Cells Pathways in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders: Pathophysiological and Therapeutic Implications

    OpenAIRE

    Giordani Rodrigues Dos Passos; Douglas Kazutoshi Sato; Jefferson Becker; Kazuo Fujihara

    2016-01-01

    Several animal and human studies have implicated CD4+ T helper 17 (Th17) cells and their downstream pathways in the pathogenesis of central nervous system (CNS) autoimmunity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), challenging the traditional Th1-Th2 paradigm. Th17 cells can efficiently cross the blood-brain barrier using alternate ways from Th1 cells, promote its disruption, and induce the activation of other inflammatory cells in the CNS. A number of e...

  2. Th17 cells and interleukin-17 increase with poor prognosis in patients with acute myeloid leukemia.

    Science.gov (United States)

    Han, Yixiang; Ye, Aifang; Bi, Laixi; Wu, Jianbo; Yu, Kang; Zhang, Shenghui

    2014-08-01

    Although Th17 cells play crucial roles in the pathogenesis of many autoimmune and inflammatory disorders, their roles in malignancies are currently under debate. The role and mechanism of Th17 cells in patients with acute myeloid leukemia (AML) remain poorly understood. Here we demonstrated that the frequency of Th17 cells was significantly increased in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells from AML patients compared with healthy donors. Plasma levels of interleukin (IL)-17, IL-22, IL-23, IL-1β, IL-6, and transforming growth factor (TGF)-β1 were significantly increased in blood and bone marrow in AML patients compared with healthy donors. The in vitro experiments demonstrated that IL-1β, IL-6, IL-23, but not TGF-β1 promoted the generation and differentiation of Th17 cells from naive CD4(+) T cells in humans. IL-17A, a signature cytokine secreted by Th17 cells, induced the proliferation of IL-17 receptor (IL-17R)-positive AML cells via IL-17R, in which activation of PI3K/Akt and Jak/Stat3 signaling pathway may play important roles. In addition, combination of IL-17A and IL-22 significantly reduced the generation of Th1 cells and the production of interferon (IFN)-γ from healthy donor or AML patient peripheral blood mononuclear cells. Patients with high Th17 cell frequency had poor prognosis, whereas patients with high Th1 cell frequency had prolonged survival. Combined analysis of Th1 and Th17 cell frequencies improved the ability to predict patient outcomes. In conclusion, Th17 cells play a crucial role in the pathogenesis of AML and may be an important therapeutic target and prognostic predictor.

  3. Characterization of Th17 and FoxP3(+) Treg Cells in Paediatric Psoriasis Patients.

    Science.gov (United States)

    Zhang, L; Li, Y; Yang, X; Wei, J; Zhou, S; Zhao, Z; Cheng, J; Duan, H; Jia, T; Lei, Q; Huang, J; Feng, C

    2016-03-01

    Psoriasis is one of the most common inflammatory skin conditions affecting both children and adults. Growing evidence indicates that T-helper 17 (Th17) cells and CD4(+) CD25(+) regulatory T (Treg) cells play an important role in the pathogenesis of psoriasis. However, the relationship between Th17 and Treg cells and their dynamic variations in paediatric psoriasis remain unclear. In this study, we found that both Th17 and FoxP3(+) Treg cells and the ratio of Th17 to Treg cell frequency in the peripheral circulation were increased in patients with paediatric psoriasis and were positively correlated with the disease severity. The function of Treg to suppress CD4(+) CD25(-) T cell proliferation and IFN-γ secretion was impaired during the onset of psoriasis. After disease remission, both the Th17 and Treg cell frequencies were decreased, and the suppressive function of the Treg cells was obviously restored. However, neither Treg cells from the disease onset nor those after remission can regulate IL-17 secretion by CD4(+) T cells. These findings will further our understanding of the associations between Th17 and Treg cells in paediatric psoriasis and their influence on disease severity.

  4. Deoxynivalenol as a new factor in the persistence of intestinal inflammatory diseases: an emerging hypothesis through possible modulation of Th17-mediated response.

    Directory of Open Access Journals (Sweden)

    Patricia M Cano

    Full Text Available BACKGROUND/AIMS: Deoxynivalenol (DON is a mycotoxin produced by Fusarium species which is commonly found in temperate regions worldwide as a natural contaminant of cereals. It is of great concern not only in terms of economic losses but also in terms of animal and public health. The digestive tract is the first and main target of this food contaminant and it represents a major site of immune tolerance. A finely tuned cross-talk between the innate and the adaptive immune systems ensures the homeostatic equilibrium between the mucosal immune system and commensal microorganisms. The aim of this study was to analyze the impact of DON on the intestinal immune response. METHODOLOGY: Non-transformed intestinal porcine epithelial cells IPEC-1 and porcine jejunal explants were used to investigate the effect of DON on the intestinal immune response and the modulation of naive T cells differentiation. Transcriptomic proteomic and flow cytometry analysis were performed. RESULTS: DON induced a pro-inflammatory response with a significant increase of expression of mRNA encoding for IL-8, IL-1α and IL-1β, TNF-α in all used models. Additionally, DON significantly induced the expression of genes involved in the differentiation of Th17 cells (STAT3, IL-17A, IL-6, IL-1β at the expenses of the pathway of regulatory T cells (Treg (FoxP3, RALDH1. DON also induced genes related to the pathogenic Th17 cells subset such as IL-23A, IL-22 and IL-21 and not genes related to the regulatory Th17 cells (rTh17 such as TGF-β and IL-10. CONCLUSION: DON triggered multiple immune modulatory effects which could be associated with an increased susceptibility to intestinal inflammatory diseases.

  5. The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells.

    Science.gov (United States)

    Brüstle, Anne; Brenner, Dirk; Knobbe, Christiane B; Lang, Philipp A; Virtanen, Carl; Hershenfield, Brian M; Reardon, Colin; Lacher, Sonja M; Ruland, Jürgen; Ohashi, Pamela S; Mak, Tak W

    2012-12-01

    Effector functions of inflammatory IL-17-producing Th (Th17) cells have been linked to autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). However, what determines Th17 cell encephalitogenicity is still unresolved. Here, we show that after EAE induction, mice deficient for the NF-κB regulator MALT1 (Malt1-/- mice) exhibit strong lymphocytic infiltration in the CNS, but do not develop any clinical signs of EAE. Loss of Malt1 interfered with expression of the Th17 effector cytokines IL-17 and GM-CSF both in vitro and in vivo. In line with their impaired GM-CSF secretion, Malt1-/- Th cells failed to recruit myeloid cells to the CNS to sustain neuroinflammation, whereas autoreactive WT Th cells successfully induced EAE in Malt1-/- hosts. In contrast, Malt1 deficiency did not affect Th1 cells. Despite their significantly decreased secretion of Th17 effector cytokines, Malt1-/- Th17 cells showed normal expression of lineage-specific transcription factors. Malt1-/- Th cells failed to cleave RelB, a suppressor of canonical NF-κB, and exhibited altered cellular localization of this protein. Our results indicate that MALT1 is a central, cell-intrinsic factor that determines the encephalitogenic potential of inflammatory Th17 cells in vivo.

  6. Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Helena S Domingues

    Full Text Available BACKGROUND: There is consensus that experimental autoimmune encephalomyelitis (EAE can be mediated by myelin specific T cells of Th1 as well as of Th17 phenotype, but the contribution of either subset to the pathogenic process has remained controversial. In this report, we compare functional differences and pathogenic potential of "monoclonal" T cell lines that recognize myelin oligodendrocyte glycoprotein (MOG with the same transgenic TCR but are distinguished by an IFN-γ producing Th1-like and IL-17 producing Th17-like cytokine signature. METHODS AND FINDINGS: CD4+ T cell lines were derived from the transgenic mouse strain 2D2, which expresses a TCR recognizing MOG peptide 35-55 in the context of I-A(b. Adoptive transfer of Th1 cells into lymphopenic (Rag2⁻/⁻ recipients, predominantly induced "classic" paralytic EAE, whereas Th17 cells mediated "atypical" ataxic EAE in approximately 50% of the recipient animals. Combination of Th1 and Th17 cells potentiated the encephalitogenicity inducing classical EAE exclusively. Th1 and Th17 mediated EAE lesions differed in their composition but not in their localization within the CNS. While Th1 lesions contained IFN-γ, but no IL-17 producing T cells, the T cells in Th17 lesions showed plasticity, substantially converting to IFN-γ producing Th1-like cells. Th1 and Th17 cells differed drastically by their lytic potential. Th1 but not Th17 cells lysed autoantigen presenting astrocytes and fibroblasts in vitro in a contact-dependent manner. In contrast, Th17 cells acquired cytotoxic potential only after antigenic stimulation and conversion to IFN-γ producing Th1 phenotype. CONCLUSIONS: Our data demonstrate that both Th1 and Th17 lineages possess the ability to induce CNS autoimmunity but can function with complementary as well as differential pathogenic mechanisms. We propose that Th17-like cells producing IL-17 are required for the generation of atypical EAE whereas IFN-γ producing Th1 cells induce

  7. Changes in the balance between Treg and Th17 cells in patients with chronic hepatitis B.

    Science.gov (United States)

    Su, Zhi-Jun; Yu, Xue-Ping; Guo, Ru-Yi; Ming, De-Song; Huang, Lv-Ye; Su, Mi-Long; Deng, Yong; Lin, Zhen-Zhong

    2013-08-01

    The purpose of this study was to explore the role of Treg cells, Th17 cells and cytokines associated with Treg/Th17 differentiation in the occurrence, development and outcome of chronic hepatitis B (CHB). To do so, we detected populations of Treg and Th17 cells and their associated cytokines in the peripheral blood of CHB patients. The populations of Treg cells (CD4(+)CD25(high)CD127(low) T cells) and Th17 cells (CD3(+)CD8(-)IL-17(+) T cells) were analyzed in 46 patients with low to moderate chronic hepatitis B (CHB-LM), 24 patients with severe chronic hepatitis B (CHB-S) and 20 healthy controls (HC) using flow cytometry. The levels of cytokines associated with Treg/Th17 differentiation, including IL-10, TGF-β1, IL-17 and IL-23, were measured by enzyme-linked immunosorbent assay (ELISA). Our study showed that the imbalance of Treg and Th17 cells might play an important role in the occurrence, development and outcome of CHB.

  8. Th17/Treg Cells Imbalance and GITRL Profile in Patients with Hashimoto’s Thyroiditis

    Directory of Open Access Journals (Sweden)

    Yingzhao Liu

    2014-11-01

    Full Text Available Hashimoto’s thyroiditis (HT is an organ-specific immune disease characterized by the presence of lymphocytic infiltration and serum autoantibodies. Previous studies have confirmed the critical role of Th17 cells in the pathopoiesis of HT patients. Additionally, regulatory T cells (Treg display a dysregulatory function in autoimmune disease. The purpose of this study is to investigate the alteration of Th17 and Treg cells in HT patients and explore contributing factors. We found there was an increased ratio of Th17/Treg in HT patients and a positive correlation with autoantibodies (anti-TgAb. In addition, there was an increased level of GITRL, which has been demonstrated to be correlated with the increassement of Th17 cells in the serum and thyroid glands of HT patients; the upregulated serum level of GITRL has a positive correlation with the percentage of Th17 cells in HT patients. In summary, an increase in GITRL may impair the balance of Th17/Treg, and contribute to the pathopoiesis of Hashimoto’s thyroiditis.

  9. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation

    NARCIS (Netherlands)

    Gagliani, Nicola; Vesely, Maria Carolina Amezcua; Iseppon, Andrea; Brockmann, Leonie; Xu, Hao; Palm, Noah W; de Zoete, Marcel R; Licona-Limón, Paula; Paiva, Ricardo S; Ching, Travers; Weaver, Casey; Zi, Xiaoyuan; Pan, Xinghua; Fan, Rong; Garmire, Lana X; Cotton, Matthew J; Drier, Yotam; Bernstein, Bradley; Geginat, Jens; Stockinger, Brigitta; Esplugues, Enric; Huber, Samuel; Flavell, Richard A

    2015-01-01

    Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The Th17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A) a

  10. Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161(+)Th1 Cells) to CD161(+)Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients.

    Science.gov (United States)

    Kotake, Shigeru; Nanke, Yuki; Yago, Toru; Kawamoto, Manabu; Kobashigawa, Tsuyoshi; Yamanaka, Hisashi

    2016-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161(+)Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161(+)Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase.

  11. Reasons for rarity of Th17 cells in inflammatory sites of human disorders.

    Science.gov (United States)

    Annunziato, Francesco; Santarlasci, Veronica; Maggi, Laura; Cosmi, Lorenzo; Liotta, Francesco; Romagnani, Sergio

    2013-11-15

    T helper 17 (Th17) cells have been reported to be responsible for several chronic inflammatory diseases. However, a peculiar feature of human Th17 cells is that they are very rare in the inflammatory sites in comparison with Th1 cells. The first reason for this rarity is the existence of some self-regulatory mechanisms that limit their expansion. The limited expansion of human Th17 cells is related to the retinoic acid orphan (ROR)C-dependent up-regulation of the interleukin (IL)-4 induced gene 1 (IL4I1), which encodes for a l-phenylalanine oxidase, that has been shown to down-regulate CD3ζ expression in T cells. This results in abnormalities of the molecular pathway which is responsible for the impairment of IL-2 production and therefore for the lack of cell proliferation in response to T-cell receptor (TCR) signalling. IL4I1 up-regulation also associates with the increased expression of Tob1, a member of the Tob/BTG anti-proliferative protein family, which is involved in cell cycle arrest. A second reason for the rarity of human Th17 cells in the inflammatory sites is their rapid shifting into the Th1 phenotype, which is mainly related to the activity of IL-12 and TNF-α. We have named these Th17-derived Th1 cells as non-classic because they differ from classic Th1 cells for the expression of molecules specific for Th17 cells, such as RORC, CD161, CCR6, IL4I1, and IL-17 receptor E. This distinction may be important for defining the respective pathogenic role of Th17, non-classic Th1 and classic Th1 cells in many human inflammatory disorders.

  12. The Role of Regulatory T Cells and TH17 Cells in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Walter M. T. Braga

    2012-01-01

    Full Text Available The development of multiple myeloma (MM involves a series of genetic alterations and changes in the bone marrow microenvironment, favoring the growth of the tumor and failure of local immune control. Quantitative and functional alterations in CD4+ and CD8+ T cells have been described in MM. The balance between T regulatory cells (Treg and T helper (Th 17 cells represents one essential prerequisite for maintaining anti-tumor immunity in MM. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against infections and tumor cells. In MM patients, Tregs seem to contribute to myeloma-related immune dysfunction and targeting them could, therefore, help to restore and enhance vital immune responses. Th17 cells protect against fungal and parasitic infections and participate in inflammatory reactions and autoimmunity. The interplay of TGF-β and IL-6, expressed at high levels in the bone marrow of myeloma patients, may affect generation of Th17 cells both directly or via other pro-inflammatory cytokines and thereby modulate antitumor immune responses. A detailed analysis of the balance between Tregs and Th17 cells seems necessary in order to design more effective and less toxic modes of immunotherapy myeloma which still is an uncurable malignancy.

  13. The role of Th1 and Th17 cells in glomerulonephritis.

    Science.gov (United States)

    Azadegan-Dehkordi, Fatemeh; Bagheri, Nader; Shirzad, Hedayatollah; Rafieian-Kopaei, Mahmoud

    2015-04-01

    T helper (Th) cells as an important part of the immune is responsible for elimination of invading pathogens. But, if Th cell responses are not regulated effectively, the autoimmune diseases might develop. The Th17 subset usually produces interleukin-17A which in experimental models of organ-specific autoimmune inflammation is very important. Directory of open access journals (DOAJ), Google Scholar, Embase, Scopus, PubMed and Web of Science have been searched. Fifty-six articles were found and searched. In the present review article, we tried to summarize the recently published data about characteristics and role of Th1 and Th17 cells and discuss in detail, the potential role of these T helpers immune responses in renal inflammation and renal injury, focusing on glomerulonephritis. Published papers in animal and human studies indicated that autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, classically believed to be Th1-mediated, are mainly derived from a Th17 immune response. Identification of the Th17 subgroup has explained seemingly paradoxical observations and improved our understanding of immune-mediated inflammatory responses. Secretion of IL-17A, as well as IL-17F, IL-21, IL-22, suggests that Th17 subset may play a crucial role as a pleiotropic pro-inflammatory Th subset. There is experimental evidence to support the notion that Th1 and Th17 cells contribute to kidney injury in renal inflammatory diseases like glomerulonephritis.

  14. Coenzyme Q10 suppresses Th17 cells and osteoclast differentiation and ameliorates experimental autoimmune arthritis mice.

    Science.gov (United States)

    Jhun, JooYeon; Lee, Seung Hoon; Byun, Jae-Kyeong; Jeong, Jeong-Hee; Kim, Eun-Kyung; Lee, Jennifer; Jung, Young-Ok; Shin, Dongyun; Park, Sung Hwan; Cho, Mi-La

    2015-08-01

    Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant synthesized in human body. This enzyme promotes immune system function and can be used as a dietary supplement. Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. RA results in severe destruction of cartilage and disability. This study aimed to investigate the effect of CoQ10 on inflammation and Th17 cell proliferation on an experimental rheumatoid arthritis (RA) mice model. CoQ10 or cotton seed oil as control was orally administrated once a day for seven weeks to mice with zymosan-induced arthritis (ZIA). Histological analysis of the joints was conducted using immunohistochemistry. Germinal center (GC) B cells, Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. mRNA expression was measured by real-time PCR and protein levels were estimated by enzyme-linked immunosorbent assay (ELISA). Flow cytometric analysis (FACS) was used to evaluate Th17 cells and Treg cells. CoQ10 mitigated the severity of ZIA and decreased serum immunoglobulin concentrations. CoQ10 also reduced RANKL-induced osteoclastogenesis, inflammatory mediators and oxidant factors. Th17/Treg axis was reciprocally controlled by CoQ10 treatment. Moreover, CoQ10 treatment on normal mouse and human cells cultured in Th17 conditions decreased the number of Th17 cells and enhanced the number of Treg cells. CoQ10 alleviates arthritis in mice with ZIA declining inflammation, Th17 cells and osteoclast differentiation. These findings suggest that CoQ10 can be a potential therapeutic substance for RA.

  15. New Subset of Effector T Cells Th17 and Atherosclerosis%效应性T细胞亚群Th17与动脉粥样硬化

    Institute of Scientific and Technical Information of China (English)

    吉庆伟

    2011-01-01

    Thl7 characterized by the production of interleukin (IL)-17 is a newly founded subset of CD4 T effect cells. Thl7 cyto-kines include IL-17, IL-17F, IL-21, tumor nuclear factor-a and so on. Th 17 have been linked to many chronic inflammatory diseases, autoimmune diseases and tumor. Several data indicated that Th17 response may play an important role in the development and progression of atherosclerosis. In this review,we will introduce the role of Thl7 in atherosclerosis.%效应性T细胞亚群Th17是新近发现的效应性T细胞的又一亚群,因分泌细胞因子IL-17而得名.Th17通过分泌多种效应分子如白细胞介素17、17F、21和肿瘤坏死因子-α等与慢性炎症性疾病、自身免疫性疾病和肿瘤等疾病密切相关.研究发现,动脉粥样硬化的发生发展也与Th17功能的异常密切相关,现拟就此进行综述.

  16. Akt-dependent enhanced migratory capacity of Th17 cells from children with lupus nephritis.

    Science.gov (United States)

    Kshirsagar, Sudhir; Riedl, Magdalena; Billing, Heiko; Tönshoff, Burkhard; Thangavadivel, Shanmugapriya; Steuber, Christian; Staude, Hagen; Wechselberger, Gottfried; Edelbauer, Monika

    2014-11-15

    Th17 cells infiltrate the kidneys of patients with lupus nephritis (LN) and are critical for the pathogenesis of this disease. In this study, we show that enhanced activity of Stat3 in CD4(+)CD45RA(-)Foxp3(-) and Foxp3(low) effector T cells from children with LN correlates with increased frequencies of IL-17-producing cells within these T cell populations. The levels of retinoic acid-related orphan receptor c and IL-17 mRNA are significantly higher in PBMCs from children with LN than in those from controls. Mammalian target of rapamycin inhibition by rapamycin reduces both Stat3 activation in effector T cells and the frequency of IL-17-producing T cells in lupus patients. Complement factor C5a slightly increases the expression of IL-17 and induces activation of Akt in anti-CD3-activated lupus effector T cells. Th17 cells from children with LN exhibit high Akt activity and enhanced migratory capacity. Inhibition of the Akt signaling pathway significantly decreases Th17 cell migration. These findings indicate that the Akt signaling pathway plays a significant role in the migratory activity of Th17 cells from children with LN and suggest that therapeutic modulation of the Akt activity may inhibit Th17 cell trafficking to sites of inflammation and thus suppress chronic inflammatory processes in children with LN.

  17. Balancing Inflammation: The Link between Th17 and Regulatory T Cells

    Directory of Open Access Journals (Sweden)

    Maggie L. Diller

    2016-01-01

    Full Text Available CD4+ T cell compartments in mouse and man are composed of multiple distinct subsets each possessing unique phenotypic and functional characteristics. IL-17-producing CD4+ T cells (Th17 cells represent a distinct subset of the CD4+ T cell lineage. Recent evidence suggests that Th17 cells carry out effector functions similar to cytotoxic CD8+ T cells and play an important role in the clearance of extracellular pathogens and fungi. Th17 cell differentiation and function are closely related to the development and function of regulatory T cells (TREG. The balance between these two cell populations is essential for immune homeostasis and dysregulation of this balance has been implicated in a variety of inflammatory conditions including autoimmunity, allograft rejection, and tumorigenesis. Emerging evidence reports a significant amount of plasticity between the Th17 and regulatory T cell compartments, and the mechanisms by which these cells communicate and influence each other are just beginning to be understood. In this review, we highlight recent findings detailing the mechanisms driving Th17 and TREG plasticity and discuss the biologic consequences of their unique relationship.

  18. Protein kinase C θ regulates the phenotype of murine CD4+ Th17 cells.

    Directory of Open Access Journals (Sweden)

    Katarzyna Wachowicz

    Full Text Available Protein kinase C θ (PKCθ is involved in signaling downstream of the T cell antigen receptor (TCR and is important for shaping effector T cell functions and inflammatory disease development. Acquisition of Th1-like effector features by Th17 cells has been linked to increased pathogenic potential. However, the molecular mechanisms underlying Th17/Th1 phenotypic instability remain largely unknown. In the current study, we address the role of PKCθ in differentiation and function of Th17 cells by using genetic knock-out mice. Implementing in vitro (polarizing T cell cultures and in vivo (experimental autoimmune encephalomyelitis model, EAE techniques, we demonstrated that PKCθ-deficient CD4+ T cells show normal Th17 marker gene expression (interleukin 17A/F, RORγt, accompanied by enhanced production of the Th1-typical markers such as interferon gamma (IFN-γ and transcription factor T-bet. Mechanistically, this phenotype was linked to aberrantly elevated Stat4 mRNA levels in PKCθ-/- CD4+ T cells during the priming phase of Th17 differentiation. In contrast, transcription of the Stat4 gene was suppressed in Th17-primed wild-type cells. This change in cellular effector phenotype was reflected in vivo by prolonged neurological impairment of PKCθ-deficient mice during the course of EAE. Taken together, our data provide genetic evidence that PKCθ is critical for stabilizing Th17 cell phenotype by selective suppression of the STAT4/IFN-γ/T-bet axis at the onset of differentiation.

  19. Changes of Th17/Treg cell and related cytokines in pancreatic cancer patients.

    Science.gov (United States)

    Wang, Xiaofang; Wang, Lei; Mo, Qingjiang; Dong, Yuqian; Wang, Guoqiang; Ji, Ankui

    2015-01-01

    To explore the mechanism of Th17 cells and Treg cells in the peripheral blood of patients with pancreatic cancer through analyzing the changes of the related genes and cytokines expression. 40 patients were divided into three groups based on clinical staging, and 20 healthy subjects were treated as normal control. Proportion of Th17 cells and Treg cells were detected by flow cytometry. RORα, RORγt, FoxP3, and CTLA-4 expression in peripheral blood mononuclear cells were detected by RT-PCR. IL-10, IL-23, INF-γ, TGF-β, and IL-17 cytokine levels in peripheral blood were determined by enzyme-linked immunosorbent assay (ELISA). The proportion of Th17 cells in peripheral blood of pancreatic cancer patients was lower than that in the normal control, while the proportion of Treg was higher. RORα and RORγt mRNA expression in Th17 cells from pancreatic cancer patients decreased, while FoxP3 and CTLA-4 mRNA expressions in Treg cells increased compared with the normal control. And the correlation analysis revealed that they were significantly correlated with clinical staging. Compared with healthy control, IL-23, IL-17 and INF-γ levels were lower in pancreatic cancer patients, while IL-10 and TGF-β levels were higher. Following the progression of disease, patients in advanced stage exhibited higher level of IL-10 and TGF-β, and lower levels of IL-23 and INF-γ. Pancreatic cancer patients exhibited Th17/Treg balance disorders with higher Treg and lower Th17 cells. They affect cytokine IL-10, IL-23, INF-γ, TGF-β, and IL-17 expression changes mainly through regulating transcription factors such as RORα, RORγt, FoxP3 and CTLA-4, suggesting that Th17/Treg balance disorders plays an important role in the tumorigenesis of pancreatic cancer.

  20. Th17细胞与Graves病及桥本甲状腺炎%Relationship between Th17 cells and Graves' disease, Hashimoto's thyroiditis

    Institute of Scientific and Technical Information of China (English)

    贾媛媛; 陈莉丽

    2014-01-01

    Th17细胞是一种新近发现的Th细胞亚群,主要通过分泌白细胞介素(IL)-17、IL-21、IL-22、IL-6等细胞因子参与炎性反应、自身免疫性疾病、肿瘤等发生过程.近年来研究表明,Th17细胞及其所分泌的细胞因子在Graves病和桥本甲状腺炎的患者外周血单个核细胞中比例显著升高,提示Th17细胞可能在甲状腺疾病的发病机制中起重要作用.对Th17细胞不断深入的研究必将为甲状腺疾病的防治提供有益的帮助.%Th17 cells are considered as a novel Th-cell subset which has been recently proposed.Th17 cells are involved in a number of diseases,including inflammation,autoimmune disorders and cancer by secreting interleukine(IL)-17,IL-21,IL-22 and IL-6.Recent studies have identified that the proportions of Thl7-related cytokines in the peripheral blood of patients with Graves' disease and Hashimoto thyroiditis are significantly elevated.It is suggested that Thl7-related cytokines may play a pathophysiological role in thyroid diseases.The study of Thl7-related cytokines is helpful in elucidating the pathogenesis of thyroid diseases and in developing new therapeutic approaches.

  1. Relationship of Th17/Treg Cells and Radiation Pneumonia in Locally Advanced Esophageal Carcinoma.

    Science.gov (United States)

    Wang, Yan; Xu, Gang; Wang, Jie; Li, Xin-Hua; Sun, Ping; Zhang, Wei; Li, Jun-Xia; Wu, Chao-Yang

    2017-08-01

    Radiation pneumonia is a main side-effect that has limited the clinical usage of radiotherapy in locally advanced esophageal carcinoma. T helper cells 17 (Th 17) and T regulatory cells (Tregs) play an important role in inflammatory diseases. The balance between Treg and Th17 cells is a key factor in the progression of many inflammatory and autoimmune diseases. Whether Tregs and Th17 cells are predictive factors of radiation pneumonia has not yet been reported. In this study, we investigated the relationships of Treg/Th17 cells and radiation pneumonia in patients with locally advanced esophageal cancer who received radiotherapy. One hundred and forty-eight patients with locally advanced esophageal cancer who received radical and palliative radiotherapy were enrolled. The levels of Th17 and Treg cells in the blood of patients were detected using flow cytometry at the time point of pre-radiotherapy, 1st, 2nd, 3rd, 4th, 5th and 6th week from the start of radiation and 4 weeks after completion of radiotherapy. Radiation pneumonia was evaluated according to Radiation Therapy Oncology Group's acute radiation pneumonia standards, with the endpoint being grade 2 or above radiation pneumonia. There were 24 cases of radiation pneumonia in 148 cases of locally advanced esophageal cancer patients who underwent radiotherapy. Th17 cells increased and, in contrast, Treg cells decreased in the radiation pneumonia group. The change in the ratio of Th17/Treg was more pronounced and the difference was statistically significant from the 5th week after irradiation compared to patients with no radiation pneumonia (pcells may be an effective predictive factor of radiation pneumonia. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Natural killer cells regulate Th1/Treg and Th17/Treg balance in chlamydial lung infection.

    Science.gov (United States)

    Li, Jing; Dong, Xiaojing; Zhao, Lei; Wang, Xiao; Wang, Yan; Yang, Xi; Wang, Hong; Zhao, Weiming

    2016-07-01

    Natural killer (NK) cell is an important component in innate immunity, playing a critical role in bridging innate and adaptive immunity by modulating the function of other immune cells including T cells. In this study, we focused on the role of NK cells in regulating Th1/Treg and Th17/Treg balance during chlamydial lung infection. We found that NK cell-depleted mice showed decreased Th1 and Th17 cells, which was correlated with reduced interferon-γ, interleukin (IL)-12, IL-17 and IL-22 production as well as T-bet and receptor-related orphan receptor gamma t expression compared with mice treated with the isotype control antibody. In contrast, NK cell depletion significantly increased Treg in cell number and related transcription factor (Foxp3) expression. The opposite trends of changes of Th1/Th17 and Treg led to significant reduction in the Th1/Treg and Th17/Treg ratios. The data implicate that NK cells play an important role in host defence against chlamydial lung infection, mainly through maintaining Th1/Treg and Th17/Treg balance.

  3. Positive and Negative Regulation of Th17 Cell Differentiation: Evaluating The Impact of RORC2

    Directory of Open Access Journals (Sweden)

    Mazdak Ganjalikhani Hakemi

    2014-04-01

    Full Text Available Objective: Th17 cells are known to be involved in some types of inflammations and autoimmune disorders. RORC2 is the key transcription factor coordinating Th17 cell differentiation. Thus, blocking RORC2 may be useful in suppressing Th17-dependent inflammatory processes. The aim was to silence RORC2 by specific siRNAs in naïve T cells differentiating to Th17. Time-dependent expression of RORC2 as well as IL-17 and IL-23R were considered before and after RORC2 silencing. Materials and Methods: In this experimental study, naïve CD4+ T cells were isolated from human cord blood samples. Cytokines TGFβ plus IL-6 and IL-23 were used to polarize the naïve T cells to Th17 cells in X-VIVO 15 serum free medium. A mixture of three siRNAs specific for RORC2 was applied for blocking its expression. RORC2, IL-17 and IL-23R mRNA and protein levels were measured using qRT-PCR, ELISA and flow cytometry techniques. Pearson correlation and one-way ANOVA were used for statistical analyses. Results: Significant correlations were obtained in time-dependent analysis of IL-17 and IL-23R expression in relation with RORC2 (R=0.87 and 0.89 respectively, p<0.05. Silencing of RORC2 was accompanied with almost complete suppression of IL-17 (99.3%; p<0.05 and significant decrease in IL-23R gene expression (77.2%, p<0.05. Conclusion: Our results showed that RORC2 is the main and the primary trigger for upregulation of IL-17 and IL-23R genes in human Th17 cell differentiation. Moreover, we show that day 3 could be considered as the key day in the Th17 differentiation process.

  4. Imbalance of Th17 and Treg in peripheral blood mononuclear cells of active tuberculosis patients

    Directory of Open Access Journals (Sweden)

    Jie Luo

    Full Text Available Abstract Objective: Maintaining a right balance between Th17 and Treg might be critical to the immunopathogenesis of active tuberculosis (TB. This study aimed to assess whether the Th17/Treg balance is altered in active TB patients. Methods: 250 study subjects (90 active TB patients, 80 latent TB subjects, and 80 healthy controls were recruited for the study. The expression of Th17 and Treg in peripheral blood mononuclear cells (PBMCs in the 250 subjects was investigated by flow cytometry. Plasma levels of cytokines IL-17 and IL-10, which are related to Th17 and Treg, respectively, were determined by ELISA. Results: The percentages of Th17 and Treg in PBMCs from active TB patients were significantly higher than those from latent TB or control groups (Th17: 4.31 ± 1.35% vs. 1.58 ± 0.71% or 1.15 ± 0.49%, p < 0.05; Treg: 11.44 ± 2.69% vs. 7.54 ± 1.56% or 4.10 ± 0.99%, p < 0.05. The expression of IL-17 and IL-10 was significantly increased in active TB patients in comparison to that in latent TB or control groups (IL-17: 16.85 ± 9.68 vs. 7.23 ± 5.19 or 8.21 ± 5.51 pg/mL, p < 0.05; IL-10: 28.70 ± 11.27 vs. 20.25 ± 8.57 or 13.94 ± 9.00 pg/mL, p < 0.05. Conclusions: Our study demonstrated an altered balance of Treg/Th17 in active TB patients, with higher percentages of Th17 and Treg in PBMCs. Further research on this imbalance may offer a new direction for TB treatment.

  5. Intranasal delivery of cholera toxin induces th17-dominated T-cell response to bystander antigens.

    Directory of Open Access Journals (Sweden)

    Jee-Boong Lee

    Full Text Available Cholera toxin (CT is a potent vaccine adjuvant, which promotes mucosal immunity to protein antigen given by nasal route. It has been suggested that CT promotes T helper type 2 (Th2 response and suppresses Th1 response. We here report the induction of Th17-dominated responses in mice by intranasal delivery of CT. This dramatic Th17-driving effect of CT, which was dependent on the B subunit, was observed even in Th1 or Th2-favored conditions of respiratory virus infection. These dominating Th17 responses resulted in the significant neutrophil accumulation in the lungs of mice given CT. Both in vitro and in vivo treatment of CT induced strongly augmented IL-6 production, and Th17-driving ability of CT was completely abolished in IL-6 knockout mice, indicating a role of this cytokine in the Th17-dominated T-cell responses by CT. These data demonstrate a novel Th17-driving activity of CT, and help understand the mechanisms of CT adjuvanticity to demarcate T helper responses.

  6. Imbalance Between Th17 Cells and Regulatory T Cells During Monophasic Experimental Autoimmune Uveitis.

    Science.gov (United States)

    Zhang, Lian; Wan, Fangzhu; Song, Jike; Tang, Kai; Zheng, Fengming; Guo, Junguo; Guo, Dadong; Bi, Hongsheng

    2016-02-01

    The aim of this study is to explore the dynamic changes in IL-17-expressing T cells (Th17)/Treg expression in monophasic experimental autoimmune uveitis (mEAU). mEAU was induced in Lewis rats with IRBP1177-1191 peptide and evaluated clinically and pathologically on days 9, 13, 18, 23, 28, 35, and 48. Lymphocytes isolated from inguinal lymph nodes were subjected to flow cytometry to analyze the frequency of Th17/Treg cells. The levels of cytokines (IL-17, IL-6, IL-10, transforming growth factor (TGF)-β) in serum were detected by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative PCR (RT-PCR) was used for measuring the levels of IL-17, IL-6, TGF-β, and Foxp3. Clinical and histopathologic assessment showed that mEAU began on day 9, peaked on day 13, and decreased to normal on day 18. The frequency of Th17 cells increased obviously on day 9, peaking on day 13, while the frequency of Treg cells increased on day 13, peaked on day 18, and remained at a high level until day 48. In the serum, the levels of IL-17 and IL-6 peaked on day 9 and gradually decreased to normal on day 28. The level of TGF-β increased on day 9, peaked on day 13, and decreased to normal on day 35. Meanwhile, the level of IL-10 increased on day 9 and stayed at a high level until day 48. Additionally, the above results were further confirmed by RT-PCR. The imbalance between Th17 and Treg cells contributes to the onset and progression of mEAU, and a compartmental imbalance of Treg over Th17 exists in the recovery phase of mEAU.

  7. CD69 Association with Jak3/Stat5 Proteins Regulates Th17 Cell Differentiation ▿

    OpenAIRE

    Martín, Pilar; Gómez, Manuel; Lamana, Amalia; Cruz-Adalia, Arantxa; Ramírez-Huesca, Marta; Ursa, María Ángeles; Yáñez-Mo, María; Sánchez-Madrid, Francisco

    2010-01-01

    T-cell differentiation involves the early decision to commit to a particular pattern of response to an antigen. Here, we show that the leukocyte activation antigen CD69 limits differentiation into proinflammatory helper T cells (Th17 cells). Upon antigen stimulation in vitro, CD4+ T cells from CD69-deficient mice generate an expansion of Th17 cells and the induction of greater mRNA expression of interleukin 17 (IL-17), IL 23 receptor (IL-23R), and the nuclear receptor retinoic acid-related or...

  8. CTLA4 blockade increases Th17 cells in patients with metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Comin-Anduix Begonya

    2009-05-01

    Full Text Available Abstract Background Th17 cells are CD4+ cells that produce interleukin 17 (IL-17 and are potent inducers of tissue inflammation and autoimmunity. We studied the levels of this T cell subset in peripheral blood of patients treated with the anti-CTLA4 antibody tremelimumab since its major dose limiting toxicities are inflammatory and autoimmune in nature. Methods Peripheral blood mononuclear cells (PBMC were collected before and after receiving tremelimumab within two clinical trials, one with tremelimumab alone (21 patients and another together with autologous dendritic cells (DC pulsed with the melanoma epitope MART-126–35 (6 patients. Cytokines were quantified directly in plasma from patients and after in vitro stimulation of PBMC. We also quantified IL-17 cytokine-producing cells by intracellular cytokine staining (ICS. Results There were no significant changes in 13 assayed cytokines, including IL-17, when analyzing plasma samples obtained from patients before and after administration of tremelimumab. However, when PBMC were activated in vitro, IL-17 cytokine in cell culture supernatant and Th17 cells, detected as IL-17-producing CD4 cells by ICS, significantly increased in post-dosing samples. There were no differences in the levels of Th17 cells between patients with or without an objective tumor response, but samples from patients with inflammatory and autoimmune toxicities during the first cycle of therapy had a significant increase in Th17 cells. Conclusion The anti-CTLA4 blocking antibody tremelimumab increases Th17 cells in peripheral blood of patients with metastatic melanoma. The relation between increases in Th17 cells and severe autoimmune toxicity after CTLA4 blockade may provide insights into the pathogenesis of anti-CTLA4-induced toxicities. Trial Registration Clinical trial registration numbers: NCT0090896 and NCT00471887

  9. Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells.

    Science.gov (United States)

    Abimannan, Thiruvaimozhi; Peroumal, Doureradjou; Parida, Jyoti R; Barik, Prakash K; Padhan, Prasanta; Devadas, Satish

    2016-10-01

    Reactive oxygen species (ROS) signaling is critical in T helper (Th) cell differentiation; however its role in differentiated Th cell functions is unclear. In this study, we investigated the role of oxidative stress on the effector functions of in vitro differentiated mouse Th17 and Th1 cells or CD4(+) T cells from patients with Rheumatoid Arthritis using pro-oxidants plumbagin (PB) and hydrogen peroxide. We found that in mouse Th cells, non-toxic concentration of pro-oxidants inhibited reactivation induced expression of IL-17A in Th17 and IFN-γ in Th1 cells by reducing the expression of their respective TFs, RORγt and T-bet. Interestingly, in both the subsets, PB increased the expression of IL-4 by enhancing reactivation induced ERK1/2 phosphorylation. We further investigated the cytokine modulatory effect of PB on CD4(+) T cells isolated from PBMCs of patients with Rheumatoid Arthritis, a well-known Th17 and or Th1 mediated disease. In human CD4(+) T cells from Rheumatoid Arthritis patients, PB reduced the frequencies of IL-17A(+) (Th17), IFN(-)γ(+) (Th1) and IL-17A(+)/IFN(-)γ(+) (Th17/1) cells and also inhibited the production of pro-inflammatory cytokines TNF-α and IL-6. N-Acetyl Cysteine (NAC) an antioxidant completely reversed PB mediated cytokine modulatory effects in both mouse and human cells indicating a direct role for ROS. Together our data suggest that oxidative microenvironment can alter cytokine response of terminally differentiated cells and thus altering intracellular ROS could be a potential way to target Th17 and Th1 cells in autoimmune disorders.

  10. Increased Th17 cells and IL‑17 in rats with traumatic optic neuropathy.

    Science.gov (United States)

    Zheng, Huabin; Zhang, Zhuhong; Luo, Na; Liu, Yuanyuan; Chen, Qingzhong; Yan, Hua

    2014-10-01

    T helper 17 (Th17) cells are strong inducers of numerous autoimmune diseases and inflammation. However, the role of Th17 cells and interleukin (IL)‑17 in traumatic optic neuropathy (TON) are yet to be elucidated. In the present study, a rat model of TON was established using a fluid percussion brain injury device. Th17 cells were found to be upregulated in the spleens of rats in the TON group. In addition, the level of IL‑17 in the retina of rats in the TON group was observed to increase with the upregulation of the Th17 cells. Furthermore, the expression of IL‑17 in the optic nerve was found to be upregulated between one and seven days following injury in the rats in the TON group. These findings strongly suggest that the ratio of Th17 cells and the expression of IL‑17 are upregulated in rats with TON. These findings also provide a rationale for developing therapeutic agents to treat TON.

  11. CD43 Functions as an E-Selectin Ligand for Th17 Cells In Vitro and Is Required for Rolling on the Vascular Endothelium and Th17 Cell Recruitment during Inflammation In Vivo.

    Science.gov (United States)

    Velázquez, Francisco; Grodecki-Pena, Anna; Knapp, Andrew; Salvador, Ane M; Nevers, Tania; Croce, Kevin J; Alcaide, Pilar

    2016-02-01

    Endothelial E- and P-selectins mediate lymphocyte trafficking in inflammatory processes by interacting with lymphocyte selectin ligands. These are differentially expressed among different T cell subsets and function alone or in cooperation to mediate T cell adhesion. In this study, we characterize the expression and functionality of E-selectin ligands in Th type 17 lymphocytes (Th17 cells) and report that CD43 functions as a Th17 cell E-selectin ligand in vitro that mediates Th17 cell rolling on the vascular endothelium and recruitment in vivo. We demonstrate Th17 cells express CD44, P-selectin glycoprotein ligand (PSGL)-1, and CD43. Few PSGL-1(-/-)CD43(-/-) Th17 cells accumulated on E-selectin under shear flow conditions compared with wild-type cells. CD43(-/-) Th17 cell accumulation on E-selectin was impaired as compared with wild-type and PSGL-1(-/-), and similar to that observed for PSGL-1(-/-)CD43(-/-) Th17 cells, indicating that CD43 alone is a dominant ligand for E-selectin. Notably, this finding is Th17 cell subset specific because CD43 requires cooperation with PSGL-1 in Th1 cells for binding to E-selectin. In vivo, Th17 cell recruitment into the air pouch was reduced in CD43(-/-) mice in response to CCL20 or TNF-α, and intravital microscopy studies demonstrated that CD43(-/-) Th17 cells had impaired rolling on TNF-α-treated microvessels. Furthermore, CD43(-/-) mice were protected from experimental autoimmune encephalomyelitis and had impaired recruitment of Th17 cells in the spinal cord. Our findings demonstrate that CD43 is a major E-selectin ligand in Th17 cells that functions independent of PSGL-1, and they suggest that CD43 may hold promise as a therapeutic target to modulate Th17 cell recruitment.

  12. Th17 Cells Pathways in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders: Pathophysiological and Therapeutic Implications.

    Science.gov (United States)

    Dos Passos, Giordani Rodrigues; Sato, Douglas Kazutoshi; Becker, Jefferson; Fujihara, Kazuo

    2016-01-01

    Several animal and human studies have implicated CD4+ T helper 17 (Th17) cells and their downstream pathways in the pathogenesis of central nervous system (CNS) autoimmunity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), challenging the traditional Th1-Th2 paradigm. Th17 cells can efficiently cross the blood-brain barrier using alternate ways from Th1 cells, promote its disruption, and induce the activation of other inflammatory cells in the CNS. A number of environmental factors modulate the activity of Th17 pathways, so changes in the diet, exposure to infections, and other environmental factors can potentially change the risk of development of autoimmunity. Currently, new drugs targeting specific points of the Th17 pathways are already being tested in clinical trials and provide basis for the development of biomarkers to monitor disease activity. Herein, we review the key findings supporting the relevance of the Th17 pathways in the pathogenesis of MS and NMOSD, as well as their potential role as therapeutic targets in the treatment of immune-mediated CNS disorders.

  13. Th17 Cells Pathways in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders: Pathophysiological and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Giordani Rodrigues Dos Passos

    2016-01-01

    Full Text Available Several animal and human studies have implicated CD4+ T helper 17 (Th17 cells and their downstream pathways in the pathogenesis of central nervous system (CNS autoimmunity in multiple sclerosis (MS and neuromyelitis optica spectrum disorders (NMOSD, challenging the traditional Th1-Th2 paradigm. Th17 cells can efficiently cross the blood-brain barrier using alternate ways from Th1 cells, promote its disruption, and induce the activation of other inflammatory cells in the CNS. A number of environmental factors modulate the activity of Th17 pathways, so changes in the diet, exposure to infections, and other environmental factors can potentially change the risk of development of autoimmunity. Currently, new drugs targeting specific points of the Th17 pathways are already being tested in clinical trials and provide basis for the development of biomarkers to monitor disease activity. Herein, we review the key findings supporting the relevance of the Th17 pathways in the pathogenesis of MS and NMOSD, as well as their potential role as therapeutic targets in the treatment of immune-mediated CNS disorders.

  14. Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A.

    Science.gov (United States)

    Schewitz-Bowers, Lauren P; Lait, Philippa J P; Copland, David A; Chen, Ping; Wu, Wenting; Dhanda, Ashwin D; Vistica, Barbara P; Williams, Emily L; Liu, Baoying; Jawad, Shayma; Li, Zhiyu; Tucker, William; Hirani, Sima; Wakabayashi, Yoshiyuki; Zhu, Jun; Sen, Nida; Conway-Campbell, Becky L; Gery, Igal; Dick, Andrew D; Wei, Lai; Nussenblatt, Robert B; Lee, Richard W J

    2015-03-31

    Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients' glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual's disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

  15. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids.

    Science.gov (United States)

    Ramesh, Radha; Kozhaya, Lina; McKevitt, Kelly; Djuretic, Ivana M; Carlson, Thaddeus J; Quintero, Maria A; McCauley, Jacob L; Abreu, Maria T; Unutmaz, Derya; Sundrud, Mark S

    2014-01-13

    IL-17A-expressing CD4(+) T cells (Th17 cells) are generally regarded as key effectors of autoimmune inflammation. However, not all Th17 cells are pro-inflammatory. Pathogenic Th17 cells that induce autoimmunity in mice are distinguished from nonpathogenic Th17 cells by a unique transcriptional signature, including high Il23r expression, and these cells require Il23r for their inflammatory function. In contrast, defining features of human pro-inflammatory Th17 cells are unknown. We show that pro-inflammatory human Th17 cells are restricted to a subset of CCR6(+)CXCR3(hi)CCR4(lo)CCR10(-)CD161(+) cells that transiently express c-Kit and stably express P-glycoprotein (P-gp)/multi-drug resistance type 1 (MDR1). In contrast to MDR1(-) Th1 or Th17 cells, MDR1(+) Th17 cells produce both Th17 (IL-17A, IL-17F, and IL-22) and Th1 (IFN-γ) cytokines upon TCR stimulation and do not express IL-10 or other anti-inflammatory molecules. These cells also display a transcriptional signature akin to pathogenic mouse Th17 cells and show heightened functional responses to IL-23 stimulation. In vivo, MDR1(+) Th17 cells are enriched and activated in the gut of Crohn's disease patients. Furthermore, MDR1(+) Th17 cells are refractory to several glucocorticoids used to treat clinical autoimmune disease. Thus, MDR1(+) Th17 cells may be important mediators of chronic inflammation, particularly in clinical settings of steroid resistant inflammatory disease.

  16. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis.

    Science.gov (United States)

    Harbour, Stacey N; Maynard, Craig L; Zindl, Carlene L; Schoeb, Trenton R; Weaver, Casey T

    2015-06-02

    Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such that some progeny of Th17 cell precursors retain a predominantly IL-17A(+) phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-γ, giving rise to "Th1-like" cells. It remains unclear what role these subsets play in inflammatory bowel disease. Using a Th17 transfer model of colitis, we found that IFN-γ-deficient Th17 cells retained an IL-17A(+) phenotype and were unable to induce colitis in recipients. Development of disease required the transition of a subset of Th17 precursors to Th1-like cells and was contingent on the expression of both Stat4 and T-bet, but not the IL-12 or IFN-γ receptors. Moreover, Th17 cells could provide "help" for the development of pathogenic Th1 cells from naïve precursors. These results indicate that Th17 cells are potent mediators of colitis pathogenesis by dual mechanisms: by directly transitioning to Th1-like cells and by supporting the development of classic Th1 cells.

  17. Decreased IL-27 Negatively Correlated with Th17 Cells in Non-Small-Cell Lung Cancer Patients.

    Science.gov (United States)

    Duan, Minchao; Ning, Zhengqing; Fu, Zhijun; Zhang, Jianquan; Liu, Guangnan; Wei, Qiu; Zheng, Xiaoyu

    2015-01-01

    The presence of Th17 cells and IL-27 is observed in a variety of inflammatory associated cancers. However, there are some data on the role of Th17 cells and IL-27 in the regulation of immune reactions in non-small-cell lung cancer (NSCLC). The aim of this study is to assess the variation of Th17 cells and IL-27 in the peripheral blood (PB) of patients with NSCLC. The proportion of Th17 cells in peripheral blood mononuclear cells (PBMCs) was evaluated by flow cytometry. The serum concentrations of IL-27 and IL-17 were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of RORγt and IL-27 in the peripheral blood was examined by real-time quantitative polymerase chain reaction (QPCR). Expression of IL-27 was lower in NSCLC patients compared with normal controls. The frequency of Th17 cells was increased in NSCLC patients, accompanied by the upregulation of IL-17 and RORγt. IL-27 negatively correlated with the number of Th17 cells and the RORγt mRNA. Our results indicate that IL-27 might inhibit Th17 differentiation in NSCLC patients and better understanding of the regulatory effects of IL-27 on Th17 cells may shed light on potential new targets in cancer prevention and therapy.

  18. Monocyte-induced development of Th17 cells and the release of S100 proteins are involved in the pathogenesis of graft-versus-host disease.

    Science.gov (United States)

    Reinhardt, Katharina; Foell, Dirk; Vogl, Thomas; Mezger, Markus; Wittkowski, Helmut; Fend, Falko; Federmann, Birgit; Gille, Christian; Feuchtinger, Tobias; Lang, Peter; Handgretinger, Rupert; Andreas Bethge, Wolfgang; Holzer, Ursula

    2014-10-01

    Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. However, the pathophysiology of GvHD remains poorly understood. In this study, we analyzed the induction of Th17 cells by monocytes of patients with GvHD in vitro, demonstrating that monocytes isolated from patients with acute skin and intestinal GvHD stage I-IV and chronic GvHD induce significantly increased levels of Th17 cells compared with patients without GvHD. S100 proteins are known to act as innate amplifier of inflammation. We therefore investigated the presence of S100 proteins in the stool, serum, and bowel tissue of patients with GvHD and the influence of S100 proteins on the induction of Th17 cells. Elevated levels of S100 proteins could be detected in patients with acute GvHD, demonstrating the release of these phagocyte-specific proteins during GvHD. Furthermore, stimulation of monocytes with S100 proteins was found to promote Th17 development, emphasizing the role of S100 proteins in Th17-triggered inflammation. Altogether, our results indicate that induction of Th17 cells by activated monocytes and the stimulatory effects of proinflammatory S100 proteins might play a relevant role in the pathogenesis of acute GvHD. Regarding our data, S100 proteins might be novel markers for the diagnosis and follow-up of GvHD.

  19. Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1

    Directory of Open Access Journals (Sweden)

    Yusuke Endo

    2015-08-01

    Full Text Available Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORγt to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO+CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORγt through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells.

  20. Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis.

    Science.gov (United States)

    Kulcsar, Kirsten A; Baxter, Victoria K; Greene, Ivorlyne P; Griffin, Diane E

    2014-11-11

    Mosquito-borne alphaviruses are important causes of epidemic encephalomyelitis. Neuronal cell death during fatal alphavirus encephalomyelitis is immune-mediated; however, the types of cells involved and their regulation have not been determined. We show that the virus-induced inflammatory response was accompanied by production of the regulatory cytokine IL-10, and in the absence of IL-10, paralytic disease occurred earlier and mice died faster. To determine the reason for accelerated disease in the absence of IL-10, immune responses in the CNS of IL-10(-/-) and wild-type (WT) mice were compared. There were no differences in the amounts of brain inflammation or peak virus replication; however, IL-10(-/-) animals had accelerated and increased infiltration of CD4(+)IL-17A(+) and CD4(+)IL-17A(+)IFNγ(+) cells compared with WT animals. Th17 cells infiltrating the brain demonstrated a pathogenic phenotype with the expression of the transcription factor, Tbet, and the production of granzyme B, IL-22, and GM-CSF, with greater production of GM-CSF in IL-10(-/-) mice. Therefore, in fatal alphavirus encephalomyelitis, pathogenic Th17 cells enter the CNS at the onset of neurologic disease and, in the absence of IL-10, appear earlier, develop into Th1/Th17 cells more often, and have greater production of GM-CSF. This study demonstrates a role for pathogenic Th17 cells in fatal viral encephalitis.

  1. Better safe than sorry: TOB1 employs multiple parallel regulatory pathways to keep Th17 cells quiet.

    Science.gov (United States)

    Salerno, Fiamma; van Lier, René A W; Wolkers, Monika C

    2014-03-01

    Th17 cells are key players in antibacterial and antifungal immunity, but have also been implicated in autoimmunity. Interestingly, Th17 cells poorly proliferate upon stimulation, a phenotype that was attributed to a decreased sensitivity to T-cell receptor (TCR) stimulation, and to low IL-2 production by Th17 cells. In this issue of the European Journal of Immunology, Santarlasci et al. [Eur. J. Immunol. 2014. 44: 654-661] shed further light on the molecular mechanism that keeps Th17 cells at bay. They identify the transcriptional regulator TOB1, which not only impairs IL-2 production in Th17 cells, but also blocks the expression of cell cycle genes. Strikingly, TOB1 suppresses Th17-cell proliferation through several pathways, including impaired signal transduction, transcription, and possibly also post-transcriptional regulation.

  2. The emerging role of aryl hydrocarbon receptor in the activation and differentiation of Th17 cells.

    Science.gov (United States)

    Baricza, Eszter; Tamási, Viola; Marton, Nikolett; Buzás, Edit I; Nagy, György

    2016-01-01

    The aryl hydrocarbon receptor (AHR) is a cytoplasmic transcription factor, which plays an essential role in the xenobiotic metabolism in a wide variety of cells. The AHR gene is evolutionarily conserved and it has a central role not only in the differentiation and maturation of many tissues, but also in the toxicological metabolism of the cell by the activation of metabolizing enzymes. Several lines of evidence support that both AHR agonists and antagonists have profound immunological effects; and recently, the AHR has been implicated in antibacterial host defense. According to recent studies, the AHR is essential for the differentiation and activation of T helper 17 (Th17) cells. It is well known that Th17 cells have a central role in the development of inflammation, which is crucial in the defense against pathogens. In addition, Th17 cells play a major role in the pathogenesis of several autoimmune diseases such as rheumatoid arthritis. Therefore, the AHR may provide connection between the environmental chemicals, the immune regulation, and autoimmunity. In the present review, we summarize the role of the AHR in the Th17 cell functions.

  3. RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells.

    Science.gov (United States)

    Park, Tae-Yoon; Park, Sung-Dong; Cho, Jen-Young; Moon, Jae-Seung; Kim, Na-Yeon; Park, Kyungsoo; Seong, Rho Hyun; Lee, Sang-Won; Morio, Tomohiro; Bothwell, Alfred L M; Lee, Sang-Kyou

    2014-12-30

    The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to TH17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of RORγt using cell-transducible form of transcription modulation domain of RORγt (tRORγt-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tRORγt-TMD specifically inhibited TH17-related cytokines induced by RORγt, thereby suppressing the differentiation of naïve T cells into TH17, but not into TH1, TH2, or Treg cells. tRORγt-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4(+) T cells and spinal cord-infiltrating CD4(+) T cells, and suppress the functions of TH17 cells. The clinical severity and incidence of EAE were ameliorated by tRORγt-TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4(+) IL-17(+) T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tRORγt-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking TH1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tRORγt-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with TH17 or TH1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.

  4. Enhanced Th17-cell responses render CCR2-deficient mice more susceptible for autoimmune arthritis.

    Directory of Open Access Journals (Sweden)

    Rishi R Rampersad

    Full Text Available CCR2 is considered a proinflammatory mediator in many inflammatory diseases such as rheumatoid arthritis. However, mice lacking CCR2 develop exacerbated collagen-induced arthritis. To explore the underlying mechanism, we investigated whether autoimmune-associated Th17 cells were involved in the pathogenesis of the severe phenotype of autoimmune arthritis. We found that Th17 cells were expanded approximately 3-fold in the draining lymph nodes of immunized CCR2(-/- mice compared to WT controls (p = 0.017, whereas the number of Th1 cells and regulatory T cells are similar between these two groups of mice. Consistently, levels of the Th17 cell cytokine IL-17A and Th17 cell-associated cytokines, IL-6 and IL-1β were approximately 2-6-fold elevated in the serum and 22-28-fold increased in the arthritic joints in CCR2(-/- mice compared to WT mice (p = 0.04, 0.0004, and 0.01 for IL-17, IL-6, and IL-1β, respectively, in the serum and p = 0.009, 0.02, and 0.02 in the joints. Furthermore, type II collagen-specific antibodies were significantly increased, which was accompanied by B cell and neutrophil expansion in CCR2(-/- mice. Finally, treatment with an anti-IL-17A antibody modestly reduced the disease severity in CCR2(-/- mice. Therefore, we conclude that while we detect markedly enhanced Th17-cell responses in collagen-induced arthritis in CCR2-deficient mice and IL-17A blockade does have an ameliorating effect, factors additional to Th17 cells and IL-17A also contribute to the severe autoimmune arthritis seen in CCR2 deficiency. CCR2 may have a protective role in the pathogenesis of autoimmune arthritis. Our data that monocytes were missing from the spleen while remained abundant in the bone marrow and joints of immunized CCR2(-/- mice suggest that there is a potential link between CCR2-expressing monocytes and Th17 cells during autoimmunity.

  5. CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells.

    Science.gov (United States)

    Kara, Ervin E; McKenzie, Duncan R; Bastow, Cameron R; Gregor, Carly E; Fenix, Kevin A; Ogunniyi, Abiodun D; Paton, James C; Mack, Matthias; Pombal, Diana R; Seillet, Cyrill; Dubois, Bénédicte; Liston, Adrian; MacDonald, Kelli P A; Belz, Gabrielle T; Smyth, Mark J; Hill, Geoffrey R; Comerford, Iain; McColl, Shaun R

    2015-10-29

    IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(-)CCR2(+)) of GM-CSF/IFNγ-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNγ/TNFα/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFNγ-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNγ-producing Th17 cells.

  6. The role and modulation of CCR6+ Th17 cell populations in rheumatoid arthritis.

    Science.gov (United States)

    Paulissen, Sandra M J; van Hamburg, Jan Piet; Dankers, Wendy; Lubberts, Erik

    2015-07-01

    The IL-17A producing T-helper-17 (Th17) cell population plays a major role in rheumatoid arthritis (RA) pathogenesis and has gained wide interest as treatment target. IL-17A expressing Th cells are characterized by the expression of the chemokine receptor CCR6 and the transcription factor RORC. In RA, CCR6+ Th cells were identified in peripheral blood, synovial fluid and inflamed synovial tissue. CCR6+ Th cells might drive the progression of an early inflammation towards a persistent arthritis. The CCR6+ Th cell population is heterogeneous and several subpopulations can be distinguished, including Th17, Th22, Th17.1 (also called non-classic Th1 cells), and unclassified or intermediate populations. Interestingly, some of these populations produce low levels of IL-17A but are still very pathogenic. Furthermore, the CCR6+ Th cells phenotype is unstable and plasticity exists between CCR6+ Th cells and T-regulatory (Treg) cells and within the CCR6+ Th cell subpopulations. In this review, characteristics of the different CCR6+ Th cell populations, their plasticity, and their potential impact on rheumatoid arthritis are discussed. Moreover, current approaches to target CCR6+ Th cells and future directions of research to find specific CCR6+ Th cell targets in the treatment of patients with RA and other CCR6+ Th cell mediated autoimmune diseases are highlighted.

  7. Distribution of Th17 cells and Th1 cells in peripheral blood and cerebrospinal fluid in chronic inflammatory demyelinating polyradiculoneuropathy.

    Science.gov (United States)

    Chi, Li Jun; Xu, Wan Hai; Zhang, Zong Wen; Huang, Hui Tao; Zhang, Li Ming; Zhou, Jin

    2010-12-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated demyelinating disease of the peripheral nervous system. Th17 and Th1 cells contribute to the pathogenesis of most autoimmune diseases, but little is known about their distribution and reciprocal relationship in CIDP. In this study, we analyzed the distribution of Th17, Th1, and Th17/Th1 cells in the peripheral blood and cerebrospinal fluid (CSF). The results showed that the frequency of Th17 cells was significantly higher in the peripheral blood mononuclear cell (PBMCs) and CSF of active CIDP in comparison with remitting CIDP or to other non-inflammatory neurological diseases (ONDs), accompanied by similar findings for Th17/Th1 cells. Both active and remitting CIDP have higher percentage of Th1 cells in the CSF than OND. CSF protein levels positively correlated with the frequencies of Th17 cells either in the PBMCs or CSF of active CIDP, while there was no significant correlation with Th1 cells. In line with these observations, the levels of interleukin-17 (IL-17) in plasma and transcript factors retinoic acid receptor-related orphan receptor (ROR)γt expressed by PBMCs were significantly higher in the active CIDP than remitting CIDP or OND. In summary, our preliminary findings suggest that elevated numbers of inflammatory T cells, especially for Th17 cells, might be an important determinant in the evolution of CIDP.

  8. The IL-17 and Th17 cell immune response in cervical cancer : angels or demons : it depends on the context

    NARCIS (Netherlands)

    Punt, Birgitte Simone

    2015-01-01

    This thesis provides novel insights into the role of IL-17 and Th17 cells in cervical cancer. While IL-17 was shown to be predominantly produced by innate myeloid cells such as neutrophils and correlated with poor survival, Th17 cells were generally a small cell population correlated with improved s

  9. The IL-17 and Th17 cell immune response in cervical cancer : angels or demons : it depends on the context

    NARCIS (Netherlands)

    Punt, Birgitte Simone

    2015-01-01

    This thesis provides novel insights into the role of IL-17 and Th17 cells in cervical cancer. While IL-17 was shown to be predominantly produced by innate myeloid cells such as neutrophils and correlated with poor survival, Th17 cells were generally a small cell population correlated with improved

  10. STAT3 activation in Th17 and Th22 cells controls IL-22-mediated epithelial host defense during infectious colitis.

    Science.gov (United States)

    Backert, Ingo; Koralov, Sergei B; Wirtz, Stefan; Kitowski, Vera; Billmeier, Ulrike; Martini, Eva; Hofmann, Katharina; Hildner, Kai; Wittkopf, Nadine; Brecht, Katrin; Waldner, Maximilian; Rajewsky, Klaus; Neurath, Markus F; Becker, Christoph; Neufert, Clemens

    2014-10-01

    The Citrobacter rodentium model mimics the pathogenesis of infectious colitis and requires sequential contributions from different immune cell populations, including innate lymphoid cells (ILCs) and CD4(+) lymphocytes. In this study, we addressed the role of STAT3 activation in CD4(+) cells during host defense in mice against C. rodentium. In mice with defective STAT3 in CD4(+) cells (Stat3(ΔCD4)), the course of infection was unchanged during the innate lymphoid cell-dependent early phase, but significantly altered during the lymphocyte-dependent later phase. Stat3(ΔCD4) mice exhibited intestinal epithelial barrier defects, including downregulation of antimicrobial peptides, increased systemic distribution of bacteria, and prolonged reduction in the overall burden of C. rodentium infection. Immunomonitoring of lamina propria cells revealed loss of virtually all IL-22-producing CD4(+) lymphocytes, suggesting that STAT3 activation was required for IL-22 production not only in Th17 cells, but also in Th22 cells. Notably, the defective host defense against C. rodentium in Stat3(∆CD4) mice could be fully restored by specific overexpression of IL-22 through a minicircle vector-based technology. Moreover, expression of a constitutive active STAT3 in CD4(+) cells shaped strong intestinal epithelial barrier function in vitro and in vivo through IL-22, and it promoted protection from enteropathogenic bacteria. Thus, our work indicates a critical role of STAT3 activation in Th17 and Th22 cells for control of the IL-22-mediated host defense, and strategies expanding STAT3-activated CD4(+) lymphocytes may be considered as future therapeutic options for improving intestinal barrier function in infectious colitis.

  11. A role for Th17 cells in the immunopathogenesis of atopic dermatitis?

    Science.gov (United States)

    Di Cesare, Antonella; Di Meglio, Paola; Nestle, Frank O

    2008-11-01

    Atopic dermatitis (AD) is a common inflammatory skin disease. Both epidermal barrier dysfunction and immunodysregulation are suggested to influence the pathogenesis of AD. AD has been considered a paradigmatic T helper cell (Th) 2-mediated disease, with a switch to a Th1 cell environment during the chronic phase of the disease. Previously unreported findings now suggest a possible role for Th17 cells as well.

  12. TH17 cells are increased in the peripheral blood of patients with SAPHO syndrome.

    Science.gov (United States)

    Firinu, Davide; Barca, Maria Pina; Lorrai, Maria Maddalena; Perra, Silvia; Cabras, Stefano; Muggianu, Emma; Di Martino, Maria Luisa; Manconi, Paolo Emilio; Del Giacco, Stefano R

    2014-09-01

    To assess whether the immune derangement previously observed in SAPHO syndrome could be linked to variations in blood TH1, TH2 or TH17 lymphocytes frequency. Seven SAPHO patients with a protracted course of the disease were studied ex-vivo for intracellular cytokines production by means of flow-cytometry and compared with matched groups of Psoriatic Arthritis patients and healthy controls. The Kruskal-Wallis test on the median of the three categories showed that there is a significant association between the TH17 levels and the category (p value = 0.02474). The mean and variance for the proportion of IL-17 producing CD4+ cells were compared between groups showing significant differences between SAPHO versus PsA subgroup (p = 0.05) and SAPHO versus healthy controls (p = 0.008). Interestingly, activation of TH17 axis, but not of TH1 and TH2, has been found, and can be observed both in patients with different activity of the disease or treated with different drugs. The TH17 increase in peripheral blood of our SAPHO subjects resembles the one recently found in patients with different AIDs. Novel therapeutic options in these patients may therefore include IL-17 blockade.

  13. Reciprocity between Regulatory T Cells and Th17 Cells: Relevance to Polarized Immunity in Leprosy.

    Science.gov (United States)

    Sadhu, Soumi; Khaitan, Binod Kumar; Joshi, Beenu; Sengupta, Utpal; Nautiyal, Arvind Kumar; Mitra, Dipendra Kumar

    2016-01-01

    T cell defect is a common feature in lepromatous or borderline lepromatous leprosy (LL/BL) patients in contrast to tuberculoid or borderline tuberculoid type (TT/BT) patients. Tuberculoid leprosy is characterized by strong Th1-type cell response with localized lesions whereas lepromatous leprosy is hallmarked by its selective Mycobacterium leprae specific T cell anergy leading to disseminated and progressive disease. FoxP3+ Regulatory T cells (Treg) which are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases also dampen proinflammatory T cells that include T helper 17 (Th17) cells. This study is aimed at evaluating the role of Treg cells in influencing other effector T cells and its relationship with the cytokine polarized state in leprosy patients. Peripheral blood mononuclear cells from of BT/TT (n = 15) and BL/LL (n = 15) patients were stimulated with M. leprae antigen (WCL) in presence of golgi transport inhibitor monensin for FACS based intracellular cytokine estimation. The frequency of Treg cells showed >5-fold increase in BL/LL in comparison to BT/TT and healthy contacts. These cells produced suppressive cytokine, IL-10 in BL/LL as opposed to BT/TT (p = 0.0200) indicating their suppressive function. The frequency of Th17 cells (CD4, CD45RO, IL-17) was, however, higher in BT/TT. Significant negative correlation (r = -0.68, P = 0.03) was also found between IL-10 of Treg cells and IL-17+ T cells in BL/LL. Blocking IL-10/TGF-β restored the IL-17+ T cells in BL/LL patients. Simultaneously, presence of Th17 related cytokines (TGF-β, IL-6, IL-17 and IL-23) decreased the number of FoxP3+ Treg cells concomitantly increasing IL-17 producing CD4+ cells in lepromatous leprosy. Higher frequency of Programmed Death-1/PD-1+ Treg cells and its ligand, PDL-1 in antigen presenting cells (APCs) was found in BL/LL patients. Inhibition of this pathway led to rescue of IFN-γ and IL-17 producing T cells

  14. Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis.

    Science.gov (United States)

    Neitzke, Daniel J; Bowers, Jacob S; Andrijauskaite, Kristina; O'Connell, Nathaniel S; Garrett-Mayer, Elizabeth; Wrangle, John; Li, Zihai; Paulos, Chrystal M; Cole, David J; Rubinstein, Mark P

    2017-03-09

    Adoptive cellular therapy (ACT) with the Th17 subset of CD4(+) T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets, including conventionally activated CD8(+) T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.

  15. Reducing CD73 expression by IL1β-Programmed Th17 cells improves immunotherapeutic control of tumors.

    Science.gov (United States)

    Chatterjee, Shilpak; Thyagarajan, Krishnamurthy; Kesarwani, Pravin; Song, Jin H; Soloshchenko, Myroslawa; Fu, Jianing; Bailey, Stefanie R; Vasu, Chenthamarkshan; Kraft, Andrew S; Paulos, Chrystal M; Yu, Xue-Zhong; Mehrotra, Shikhar

    2014-11-01

    T cells of the T helper (Th)17 subset offer promise in adoptive T-cell therapy for cancer. However, current protocols for ex vivo programming of Th17 cells, which include TGFβ exposure, increase the expression of CD39 and CD73, two cell surface ATP ectonucleotidases that reduce T-cell effector functions and promote immunosuppression. Here, we report that ATP-mediated suppression of IFNγ production by Th17 cells can be overcome by genetic ablation of CD73 or by using IL1β instead of TGFβ to program Th17 cells ex vivo. Th17 cells cultured in IL1β were also highly polyfunctional, expressing high levels of effector molecules and exhibiting superior short-term control of melanoma in mice, despite reduced stem cell-like properties. TGFβ addition at low doses that did not upregulate CD73 expression but induced stemness properties drastically improved the antitumor effects of IL1β-cultured Th17 cells. Effector properties of IL1β-dependent Th17 cells were likely related to their high glycolytic capacity, since ex vivo programming in pyruvate impaired glycolysis and antitumor effects. Overall, we show that including TGFβ in ex vivo cultures used to program Th17 cells blunts their immunotherapeutic potential and demonstrate how this potential can be more fully realized for adoptive T-cell therapy.

  16. Interleukin-10 Signaling in Regulatory T Cells Is Required for Suppression of Th17 Cell-Mediated Inflammation

    National Research Council Canada - National Science Library

    Chaudhry, Ashutosh; Samstein, Robert M; Treuting, Piper; Liang, Yuqiong; Pils, Marina C; Heinrich, Jan-Michael; Jack, Robert S; Wunderlich, F. Thomas; Brüning, Jens C; Müller, Werner; Rudensky, Alexander Y

    2011-01-01

    .... Here, we showed that anti-inflammatory interleukin-10 (IL-10), and not proinflammatory IL-6 and IL-23 cytokine signaling, endowed Treg cells with the ability to suppress pathogenic Th17 cell responses...

  17. Th1/Th17 Plasticity Is a Marker of Advanced β Cell Autoimmunity and Impaired Glucose Tolerance in Humans

    Science.gov (United States)

    Reinert-Hartwall, Linnea; Honkanen, Jarno; Salo, Harri M.; Nieminen, Janne K.; Luopajärvi, Kristiina; Härkönen, Taina; Veijola, Riitta; Simell, Olli; Ilonen, Jorma; Peet, Aleksandr; Tillmann, Vallo; Knip, Mikael; Knip, Mikael; Koski, Katriina; Koski, Matti; Härkönen, Taina; Ryhänen, Samppa; Hämäläinen, Anu-Maaria; Ormisson, Anne; Peet, Aleksandr; Tillmann, Vallo; Ulich, Valentina; Kuzmicheva, Elena; Mokurov, Sergei; Markova, Svetlana; Pylova, Svetlana; Isakova, Marina; Shakurova, Elena; Petrov, Vladimir; Dorshakova, Natalya V.; Karapetyan, Tatyana; Varlamova, Tatyana; Ilonen, Jorma; Kiviniemi, Minna; Alnek, Kristi; Janson, Helis; Uibo, Raivo; Salum, Tiit; von Mutius, Erika; Weber, Juliane; Ahlfors, Helena; Kallionpää, Henna; Laajala, Essi; Lahesmaa, Riitta; Lähdesmäki, Harri; Moulder, Robert; Nieminen, Janne; Ruohtula, Terhi; Vaarala, Outi; Honkanen, Hanna; Hyöty, Heikki; Kondrashova, Anita; Oikarinen, Sami; Harmsen, Hermie J. M.; De Goffau, Marcus C.; Welling, Gjalt; Alahuhta, Kirsi; Virtanen, Suvi M.

    2015-01-01

    Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions. PMID:25480564

  18. Mangiferin corrects the imbalance of Th17/Treg cells in mice with TNBS-induced colitis.

    Science.gov (United States)

    Lim, Su-Min; Jeong, Jin-Ju; Choi, Hyun Sik; Chang, Hwan Bong; Kim, Dong-Hyun

    2016-05-01

    In the previous study, 80% ethanol extract of the rhizome mixture of Anemarrhena asphodeloides and Coptidis chinensis (AC) and its main constituent mangiferin improved TNBS-induced colitis in mice by inhibiting macrophage activation related to the innate immunity. In the preliminary study, we found that AC could inhibit Th17 cell differentiation in mice with TNBS-induced colitis. Therefore, we investigated whether AC and it main constituent mangiferin are capable of inhibiting inflammation by regulating T cell differentiation related to the adaptive immunity in vitro and in vivo. AC and mangiferin potently suppressed colon shortening and myeloperoxidase activity in mice with TNBS-induced colitis. They also suppressed TNBS-induced Th17 cell differentiation and IL-17 expression, but increased TNBS-suppressed Treg cell differentiation and IL-10 expression. Moreover, AC and mangiferin strongly inhibited the expression of TNF-α and IL-17, as well as the activation of NF-κB. Furthermore, mangiferin potently inhibited the differentiation of splenocytes into Th7 cells and increased the differentiation into Treg cells in vitro. Mangiferin also inhibited RORγt and IL-17 expression and STAT3 activation in splenocytes and induced Foxp3 and IL-10 expression and STAT5 activation. Based on these findings, mangiferin may ameliorate colitis by the restoration of disturbed Th17/Treg cells and inhibition of macrophage activation.

  19. Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia.

    Science.gov (United States)

    Liu, Yong-Jun; Li, Kang; Yang, Li; Tang, Shao-Tao; Wang, Xin-Xing; Cao, Guo-Qing; Li, Shuai; Lei, Hai-Yan; Zhang, Xi

    2015-01-01

    Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells' suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

  20. The ratio of Treg/Th17 cells correlates with the disease activity of primary immune thrombocytopenia.

    Directory of Open Access Journals (Sweden)

    Lili Ji

    Full Text Available BACKGROUND: Primary immune thrombocytopenia (ITP is an autoimmune heterogeneous disorder that is characterized by decreased platelet count. Regulatory T (Treg cells and T helper type 17 (Th17 cells are two subtypes of CD4(+ T helper (Th cells. They play opposite roles in immune tolerance and autoimmune diseases, while they share a common differentiation pathway. The imbalance of Treg/Th17 has been demonstrated in several autoimmune diseases. In this study, we aimed to investigate the ratio of the number of Treg cells to the number of Th17 cells in ITP patients and evaluate the clinical implications of the alterations in this ratio. METHODS: Thirty adult patients with newly diagnosed ITP enrolled in this study. Twelve patients had been clinically followed up for 12 months. The percentages of CD4(+CD25(hiFoxp3(+ Treg cells and CD3(+CD4(+IL-17-producing Th17 cells in these patients and healthy controls (n = 17 were longitudinally analyzed by flow cytometry. RESULTS: The percentage of Treg cells in ITP patients was significantly lower than that of healthy controls, and the percentage of Th17 cells increased significantly at disease onset. The ratio of Treg/Th17 correlated with the disease activity. CONCLUSION: The ratio of Treg/Th17 might be relevant to the clinical diversity of ITP patients, and this Treg/Th17 ratio might have prognostic role in ITP patients.

  1. Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers

    Directory of Open Access Journals (Sweden)

    I. V. Lyadova

    2015-01-01

    Full Text Available The outcome of Mycobacterium tuberculosis (Mtb infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI to active tuberculosis (TB disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen “activity,” host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4+ T cells play critical role during Mtb infection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4+ T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-γ and activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells during Mtb infection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring.

  2. Paeoniflorin inhibits imiquimod-induced psoriasis in mice by regulating Th17 cell response and cytokine secretion.

    Science.gov (United States)

    Zhao, Jingxia; Di, Tingting; Wang, Yan; Wang, Ying; Liu, Xin; Liang, Daiying; Li, Ping

    2016-02-05

    Paeoniflorin (PF) is the main active ingredients of radix paeoniae rubra and radix paeoniae alba, which are used widely in Traditional Chinese Medicine. This study aimed to assess the capacity of PF to inhibit imiquimod (IMQ)-induced psoriasis. Mice treated with IMQ were divided into four groups and administered 240mg/kg/day or 120mg/kg/day of PF, 1mg/kg/day of methotrexate (MTX), or normal saline intragastrically. Weight-matched mice treated with vaseline were used as controls. Morphology, structural features, keratinocyte proliferation and differentiation, inflammatory cell infiltration, levels of Th1/Th2/Th17/Treg cytokine mRNA, and phosphorylation of Th17 differentiation-related proteins were assessed. Mouse spleen cells were incubated under Th17 polarizing conditions, then with PF (2, 20, and 200μg/ml) and cell viability, Th17 differentiation, and Th17 cytokines and the orphan nuclear receptor (RORγt) mRNA levels were assessed. PF alleviated IMQ-induced keratinocyte proliferation and inflammatory cell infiltration, and reduced mRNA levels of Th17 cytokines at day 4 and phosphorylation of Th17 differentiation-related proteins. However, 2, 20, or 200μg/ml PF did not affect spleen cell viability, and 2 and 20μg/ml PF reduced IL-17 secretion under Th17 polarizing conditions. Finally, 2 and 20μg/ml PF inhibited mRNA expression of Th17 cytokines and phosphorylation of Stat3 in spleen cells under Th17 polarizing conditions. These results suggest that PF inhibits IMQ-induced psoriasis by regulating Th17 cell response and cytokine secretion via phosphorylation of Stat3.

  3. Endurance exercise diverts the balance between Th17 cells and regulatory T cells.

    Directory of Open Access Journals (Sweden)

    Chava Perry

    Full Text Available Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes, Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs. While interleukin (IL-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF β levels were significantly elevated. Treg levels in sedentary controls' decreased in vitro after incubation with athletes' post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies. Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma.

  4. Lactobacillus plantarum NCU116 Attenuates Cyclophosphamide-Induced Immunosuppression and Regulates Th17/Treg Cell Immune Responses in Mice.

    Science.gov (United States)

    Xie, Junhua; Nie, Shaoping; Yu, Qiang; Yin, Junyi; Xiong, Tao; Gong, Deming; Xie, Mingyong

    2016-02-17

    The balance of T helper cells 17 (Th17)/regulatory T cells (Treg) plays a key role in maintaining a normal immune response. It is well-known that cyclophosphamide (CTX) applied at high dose often damages the immune system by inhibiting immune cell proliferation. In this study, the immunomodulating effects of Lactobacillus plantarum NCU116 in CTX-induced immunosuppression mice were investigated. Results showed that the levels of cytokines interleukin (IL)-17 and IL-21 were significantly increased after 10 days of treatment with a high dose of NCU116 (46.92 ± 4.28 and 119.92 ± 10.89, respectively) compared with the model group (36.20 ± 2.63, 61.00 ± 6.92, respectively), and the levels of cytokines IL-23 and TGF-β3 of the three NCU116 treatment groups were significantly higher than that of the model group (90.48 ± 6.33 and 140.45 ± 14.30, respectively) (p < 0.05) and close to 62 and 69% of the normal group's level (140.98 ± 14.74 and 266.95 ± 23.11, respectively) at 10 days. The bacterium was also found to increase the expression levels of Th17 immune response and Treg immune response specific transcription factors RORγt and Foxp3. In addition, the bacterium significantly increased the number of CD4(+)T cells and dendrtic cells (DCs) and up-regulated mRNA expression of Toll-like receptors (TLRs). These findings demonstrated that NCU116 has the potential ability to enhance intestinal mucosa immunity and regulate the Th17/Treg balance, which may be attributed to the TLR pathway in DCs.

  5. Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease.

    Science.gov (United States)

    Liu, Zhan; Huang, Yan; Cao, Bei-Bei; Qiu, Yi-Hua; Peng, Yu-Ping

    2016-11-14

    T helper (Th)17 cells, a subset of CD4(+) T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP(+))-induced PD models. Blood-brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP(+)-treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

  6. Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion

    Science.gov (United States)

    Bowers, Jacob S.; Nelson, Michelle H.; Majchrzak, Kinga; Bailey, Stefanie R.; Rohrer, Baerbel; Kaiser, Andrew D.M.; Atkinson, Carl; Paulos, Chrystal M.

    2017-01-01

    Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8+ T cells for treatment, they also cause decline in the cell’s therapeutic fitness. In contrast, we discovered that IL-17–producing CD4+ T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo. Three-week-expanded Th17 cells eliminated melanoma as effectively as Th17 cells expanded for 1 week when infused in equal numbers into mice. However, treating mice with large recalcitrant tumors required the infusion of all cells generated after 2 or 3 weeks of expansion, while the cell yield obtained after 1-week expansion was insufficient. Long-term-expanded Th17 cells also protected mice from tumor rechallenge including lung metastasis. Importantly, 2-week-expanded human chimeric antigen receptor–positive (CAR+) Th17 cells also retained their ability to regress human mesothelioma, while CAR+ Th1 cells did not. Our results indicate that tumor-reactive Th17 cells are an effective cell therapy for cancer, remaining uncompromised when expanded for a long duration owing to their resistance to senescence. PMID:28289713

  7. Effect of verapamil on cytokines of Th17/Treg cells%维拉帕米对Th17/Treg细胞因子的效应研究

    Institute of Scientific and Technical Information of China (English)

    刘燕婕; 邱文杰; 陈茜璐; 丁虹

    2012-01-01

    OBJECTIVE To study the effect of verapamil on cytokines of Th17/Treg cells. METHODS The levels of Th17/ Treg inflammatory cytokine produced by in vitro cultured human peripheral blood lymphocytes and the effect of verapamil on lymphocytes after activation by LPS were detected with ELISA. The effect of VER on lymphocyte proliferation was observed. RESULTS The peripheral blood T cells of normal children activated by LPS , the content of IL-17, IL-6 and TGFβ1 increased significantly (P<0. 05); when the cells cultured with LPS + 10 μmol·L-1 VER, there was no significant difference in the content of IL-17, IL-6 and TGF-β1 compared with controls (P>0.05), but it was significantly lower than that of the activated group(P<0. 05), the cells cultured with LPS+ 100 μmol·L-1 VER the content of IL-17, IL-6 and TGF-β1 was significantly lower than that of the control group and the activated group (P< 0. 05). CONCLUSION Stimulation such as foreign pathogens, enables the human lymphocytes to turn in active state of proliferation and differentiation, causes disorder of immune regulation. Ion channel blocker VER in vitro via direct action on peripheral blood lymphocytes, adjusts the production of Th17/ Treg cytokines, the cell proliferation and differentiation. So presumably, T cell membrane ion channel may play a role in the targets of autoimmune disease.%目的:研究维拉帕米(VER)对Th17/Treg细胞因子的效应作用.方法:用酶联免疫吸附试验(ELASA)法检测VER对脂多糖(LPS)激活的体外培养的人外周血淋巴细胞分泌Th1 7/Treg细胞因子的影响,观察VER对淋巴细胞增殖的效应.结果:正常儿童外周血淋巴细胞经脂多糖(LPS)激活后IL-17、IL-6和TGF-β1含量较未激活组显著增加(P<0.05);经LPS与10tmol·L-1VER共培养后,IL-17、IL6和TGF-β1含量与未激活组比较无显著差异(P>0.05),与激活组比较显著降低(P<0.05);经LPS与00 μmol·L-1VER共培养后,IL-17、TL-6和TGF-β1含量与未激

  8. Th17细胞在重症肌无力发病机制中作用的研究进展%Progress in the role of Th17 cells in the pathogenesis of myasthenia gravis

    Institute of Scientific and Technical Information of China (English)

    李永超; 张临友; 刘春全

    2015-01-01

    新辅助T细胞Th17在分化和功能上与传统的新辅助T细胞Th1和Th2不同,IL-17是其主要的细胞因子.Th17细胞与炎症反应和自身免疫性疾病密切相关,研究Th17细胞的生物学特性、Th17细胞及其细胞因子在重症肌无力(MG)、实验性重症肌无力发病机制中的作用很有意义,通过对Th17细胞的深入研究,有助于认识MG的发病机制及进一步寻找新的治疗靶点.%The new T helper cell Th17 is different from the traditional T helper cells Th1 and Th2 in differentiation and function.IL-17 is the main cytokine of Th17 cells.Th17 cells is closely related to inflammation and autoimmune diseases.Here we review the biological characteristics of Th17 cells,Focusing on the pathogenesis of Th17 cells and cytokines in myasthenia gravis(MG) and experimental autoimmune myasthenia gravis(EAMG).Study on Th17 cells would contribute to understanding the pathogenesis of myasthenia gravis and searching for new therapeutic targets.

  9. 3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation.

    Science.gov (United States)

    Okano, Takaichi; Saegusa, Jun; Nishimura, Keisuke; Takahashi, Soshi; Sendo, Sho; Ueda, Yo; Morinobu, Akio

    2017-02-10

    Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.

  10. Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation

    Science.gov (United States)

    Soroosh, Pejman; Wu, Jiejun; Xue, Xiaohua; Song, Jiao; Sutton, Steven W.; Sablad, Marciano; Yu, Jingxue; Nelen, Marina I.; Liu, Xuejun; Castro, Glenda; Luna, Rosa; Crawford, Shelby; Banie, Homayon; Dandridge, Rose A.; Deng, Xiaohu; Bittner, Anton; Kuei, Chester; Tootoonchi, Mandana; Rozenkrants, Natasha; Herman, Krystal; Gao, Jingjin; Yang, Xia V.; Sachen, Kacey; Ngo, Karen; Fung-Leung, Wai-Ping; Nguyen, Steven; de Leon-Tabaldo, Aimee; Blevitt, Jonathan; Zhang, Yan; Cummings, Maxwell D.; Rao, Tadimeti; Mani, Neelakandha S.; Liu, Changlu; McKinnon, Murray; Milla, Marcos E.; Fourie, Anne M.; Sun, Siquan

    2014-01-01

    The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17–producing CD4+ Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7β, 27-dihydroxycholesterol (7β, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ- or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17–producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7β, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17–producing cells, including CD4+ and γδ+ T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17–dependent immune responses. PMID:25092323

  11. Imbalance of placental regulatory T cell and Th17 cell population dynamics in the FIV-infected pregnant cat

    Directory of Open Access Journals (Sweden)

    Boudreaux Crystal E

    2012-05-01

    Full Text Available Abstract Background An appropriate balance in placental regulatory T cells (Tregs, an immunosuppressive cell population, and Th17 cells, a pro-inflammatory cell population, is essential in allowing tolerance of the semi-allogeneic fetus. TGF-β and IL-6 are cytokines that promote differentiation of Tregs and Th17 cells from a common progenitor; aberrant expression of the cytokines may perturb the balance in the two cell populations. We previously reported a pro-inflammatory placental environment with decreased levels of FoxP3, a Treg marker, and increased levels of IL-6 in the placentas of FIV-infected cats at early pregnancy. Thus, we hypothesized that FIV infection in the pregnant cat causes altered placental Treg and Th17 cell populations, possibly resulting in placental inflammation. Methods We examined the effect of FIV infection on Treg and Th17 populations in placentas at early pregnancy using quantitative confocal microscopy to measure FoxP3 or RORγ, a Th17 marker, and qPCR to quantify expression of the key cytokines TGF-β and IL-6. Results FoxP3 and RORγ were positively correlated in FIV-infected placentas at early pregnancy, but not placentas from normal cats, indicating virus-induced alteration in the balance of these cell populations. In control cats the expression of IL-6 and RORγ was positively correlated as predicted, but this relationship was disrupted in infected animals. TGF-β was reduced in infected queens, an occurrence that could dysregulate both Treg and Th17 cell populations. Co-expression analyses revealed a highly significant positive correlation between IL-6 and TGF-β expression in control animals that did not occur in infected animals. Conclusion Collectively, these data point toward potential disruption in the balance of Treg and Th17 cell populations that may contribute to FIV-induced inflammation in the feline placenta.

  12. Blockade of CD47 ameliorates autoimmune inflammation in CNS by suppressing IL-1-triggered infiltration of pathogenic Th17 cells.

    Science.gov (United States)

    Gao, Qiangguo; Zhang, Yi; Han, Chaofeng; Hu, Xiang; Zhang, Hua; Xu, Xiongfei; Tian, Jun; Liu, Yiqi; Ding, Yuanyuan; Liu, Juan; Wang, Chunmei; Guo, Zhenhong; Yang, Yongguang; Cao, Xuetao

    2016-05-01

    The migration of Th17 cells into central nervous system (CNS) tissue is the key pathogenic step in experimental autoimmune encephalomyelitis (EAE) model. However, the mechanism underlying the pathogenic Th17 cell migration remains elusive. Here we report that blockade of CD47 with CD47-Fc fusion protein is effective in preventing and curing EAE by impairing infiltration of Th17 cells into CNS. However, CD47 deficiency does not directly impair the migration of Th17 cells. Mechanistic studies showed that CD47 deficiency inhibited degradation of inducible nitric oxide synthase (iNOS) in proteasome of macrophages by Src activation and led to the increased nitric oxide (NO) production. Then NO suppressed inflammasome activation-induced IL-1β production. This lower IL-1β reduces the expression of IL-1R1 and migration-related chemokine receptors on CD47(-/-) Th17 cells, inhibiting the ability of Th17 cells to infiltrate into the CNS of CD47(-/-) mice and therefore suppressing EAE development. In vivo administration of exogenous IL-1β indeed promoted the infiltration CD47(-/-) Th17 cells into CNS and antagonized the protective role of CD47 deficiency in EAE pathogenesis. Our results demonstrate a potential preventive and therapeutic application of CD47 blockade in controlling EAE development.

  13. CD73 is expressed by inflammatory Th17 cells in experimental autoimmune encephalomyelitis but does not limit differentiation or pathogenesis

    Science.gov (United States)

    Hernandez-Mir, Gerard

    2017-01-01

    CD73 works together with CD39 to convert extracellular ATP to immunoregulatory adenosine, thus inhibiting inflammation. TGFβ-mediated CD73 expression on ‘regulatory’ Th17 cells limits their ability to eradicate tumors, similar to the immunosuppressive mechanism described for CD73 on Tregs. However, CD73 is also expressed on Th17 cells thought to be inflammatory in Crohn’s disease. CD73 has previously been reported to contribute to inflammation in the central nervous system (CNS). In experimental autoimmune encephalomyelitis (EAE), we found that inflammatory cytokine-producing Th17 cells showed increased CD73 expression as disease progressed. We therefore hypothesized that CD73 could be important for limiting the expansion or pathogenic function of Th17 cells in autoimmune inflammation of the CNS. Surprisingly, EAE development was not enhanced or inhibited by CD73 deficiency; there was correspondingly no difference in induction of Th17-associated cytokines IL-17, IFNγ or GM-CSF or recruitment of either inflammatory or regulatory cells to the central nervous system. We confirmed that CD73 was similarly not required for differentiation of Th17 cells in vitro. These data show that while CD73 expression is regulated during EAE, this enzyme is not absolutely required to either promote or limit Th17 cell expansion or EAE severity. PMID:28288184

  14. TH1 and TH17 cells promote crescent formation in experimental autoimmune glomerulonephritis.

    Science.gov (United States)

    Hünemörder, Stefanie; Treder, Julia; Ahrens, Stefanie; Schumacher, Valéa; Paust, Hans-Joachim; Menter, Thomas; Matthys, Patrick; Kamradt, Thomas; Meyer-Schwesinger, Catherine; Panzer, Ulf; Hopfer, Helmut; Mittrücker, Hans-Willi

    2015-09-01

    Autoimmunity against the Goodpasture antigen α3IV-NC1 results in crescentic glomerulonephritis (GN). Both antibodies and T cells directed against α3IV-NC1 have been implicated in disease development and progression. Using the model of experimental autoimmune glomerulonephritis (EAG) in DBA/1 mice, we aimed to characterize the frequency and function of α3IV-NC1-specific CD4(+) T cells in the kidneys. DBA/1 mice repeatedly immunized with human α3IV-NC1 developed necrotizing/crescentic GN. Kidneys with crescentic GN contained CD4(+) cells responding to α3IV-NC1 with the production of IFN-γ or IL-17A, demonstrating the accumulation of both α3IV-NC1-specific TH1 and TH17 cells. To test the functional relevance of TH1 and TH17 cells, EAG was induced in DBA/1 mice deficient in IFN-γR, IL-17A or IL-23p19. Mice of all knockout groups mounted α3IV-NC1 IgG, developed nephrotic range proteinuria, and IgG deposition to the glomerular basement membranes at levels similar to immunized wild-type mice. However, all knockout groups showed significantly fewer glomerular crescents and attenuated tubulointerstitial damage. Our results suggest that both α3IV-NC1-specific TH1 and TH17 cells accumulate in the kidneys and are crucial for the development of necrotizing/crescentic GN. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  15. Betahistine attenuates murine collagen-induced arthritis by suppressing both inflammatory and Th17 cell responses.

    Science.gov (United States)

    Tang, Kuo-Tung; Chao, Ya-Hsuan; Chen, Der-Yuan; Lim, Yun-Ping; Chen, Yi-Ming; Li, Yi-Rong; Yang, Deng-Ho; Lin, Chi-Chen

    2016-10-01

    The objective of this study was to evaluate the potential therapeutic effects of betahistine dihydrochloride (betahistine) in a collagen-induced arthritis (CIA) mouse model. CIA was induced in DBA/1 male mice by primary immunization with 100μl of emulsion containing 2mg/ml chicken type II collagen (CII) mixed with complete Freund's adjuvant (CFA) in an 1:1 ratio, and booster immunization with 100μl of emulsion containing 2mg/ml CII mixed with incomplete Freund's adjuvant (IFA) in an 1:1 ratio. Immunization was performed subcutaneously at the base of the tail. After being boosted on day 21, betahistine (1 and 5mg/kg) was orally administered daily for 2weeks. The severity of CIA was determined by arthritic scores and assessment of histopathological joint destruction. Expression of cytokines in the paw and anti-CII antibodies in the serum was evaluated by ELISA. The proliferative response against CII in the lymph node cells was measured by (3)H-thymidine incorporation assay. The frequencies of different CII specific CD4(+) T cell subsets in the lymph node were determined by flow-cytometric analysis. Betahistine treatment attenuated the severity of arthritis and reduced the levels of pro-inflammatory cytokines, including TNF-α, IL-6, IL-23 and IL-17A, in the paw tissues of CIA mice. Lymph node cells from betahistine-treated mice showed a decrease in proliferation, as well as a lower frequency of Th17 cells. In vitro, betahistine suppressed CD4(+) T cell differentiation into Th17 cells. These results indicate that betahistine is effective in suppressing both inflammatory and Th17 responses in mouse CIA and that it may have therapeutic value as an adjunct treatment for rheumatoid arthritis.

  16. Pro-Tumor and Anti-Tumor Functions of IL-17 and of TH17 Cells in Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Gulubova M.

    2016-10-01

    Full Text Available The current review reveals the seven subclasses of CD4+ T helper cells, i.e. Th1, Th2, Th9, Th17, Th22, regulatory T cells and Tfh, the cytokines produced by them and their role in tumor microenvironment. Main attention was paid to IL-17 and Th17 cells. IL-17-producing cells were described, among which were Treg17 cells and Tc17 cells. The transcription factors, engaged in the activation of Th17 cell differentiation were reviewed. It was shown that Th17 cells might possess regulatory functions in tumor microenvironments that directs toward immunosuppression. The reciprocity between Treg and Th17 cells is realized when the production of a large amount of TGF-β in tumors causes Treg cell differentiation, and the addition of IL-6 shifts the differentiation of naïve T cells to Th17 cells. The main pro-tumor role of IL-17 is the promotion of tumor angiogenesis through stimulation of fibroblasts and endothelial cells. The antitumor functions of IL-17 are associated with enhancement of cytotoxic activity of tumor specific CTL cells and with angiogenesis that provide channels through which immune cells might invade tumor and promote antitumor immunity.

  17. Frequency of Th17 CD4+ T Cells in Early Rheumatoid Arthritis: A Marker of Anti-CCP Seropositivity

    Science.gov (United States)

    Arroyo-Villa, Irene; Bautista-Caro, María-Belén; Balsa, Alejandro; Aguado-Acín, Pilar; Nuño, Laura; Bonilla-Hernán, María-Gema; Puig-Kröger, Amaya; Martín-Mola, Emilio; Miranda-Carús, María-Eugenia

    2012-01-01

    Objective To examine the frequency and phenotype of Th17 cells in the peripheral blood of early RA (eRA) patients. Methods CD4+ T cells were isolated from the peripheral blood of 33 eRA patients, 20 established RA patients and 53 healthy controls (HC), and from the synovial fluid of 20 established RA patients (RASF), by ficoll-hypaque gradient and magnetical negative selection. After polyclonal stimulation, the frequency of Th17 and Th1 cells was determined by flow cytometry and concentrations of IL-17, IFN-γ, TNF-α and IL-10 were measured by ELISA in cell-free supernatants. Results When all of our eRA patients were analyzed together, a significantly lower percentage of circulating Th17 cells and a lower CD4-derived IL-17 secretion were observed in comparison with HC. However, after stratifying by anti-CCP antibody status, circulating Th17 cells were decreased in anti-CCP(+) but not in anti-CCP(-)-eRA. All Th17 cells were CD45RO+CD45RA- and CCR6+. Dual Th17/Th1 cells were also exclusively decreased in anti-CCP(+)-eRA. Circulating Th17 and Th17/Th1 cells were negatively correlated with anti-CCP titres. When anti-CCP(+)-eRA patients were retested one year after initiating treatment with oral methotrexate, their circulating Th17 frequency was no longer different from HC. Of note, the percentage of circulating Th1 cells and the secretion of CD4-derived IFN-γ, TNF-α and IL-10 were not different between eRA patients and HC. In established RA patients, circulating Th17 and T17/Th1 cell frequencies were comparable to HC. In RASF, both Th17 and Th1 cells were increased when compared with blood of eRA patients, established RA patients and HC. Conclusion Decreased circulating Th17 levels in eRA seem to be a marker of anti-CCP seropositivity, and return to levels observed in healthy controls after treatment with methotrexate. PMID:22870298

  18. CD39 expression on Treg and Th17 cells is associated with metabolic factors in patients with type 2 diabetes.

    Science.gov (United States)

    Cortez-Espinosa, Nancy; Cortés-Garcia, Juan Diego; Martínez-Leija, Ernesto; Rodríguez-Rivera, Jose Guillermo; Barajas-López, Carlos; González-Amaro, Roberto; Portales-Pérez, Diana Patricia

    2015-09-01

    Th17 cells are involved in the pathogenesis of multiple inflammatory diseases such as type two diabetes (T2D). CD39(+) Treg cells have been implicated as responsible for suppressing Th17 cells. The aim of this study was to evaluate the number and function of CD4(+)CD25(high)CD39(+) Treg and Th17 cells in peripheral blood mononuclear cells (PBMC) from T2D patients and healthy control subjects. The Th17 cells were detected in PBMC under culture with human anti-CD3/CD28 and PMA/ionomycin and the levels of IL-17 were assessed by ELISA and qPCR. The T2D patients with obesity showed significantly lower percentages of CD39(+) Treg cells. A negative correlation between CD39(+) Treg cells and weight, and body mass index was detected. In contrast, the low levels of CD4(+)IL-17(+) cells in overweight and obese T2D patients showed a positive correlation with glucose and HbA1c. Additionally, we found a subpopulation of Th17 cells that express CD39 and were correlated with glucose and HbA1c. Our findings suggest that the expression of CD39 on Treg cells and also in CD4(+)IL-17(+) cells from T2D patients is related to hyperglycemia as well as to overweight and obesity and therefore may participate as a modulator of the effector capacity of Th17 cells.

  19. Plasmacytoid dendritic cell-derived IFNα modulates Th17 differentiation during early Bordetella pertussis infection in mice.

    Science.gov (United States)

    Wu, V; Smith, A A; You, H; Nguyen, T A; Ferguson, R; Taylor, M; Park, J E; Llontop, P; Youngman, K R; Abramson, T

    2016-05-01

    Whooping cough is a highly contagious respiratory disease caused by Bordetella pertussis (B. pertussis). T helper 17 (Th17) cells have a central role in the resolution of the infection. Emerging studies document that type I interferons (IFNs) suppress Th17 differentiation and interleukin (IL)-17 responses in models of infection and chronic inflammation. As plasmacytoid dendritic cells (pDCs) are a major source of type I IFNs, we hypothesize that during B. pertussis infection in mice, pDC-derived IFNα inhibits a rapid increase in Th17 cells. We found that IFNα-secreting pDCs appear in the lungs during the early stages of infection, while a robust rise of Th17 cells in the lungs is detected at 15 days post-infection or later. The presence of IFNα led to reduced Th17 differentiation and proliferation in vitro. Furthermore, in vivo blocking of IFNα produced by pDCs during infection with B. pertussis infection resulted in early increase of Th17 frequency, inflammation, and reduced bacterial loads in the airways of infected mice. Taken together, the experiments reported here describe an inhibitory role for pDCs and pDC-derived IFNα in modulating Th17 responses during the early stages of B. pertussis infection, which may explain the prolonged nature of whooping cough.

  20. Th17 Cells Exhibit Antitumor Effects in MDS Possibly through Augmenting Functions of CD8+ T Cells.

    Science.gov (United States)

    Li, Jing; Yue, Lanzhu; Wang, Huaquan; Liu, Chunyan; Liu, Hui; Tao, Jinglian; Qi, Weiwei; Wang, Yihao; Zhang, Wei; Fu, Rong; Shao, Zonghong

    2016-01-01

    Th17 cells are a newly found subset of distinct CD4+ Th effector cells' family and are found to play an important role in cancers. Myelodysplastic syndromes (MDS) are a common malignant hematological disease. Here, we showed that both the percentage and the function of Th17 cells were elevated in low-risk MDS while being decreased in high-risk MDS. Levels of upstream molecules of Th17 cells, IL-6 and IL-23, were higher in low-risk MDS but lower in high-risk MDS patients. The abnormal percentage of Th17 cells was closely related to clinical parameters including karyotype, morphologic blast percentage of bone marrow, peripheral absolute neutrophil count, and hemoglobin concentration. Furthermore, expression rates of perforin and granzyme B in BM CD3+CD8+ cells (cytotoxic T lymphocyte, CTL) positively correlated with levels of IL-17 but negatively correlated with BM blast percentage and could be significantly increased after stimulation with human recombinant IL-17 (rhIL-17). Our results suggested that Th17 cells might play an antitumor effect in the pathogenesis of MDS through IL-17/CTL pathway.

  1. Inhibition of Th1 and Th17 Cells by Medicinal Plants and Their Derivatives: A Systematic Review.

    Science.gov (United States)

    Asadi-Samani, Majid; Bagheri, Nader; Rafieian-Kopaei, Mahmoud; Shirzad, Hedayatollah

    2017-08-01

    Searching for new natural drugs that are capable of targeting Th1 and Th17 may lead to development of more effective treatments for inflammatory and autoimmune diseases. Most of the natural drugs can be derived from plants that are used in traditional medicine and folk medicine. The aim of this systematic review is to identify and introduce plants or plant derivatives that are effective on inflammatory diseases by inhibiting Th1 and Th17 responses. To achieve this purpose, the search terms herb, herbal medicine, herbal drug, medicinal plant, phytochemical, traditional Chinese medicine, Ayurvedic medicine, natural compound, inflammation, inflammatory diseases, Th1, Th17, T helper 1 or T helper 17 were used separately in Title/Keywords/Abstract in Web of Science and PubMed databases. In articles investigating the effect of the medicinal plants and their derivatives in inhibiting Th1 and Th17 cells, the effects of eight extracts of the medicinal plants, 21 plant-based compounds and some of their derivatives, and eight drugs derived from the medicinal plants' compounds in inhibiting Th1 and Th17 cells were reviewed. The results showed that medicinal plants and their derivates are able to suppress Th17 and Th1 T cell functions as well as cytokine secretion and differentiation. The results can be used to produce herbal drugs that suppress Th, especially Th17, responses. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  2. Correlation of expression of STAT3, VEGF and differentiation of Th17 cells in psoriasis vulgaris of guinea pig

    Institute of Scientific and Technical Information of China (English)

    Xiu-Fen Zheng; Yue-Dong Sun; Xue-Yan Liu

    2014-01-01

    Objective: To investigate the role of T help 17 cells (Th17) and STAT3-VEGF pathway in pathogenesis of psoriasis. Methods: A total of 50 cases of psoriasis guinea pigs and 20 normal guinea pigs were selected. The ratio of Th17/ IL-17 cell in peripheral blood were detected by flow cytometric analysis; STAT3 and VEGF concentrations were measured by immunohistochemistry and Western blot. Results: The expression of Th17 in peripheral blood were significantly increased in psoriasis [(1.76±0.88)%] compared with controls [(0.48±0.27)%] (P<0.05). Th17 related cytokine STAT3 and VEGF were significantly increased in psoriasis compared with controls (P<0.05), and were positively correlated the expression of Th17. Conclusions: The expressions of Th17, STAT3 and VEGF are elevated in psoriasis, which suggests Th17 cells have a potential role in the pathogenesis of psoriasis by STAT3-VEGF pathway.

  3. The Distribution and the Fibrotic Role of Elevated Inflammatory Th17 Cells in Patients With Primary Biliary Cirrhosis.

    Science.gov (United States)

    Shi, TianYan; Zhang, Ting; Zhang, LiNa; Yang, YunJiao; Zhang, HaoZe; Zhang, FengChun

    2015-11-01

    T helper (Th) 17 cells were reported to have the property of proinflammation and profibrosis. We first investigate the levels of Th17 cells in primary biliary cirrhosis (PBC) patients, and then explore their distribution and fibrotic role in the disease.We compared the circulating Th17 and hepatic interleukin (IL)-17-positive cells between patients and healthy controls (HCs) at different disease stages by flow cytometry and immunohistochemistry, respectively. The levels of chemokine (c-c motif) ligand (CCL) 20 were then measured. For exploration of the reason why Th17 cells increased, CD4CD161 populations were sorted and cultured with IL-23 and IL-1β to analyze their proliferation and IL-17 secretions. The serum IL-23 and IL-1β were tested by enzyme-linked immunosorbent assay. The proliferation and expressions of α-smooth muscle actin and IL-8 of hepatic stellate cells (HSCs) were identified after stimulated by different concentrations of IL-17.Circulating and hepatic Th17 cells were elevated in PBC patients compared with HCs. Early PBC patients presented with more Th17 cells in periphery blood and less in the liver than advanced PBC patients. Accordingly, the levels of both serum and hepatic CCL20 for Th17 cells were higher, especially in those with advanced disease. The progenitor of Th17, CD4CD161 cell was increased in PBC. Moreover, the percentage of Th17 cells was positively related with CD4CD161 cell. After stimulation with IL-23 and IL-1β which were improved in PBC patients, CD4CD161 cells from PBC patients expressed more IL-17, although their proliferation were not different between 2 groups. IL-17 can promote the proliferation of HSCs at a dose-dependent method, and also increase the IL-8 expression in a dose/time-dependent way. Anti-IL-17 can neutralize the above reactions.CD4CD161 cells are a source of increased Th17 in PBC patients. With disease progression, Th17 population decreased in the circulation, accompanied by greater accumulation in the

  4. Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia.

    Science.gov (United States)

    Prajeeth, Chittappen K; Löhr, Kirsten; Floess, Stefan; Zimmermann, Julian; Ulrich, Reiner; Gudi, Viktoria; Beineke, Andreas; Baumgärtner, Wolfgang; Müller, Marcus; Huehn, Jochen; Stangel, Martin

    2014-03-01

    Microglia act as sensors of inflammation in the central nervous system (CNS) and respond to many stimuli. Other key players in neuroinflammatory diseases are CD4+ T helper cell (Th) subsets that characteristically secrete IFN-γ (Th1) or IL-17 (Th17). However, the potential of a distinct cytokine milieu generated by these effector T cell subsets to modulate microglial phenotype and function is poorly understood. We therefore investigated the ability of factors secreted by Th1 and Th17 cells to induce microglial activation. In vitro experiments wherein microglia were cultured in the presence of supernatants derived from polarized Th1 or Th17 cultures, revealed that Th1-associated factors could directly activate and trigger a proinflammatory M1-type gene expression profile in microglia that was cell-cell contact independent, whereas Th17 cells or its associated factors did not have any direct influence on microglia. To assess the effects of the key Th17 effector cytokine IL-17A in vivo we used transgenic mice in which IL-17A is specifically expressed in astrocytes. Flow cytometric and histological analysis revealed only subtle changes in the phenotype of microglia suggesting only minimal effects of constitutively produced IL-17A on microglia in vivo. Neither IL-23 signaling nor addition of GM-CSF, a recently described effector molecule of Th17 cells, changed the incapacity of Th17 cells to activate microglia. These findings demonstrate a potent effect of Th1 cells on microglia, however, the mechanism of how Th17 cells achieve their effect in CNS inflammation remains unclear.

  5. [Helper T cell paradigm: Th17 and regulatory T cells involved in autoimmune inflammatory disorders, pathogen defense and allergic diseases].

    Science.gov (United States)

    Noma, Takeshi

    2010-01-01

    The helper T cell paradigm, divided into two distinct subsets, Th1 and Th2 cells, characterized by distinct cytokine and functions, has been expanded to IL-17-producing Th17 cells. Th1 cells producing IFN-γ are involved in delayed-type hypersensitivity, effective in intracellular pathogens defense, while Th2 cells secrete IL-4, IL-5, IL-13 and IL-25 and has a central role in IgE production, eosinophilic inflammation, and the protection for helminthic parasite infection. Th17 cell lineages, expressing IL-17 family of cytokines and IL-23-mediated functions on T cells, plays a role in immune response to fungi and extracellular pathogens and autoimmune inflammatory disorders. Th17 cells are required the combination of IL-6 and TGF-β and the transcription factors, RORC2/RORgt (mice) and STAT3 for differentiation, and produce IL-17, IL-22, IL-17F, IL-21 and CCL20. FOXP3+ regulatory T (Treg) cells produce TGF-β and IL-10, which regulate effector T cells, and thus maintain peripheral tolerance. Four functionally unique CD4+ T cells, including the regulatory T (Treg) cells are now involved in the regulation of immune responses to pathogens, self-antigens and allergens. Any defect in the entire CD4+T cell population might results in human diseases. In this review, the biology of Th17 cells and Treg cells and their role in immune diseases are presented.

  6. Recruitment of CCR6-expressing Th17 cells by CCL20 secreted from plasmin-stimulated macrophages

    Institute of Scientific and Technical Information of China (English)

    Qun Li; Yves Laumonnier; Tatiana Syrovets; Thomas Simmet

    2013-01-01

    In the present study,monocyte-derived human macrophages were differentiated from buffy coats.Na(i)ve CD4+ T-cells enriched from peripheral blood mononuclear cells using anti-CD4 magnetic beads and the autoMACS separation system were polarized under T-helper 17 (Th17)-promoting conditions for 6 days to get Th17 cells.The frequency of Th17 cell differentiation and the expression of C-C chemokine receptor type 6 (CCR6) on Th17 cells were investigated by flow cytometry.Plasmin-triggered induction of macrophage inflammatory protein-3alpha/C-C chemokine ligand 20 (CCL20) genes in macrophages was assessed by reverse transcription-polymerase chain reaction,and secreted protein levels were measured by enzymelinked immunosorbent assay.Th17 cell migration induced by CCL20 secreted from plasmin-stimulated macrophages was tested in vitro by chemotaxis using a transwell system.These results demonstrate that plasmin triggers the expression of chemokine CCL20 messenger RNA and the release of CCL20 protein in human monocyte-derived macrophages,which critically depend on the proteolytic activity of plasmin and activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB signaling pathways.Expression of CCR6 was detected on 87.23 ± 8.6% of Th17 cells in vitro.Similar to chemotaxis triggered by recombinant human CCL20,supernatants collected from plasmin-stimulated macrophage-induced chemotactic migration of Th17 cells,which could be inhibited by an anti-CCL20 neutralizing antibody.These results suggest that plasmin generated in inflamed tissues might elicit production of chemokine CCL20 by human macrophages leading to the recruitmentof CCR6 positive Th17 cells to the inflammatory sites.

  7. IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1.

    Science.gov (United States)

    Neufert, Clemens; Becker, Christoph; Wirtz, Stefan; Fantini, Massimo C; Weigmann, Benno; Galle, Peter R; Neurath, Markus F

    2007-07-01

    IL-27 is an IL-12-related cytokine frequently present at sites of inflammation that can promote both anti- and pro-inflammatory immune responses. Here, we have analyzed the mechanisms how IL-27 may drive such divergent immune responses. While IL-27 suppressed the development of proinflammatory Th17 cells, a novel role for this cytokine in inhibiting the development of anti-inflammatory, inducible regulatory T cells (iTreg) was identified. In fact, IL-27 suppressed the development of adaptive, TGF-beta-induced Forkhead box transcription factor p3-positive (Foxp3(+)) Treg. Whereas the blockade of Th17 development was dependent on the transcription factor STAT1, the suppression of iTreg development was STAT1 independent, suggesting that IL-27 utilizes different signaling pathways to shape T cell-driven immune responses. Our data thus demonstrate that IL-27 controls the development of Th17 and iTreg cells via differential effects on STAT1.

  8. Renal allograft rejection: examination of delayed differentiation of Treg and Th17 effector T cells.

    Science.gov (United States)

    Pekalski, Marcin; Jenkinson, Sarah E; Willet, Joseph D P; Poyner, Elizabeth F M; Alhamidi, Abdulaziz H; Robertson, Helen; Ali, Simi; Kirby, John A

    2013-03-01

    Antigen presentation after kidney transplantation occurs in lymphoid tissues remote from the allograft, with activated T cells then migrating towards the graft. This study examined the possibility that these activated T cells can differentiate to acquire Th17 or Treg phenotypes after a time consistent with their arrival within renal allograft tissues. An immunocytochemical study was performed to demonstrate the response to intragraft TGF-β and the phenotype of lymphoid cells within rejecting human renal allograft tissue. A series of in vitro experiments was then performed to determine the potential to induce these phenotypes by addition of appropriate cytokines 3days after initial T cell activation. During renal allograft rejection there was a strong response to TGF-β, and both FOXP3 and IL-17A were expressed by separate lymphoid cells in the graft infiltrate. FOXP3 could be induced to high levels by the addition of TGF-β1 3days after the initiation of allogeneic mixed leukocyte culture. This Treg marker was enriched in the sub-population of T cells expressing the cell-surface αE(CD103)β7 integrin. The RORγt transcription factor and IL-17A were induced 3days after T cell activation by the addition of TGF-β1, IL-1β, IL-6 and IL-23; many of these Th17 cells also co-expressed CD103. T cells can develop an effector phenotype following cytokine stimulation 3days after initial activation. This suggests that the intragraft T cell phenotype may be indicative of the prevailing cytokine microenvironment.

  9. Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development.

    Directory of Open Access Journals (Sweden)

    Seung-Joo Lee

    2012-01-01

    Full Text Available Pathogens can substantially alter gene expression within an infected host depending on metabolic or virulence requirements in different tissues, however, the effect of these alterations on host immunity are unclear. Here we visualized multiple CD4 T cell responses to temporally expressed proteins in Salmonella-infected mice. Flagellin-specific CD4 T cells expanded and contracted early, differentiated into Th1 and Th17 lineages, and were enriched in mucosal tissues after oral infection. In contrast, CD4 T cells responding to Salmonella Type-III Secretion System (TTSS effectors steadily accumulated until bacterial clearance was achieved, primarily differentiated into Th1 cells, and were predominantly detected in systemic tissues. Thus, pathogen regulation of antigen expression plays a major role in orchestrating the expansion, differentiation, and location of antigen-specific CD4 T cells in vivo.

  10. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling.

    Science.gov (United States)

    Boniface, Katia; Bak-Jensen, Kristian S; Li, Ying; Blumenschein, Wendy M; McGeachy, Mandy J; McClanahan, Terrill K; McKenzie, Brent S; Kastelein, Robert A; Cua, Daniel J; de Waal Malefyt, René

    2009-03-16

    Prostaglandins, particularly prostaglandin E2 (PGE2), play an important role during inflammation. This is exemplified by the clinical use of cyclooxygenase 2 inhibitors, which interfere with PGE2 synthesis, as effective antiinflammatory drugs. Here, we show that PGE2 directly promotes differentiation and proinflammatory functions of human and murine IL-17-producing T helper (Th17) cells. In human purified naive T cells, PGE2 acts via prostaglandin receptor EP2- and EP4-mediated signaling and cyclic AMP pathways to up-regulate IL-23 and IL-1 receptor expression. Furthermore, PGE2 synergizes with IL-1beta and IL-23 to drive retinoic acid receptor-related orphan receptor (ROR)-gammat, IL-17, IL-17F, CCL20, and CCR6 expression, which is consistent with the reported Th17 phenotype. While enhancing Th17 cytokine expression mainly through EP2, PGE2 differentially regulates interferon (IFN)-gamma production and inhibits production of the antiinflammatory cytokine IL-10 in Th17 cells predominantly through EP4. Furthermore, PGE2 is required for IL-17 production in the presence of antigen-presenting cells. Hence, the combination of inflammatory cytokines and noncytokine immunomodulators, such as PGE2, during differentiation and activation determines the ultimate phenotype of Th17 cells. These findings, together with the altered IL-12/IL-23 balance induced by PGE2 in dendritic cells, further highlight the crucial role of the inflammatory microenvironment in Th17 cell development and regulation.

  11. Treg/Th17 Cell Imbalance and IL-6 Profile in Patients With Unexplained Recurrent Spontaneous Abortion.

    Science.gov (United States)

    Zhu, Liqiong; Chen, Hui; Liu, Meilan; Yuan, Yu; Wang, Zhaohua; Chen, Ying; Wei, Jing; Su, Fang; Zhang, Jianping

    2016-10-02

    Regulatory T cells (Treg) and T helper 17 cells (Th17) are 2 distinct subsets of CD4(+) T cells, which are mutually antagonistic in the immune response. Recently, dysregulation of these 2 cell subsets have been described in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). The purpose of this study was to investigate whether the Treg/Th17 balance was perturbed in URSA patients and to explore contributing factors. We found that the proportion of Treg cells and expression of forkhead box P3 (Foxp3) messenger RNA (mRNA) were significantly lower in URSA patients than in healthy controls. However, the proportion of Th17 cells and expression of retinoid-related orphan nuclear receptor-γt (ROR-γt) mRNA were higher in URSA patients than in controls, revealing inverse correlation with Treg. The ratio of Treg/Th17 and Foxp3/ROR-γt decreased in patients with URSA compared to healthy controls. The serum levels of interleukin (IL)-6 and IL-17A were significantly higher, whereas IL-10 was lower in URSA patients compared with controls, and the level of IL-6 showed a positive correlation with Th17, ROR-γt and inverse correlation with Treg, Foxp3. The present study indicated that an imbalance between Treg and Th17 cells might be implicated in the pathogenesis of URSA and this seems to relate to elevation in serum IL-6 level.

  12. Complement component C5a permits the coexistence of pathogenic Th17 cells and type I IFN in lupus.

    Science.gov (United States)

    Pawaria, Sudesh; Ramani, Kritika; Maers, Kelly; Liu, Youhua; Kane, Lawrence P; Levesque, Marc C; Biswas, Partha S

    2014-10-01

    Systemic lupus erythematosus (SLE) is a type I IFN (IFN-I)-driven autoimmune disorder with exaggerated B and Th cell responses. Th17 cells, a recently identified Th cell subset, have been strongly implicated in the pathogenesis of SLE. Because IFN-I suppresses the generation and expansion of Th17 cells in an IL-27-dependent manner, it is unclear how pathogenic Th17 cells are generated in SLE in the presence of an environment characterized by high IFN-I levels. In this study, we showed that activation of c5aR on murine macrophages blocked IFN-I-mediated IL-27 production, thus permitting the development of Th17 cells. C5aR activation on IFN-I-responsive macrophages inhibits IRF-1-mediated transactivation of IL-27 gene expression via the PI3K/Akt pathway. Consistently, C5aR-deficient mice exhibited increased IL-27 expression and fewer Th17 cells and consequently developed reduced lupus nephritis in comparison with wild-type mice. In support of these findings in mice, we found that C5a inhibited IFN-I-induced IL-27 production from macrophages of lupus subjects. Moreover, the level of serum C5a correlated with Th17 frequency in peripheral blood. Collectively, these data indicate an essential role for C5a in the generation of pathogenic Th17 responses in SLE. Thus, therapeutic strategies to block C5aR activation may be beneficial for controlling pathogenic Th17-mediated inflammation in SLE.

  13. Gestational and lactational exposure to low-dose bisphenol A increases Th17 cells in mice offspring.

    Science.gov (United States)

    Luo, Shimeng; Li, Yun; Li, Yingpei; Zhu, Qixing; Jiang, Jianhua; Wu, Changhao; Shen, Tong

    2016-10-01

    Increasing evidence demonstrates that perinatal exposure to Bisphenol A (BPA) can cause immune disorders throughout the life span. However, the biological basis for these immune disorders is poorly understood and the effects of exposure to BPA on Th17 development are unknown. The present study sought to characterize alterations of Th17 cells in childhood and adulthood following gestational and lactational exposure to environmentally relevant low-dose of BPA and the underlying mechanisms. Pregnant dams were exposed to BPA (10, 100 or 1000nM) via drinking water from gestational day (GD) 0 to postnatal day (PND) 21. At PNDs 21 and 42, offspring mice were anesthetized, blood was obtained for cytokine assay and spleens were collected for Th17 cell frequency and RORγt mRNA expression analysis. Perinatal exposure to low-dose BPA resulted in a dose-dependent and gender-specific persistent rise in Th17 cells accompanied by an increase of RORγt mRNA expression in the offsprings. The contents of major Th17 cell-derived cytokines (IL-17 and IL-21) and those essential for Th17 cell differentiation (IL-6 and IL-23) were also increased compared to those in controls. These changes were more pronounced in female than in male offsprings. However, perinatal exposure to low-dose BPA had little effect on serum TGF-β, another key regulator for Th17 cell development. Our results suggest that gestational and lactational exposure to a low-dose of BPA can affect Th17 cell development via an action on its transcription factor and the regulatory cytokines. These findings provide novel insight into sustained immune disorders by BPA exposure during development.

  14. Th17 cell and liver diseases%Th17细胞在肝脏疾病的研究进展

    Institute of Scientific and Technical Information of China (English)

    张耿林; 高志良

    2011-01-01

    @@ Th17是新近发现的一种辅助性T细胞亚型,Th17细胞分泌的细胞因子除白细胞介素(IL)-17外,还包括IL-17F、IL-21、IL-22、IL-6和肿瘤坏死因子α(TNFα)等.Th17细胞及其分泌的细胞因子在自身免疫性疾病、感染性疾病和变态反应性疾病中都发挥重要作用.本文仅综述Th17细胞通路在肝脏疾病中的研究进展.

  15. 宫颈癌患者癌组织中Th17/Tr细胞明显升高与疾病进程相关%Unbalance and involvement of Th17/Tr cells in patients with cervical cancer

    Institute of Scientific and Technical Information of China (English)

    付婷; 杨佩芳; 焦志军; 张建新

    2011-01-01

    目的 了解宫颈癌患者外周血、肿瘤组织中Th17/Tr细胞的比例,分析其与疾病发生、发展的关系,探讨Th17/Tr比值改变在宫颈癌临床检测中的意义.方法 采用流式细胞术检测32例宫颈癌患者外周血、肿瘤组织标本和15例健康者对照标本中的Th17、Tr细胞;采用直线相关检验方法对晚期宫颈癌组的Th17、Tr细胞进行相关性分析.结果 宫颈癌患者外周血、肿瘤组织中Th17、Tr细胞显著高于健康对照组(P<0.05),晚期宫颈癌组Th17/Tr比值低于早期组(P<0.01),晚期宫颈癌组Th17、Tr表达呈负相关.结论 宫颈癌患者Th17、Tr细胞比例明显升高,提示Th17/Tr比值与宫颈癌的发生发展可能存在着一定的关系,为官颈癌的免疫治疗提供新思路.%Objective To detect the levels of Th17 and regulatory T(Tr)cells in Imripheral blood mononuclear and tumor tissue from patients with cervical cancer and analyze the relationship hetween Th17 and Tr cells in cervical cancer progression.In addition.the significance of the Th17/Tr cells ratio in cervical cancer pathogenesis was discussed.Methods The expression levels of Th17 and Tr cells were determined by flow cytometry from 32 patients with cervical cancer and 15 health people.The mechanism of involvement of Th17 and Tr cells proportionality in cervical cancer pathogenesis and the correlation between Th17 and Trwas assessed by bivariate correlation analysis.Results The expression levels of both Th17 and Tr in patients were higher than control groups,especially in late stage patients Th17 and Tr proportionality lower than early group,and there was a negative correlation between them.Conclusion Th17 and Tr cells proportionality may be involve in the development of cervical cancer so as to provide novel strategies for tumor immunotherapy.

  16. Translational mini-review series on Th17 cells: are T helper 17 cells really pathogenic in autoimmunity?

    NARCIS (Netherlands)

    Koenders, M.I.; Berg, W.B. van den

    2010-01-01

    In this review the authors discuss the evidence for T helper type 17 (Th17) cells as pathogenic T cells in autoimmunity. Studies with cytokine-deficient mice or blocking of interleukin (IL)-17, IL-21 and IL-22 have resulted in a conflicting data set. Although in the experimental autoimmune encephalo

  17. Characteristics and significance of peripheral blood Th17 cells and regulatory T cells in liver transplantation patients with acute rejection

    Directory of Open Access Journals (Sweden)

    Wei-guo REN

    2012-04-01

    Full Text Available Objective To investigate the characteristics of changes and clinical significance of Th17 cells and CD4+CD25+Foxp3+ regulatory T cells (Treg in peripheral blood in liver transplant patients suffering from acute transplant rejection. Methods A total of 25 liver transplant patients admitted in 302 Hospital of People's Liberation Army from January to September 2011 underwent needle biopsy for the transplanted hepatic tissue. The patients were divided into two groups: acute rejection group (12 cases and stable-graft group (13 cases. In addition, 13 healthy people were enlisted in the study and regarded as control. Flow cytometric analysis was used to measure the proportion of Th17 cells and Treg cells in peripheral blood among CD4+ T cells, and to observe the relationship between change in Th17/Treg ratio and liver injury. Results The proportion of Th17/CD4+T in acute rejection group (3.50%±0.86% after transplantation was higher than that in the stable-graft group (2.10%±0.52% and control group (1.79%±0.42%, P 0.05. The Treg/CD4+T cell ratio in the peripheral blood of the patients from acute rejection and stable-graft group (0.90%±0.25% and 1.51%±0.23%, respectively were significantly lower than that of control group (2.57%±0.79%, P < 0.01, and that of acute rejection group was notably lower than that of stable-graft group (P < 0.05. The Th17/Treg ratio in acute rejection group (4.20±1.69 was significantly higher than that of stable-graft group (1.43±0.47 and control group (0.75±0.28, P < 0.01, and that of stable-graft group was higher than that of control group (P < 0.01. The ratio of Th17/Treg was positively correlated with alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, and glutamate transaminase (GGT levels (r=0.5023, P=0.0105; r=0.4561, P=0.0219; r=0.4393, P=0.0280; and r=0.5516, P=0.0043, respectively. Conclusions Th17/ Treg imbalance exists in liver transplant patients suffering from

  18. Th17细胞为靶点治疗类风湿性关节炎研究进展%Progress in studies of targeting at Th17 cells in the treatment of rheumatoid arthritis

    Institute of Scientific and Technical Information of China (English)

    傅德杰; 王智勇

    2011-01-01

    Rheumatoid arthritis is an autoimmune disease which is characterized by chronic, progressive and invasive arthritis. Without regular treatment, the pathogenetic conditions will gradually develop and result in malformation and functional incapacitation of the joints. Th17 cells is a newly identified subset of CD4+ T cells which exist independently from Th1 and Th2. Th17 cells are characterized by the secretion of IL-17, IL-6 and TNF-α. Recent studies found a close relationship between Th17 and RA; targeting at Th17 is a new method to treat RA. This review concentrates on the achievements that treat RA targeting on Th17.%类风湿性关节炎是一种以慢性、进行性、侵袭性关节炎为主要表现的全身性自身免疫病,如果不经过正规治疗,病情会逐渐发展,最终导致关节畸形、功能丧失.Th17细胞是最近发现的不同于Th1和Th2的CD4+T细胞的新亚群,它可以分泌IL-17,IL-6,TNF-α等促炎因子.最近的研究发现Th17与RA的发生有密切关系,针对Th17来治疗RA是一种新的手段.本文就最近针对Th17细胞治疗RA所取得的成果做一综述.

  19. Anti-HMGB1 Neutralizing Antibody Ameliorates Neutrophilic Airway Inflammation by Suppressing Dendritic Cell-Mediated Th17 Polarization

    Directory of Open Access Journals (Sweden)

    Fang Zhang

    2014-01-01

    Full Text Available We demonstrate that high mobility group box 1 protein (HMGB1 directs Th17 skewing by regulating dendritic cell (DC function. First, our in vitro studies reveal that recombinant HMGB1 (rHMGB1 activates myeloid DCs to produce IL-23 in vitro, and rHMGB1-activated DCs prime naïve lymphocytes to produce the Th17 cytokine IL-17A. Second, we demonstrate that anti-HMGB1 neutralizing antibody attenuates HMGB1 expression, neutrophilic inflammation, airway hyperresponsiveness, and Th17-related cytokine secretion in vivo by using a murine model of neutrophilic asthma induced by ovalbumin (OVA plus lipopolysaccharide (LPS. Furthermore, anti-HMGB1 neutralizing antibody decreases the number of Th17 cells in lung cells and suppresses the production of IL-23 by lung CD11C+ APCs. Finally, we show that intranasal adoptive transfer of rHMGB1-activated DCs was sufficient to restore lung neutrophilic inflammation and the Th17 response in a DC-driven model of asthma, whereas the transfer of rHMGB1 plus anti-HMGB1-treated mDCs significantly reduced these inflammation phenotypes. These data suggest, for the first time, that HMGB1 drives the DC-polarized Th17-type response in allergic lung inflammation and that blocking HMGB1 may benefit the attenuation of neutrophilic airway inflammation in asthma.

  20. A natural flavonoid glucoside icariin inhibits Th1 and Th17 cell differentiation and ameliorates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Shen, Ruile; Deng, Wenjing; Li, Chun; Zeng, Guangwei

    2015-02-01

    Multiple sclerosis (MS) is an autoimmune disease that is characterized by recurrent episodes of T cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. Icariin, a natural flavonoid glucoside isolated from plants in the Epimedium family, has been proved to have various pharmacological activities. However, the effect of icariin on experimental autoimmune encephalomyelitis (EAE) has never been investigated. In our current study, we found that icariin treatment leads to alleviated inflammatory infiltration and reduced blood-brain barrier leakage (BBB) of the paracellular tracer (FITC-dextran) in EAE. Mice that received icariin-treated T cells also displayed lower EAE scores and better clinical recovery from EAE. Icariin administration suppresses the frequencies of Th1 and Th17 cells in the splenocytes and lymph node cells. Icariin-treated mice also show lower frequency of Th17 cells in CNS mononuclear cells. The effect of icariin on Th1 and Th17 cell differentiation may be mediated via modulation of dendritic cells (DCs). Furthermore, icariin suppresses the proliferation of T cells and the differentiation of Th1 and Th17 cells in vitro. In conclusion, icariin ameliorates EAE and this was associated with suppressed Th1 and Th17 cell differentiation. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Phenotype and susceptibility to HIV infection of CD4+ Th17 cells in the human female reproductive tract.

    Science.gov (United States)

    Rodriguez-Garcia, M; Barr, F D; Crist, S G; Fahey, J V; Wira, C R

    2014-11-01

    Prevention of sexual acquisition of HIV in women requires a substantial increase in our knowledge about HIV-target cell availability and regulation in the female reproductive tract (FRT). In this study, we analyzed the phenotype and susceptibility to HIV infection of CD4(+) T cell in the endometrium (EM), endocervix (END), and ectocervix (ECT) of the FRT. We found that T helper type 17 (Th17) cells represent a major subset in FRT tissues analyzed and that Th17 cells were the main CD4(+) T-cell population expressing C-C motif chemokine receptor 5 (CCR5) and CD90. In premenopausal women, CD4(+) T cells and Th17 cells, in particular, were significantly lower in EM relative to END and ECT. Th17 cells were elevated in EM from postmenopausal women relative to premenopausal tissues but not changed in END and ECT. Susceptibility of CD4(+) T cells to HIV infection measured as intracellular p24 was lowest in the EM and highest in the ECT. Additionally, we found that Th17 cells co-expressing CCR5 and CD90 were the most susceptible to HIV infection. Our results provide valuable information for designing preventive strategies directed at targeting highly susceptible target cells in the FRT.

  2. Research of the Balance Adjustment of Th17/Treg cells and Related Cytokines%Th17/Treg细胞及相关细胞因子平衡调节的研究

    Institute of Scientific and Technical Information of China (English)

    汤美雯

    2015-01-01

    The Th17 cells and Treg cells are new subsets of CD4+T cells. They are regulated in the process of differentiation and the development of functioning by Th1 and Th2 effector cells and the secretion of cytokines produced by them,and they participate in the development of autoimmune diseases,infections,tumors and other diseases. The imbalance of Th17/ Treg cells plays an important role in the pathogenesis of many autoimmune diseases. To block or enhance the key regulators in the process of differentiation and the development of functioning of Th17 and Treg sells can turn up or down Th17 cells and Treg cells in the disease,which benefits for the prevention and treatment of diseases.%Th17细胞和Treg细胞是CD4+T细胞的新亚群,在分化发育、功能发挥的过程中受到Th1型、 Th2型效应细胞以及自身分泌产生的细胞因子的调节,参与自身免疫、感染、肿瘤等疾病的发生发展。 Th17/ Treg细胞失衡在许多免疫性疾病的发病机制中发挥重要作用。通过对Th17和Treg 分化发育和功能发挥过程中的关键调节因子进行阻断或加强,可以上调或下调Th17细胞和Treg细胞在疾病中的表达,以用于疾病的预防和诊治。

  3. The Burgeoning World of Immunometabolites: Th17 Cells Take Center Stage.

    Science.gov (United States)

    Bantug, Glenn R; Hess, Christoph

    2017-10-03

    Dysregulation of the Th17/Treg balance is a key driver of autoimmunity. A new study by Xu et al. (2017) has revealed that small-molecule inhibition of 2-hydroxyglutarate synthesis skews Th17 differentiation to the Treg lineage, which is protective against autoimmune inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties

    DEFF Research Database (Denmark)

    Prajeeth, Chittappen K; Kronisch, Julius; Khorooshi, Reza M. H.

    2017-01-01

    , cytokines and chemokines using real-time PCR. Data obtained was analysed using Kruskal- Wallis test. Results: We observed in α4-deficient mice weak microglial activation but comparable astrogliosis to that of wild-type mice in the regions of the brain populated with Th17 infiltrates suggesting that Th17...

  5. Research Progress of the Role of Th17 Cells in Vitiligo Pathogenesis%Th17细胞在白癜风发病中的作用研究进展

    Institute of Scientific and Technical Information of China (English)

    赵玉凤

    2012-01-01

    Under the action of some specific cytokynesis, CD4 + T can differentiate into Th 17 cells, which are involved in pathogenesis of many diseases. In the progress of vitiligo, Treg cells show decrease in number and functional defect, while Th17 cells show increase in number and functional activeness. Th17 cells are involved into the pathogenesis of vitiligo with the assistance of dendritic cells. Thl7 cells mainly secrete IL -17, TNF-α, IL-21, IL - 22 and IL - 26 , and these cytokynesis takp part in the pathogpiipsis oi vitiligo, leading to generation decrease oi melanocytes atrophy and disappparing of melanocytes and ultimately the occurrence of vitiligo.%在某些特定细胞因子的作用下,CD4+T细胞分化为Th17细胞,Th17细胞可参与多种疾病的发病.在白癜风发病过程中,调节性T细胞(Treg细胞)数量减少、功能缺陷,Th17细胞数量增多,功能活跃.Th17细胞在树突细胞的协助下参与发病过程.Th17细胞主要分泌白介素17(IL-17),还分泌肿瘤坏死因子α(TNF-α)、IL-21、IL-22和IL-26等细胞因子参与白癜风发病,导致黑色素细胞生成减少,黑色素细胞萎缩、消失,最终形成白癜风.

  6. Oral-resident natural Th17 cells and γδ T cells control opportunistic Candida albicans infections.

    Science.gov (United States)

    Conti, Heather R; Peterson, Alanna C; Brane, Lucas; Huppler, Anna R; Hernández-Santos, Nydiaris; Whibley, Natasha; Garg, Abhishek V; Simpson-Abelson, Michelle R; Gibson, Gregory A; Mamo, Anna J; Osborne, Lisa C; Bishu, Shrinivas; Ghilardi, Nico; Siebenlist, Ulrich; Watkins, Simon C; Artis, David; McGeachy, Mandy J; Gaffen, Sarah L

    2014-09-22

    Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection caused by Candida albicans. OPC is frequent in HIV/AIDS, implicating adaptive immunity. Mice are naive to Candida, yet IL-17 is induced within 24 h of infection, and susceptibility is strongly dependent on IL-17R signaling. We sought to identify the source of IL-17 during the early innate response to candidiasis. We show that innate responses to Candida require an intact TCR, as SCID, IL-7Rα(-/-), and Rag1(-/-) mice were susceptible to OPC, and blockade of TCR signaling by cyclosporine induced susceptibility. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1-2 d by tongue-resident populations of γδ T cells and CD3(+)CD4(+)CD44(hi)TCRβ(+)CCR6(+) natural Th17 (nTh17) cells, but not by TCR-deficient innate lymphoid cells (ILCs) or NK cells. These cells function redundantly, as TCR-β(-/-) and TCR-δ(-/-) mice were both resistant to OPC. Whereas γδ T cells were previously shown to produce IL-17 during dermal candidiasis and are known to mediate host defense at mucosal surfaces, nTh17 cells are poorly understood. The oral nTh17 population expanded rapidly after OPC, exhibited high TCR-β clonal diversity, and was absent in Rag1(-/-), IL-7Rα(-/-), and germ-free mice. These findings indicate that nTh17 and γδ T cells, but not ILCs, are key mucosal sentinels that control oral pathogens.

  7. Imbalances of Th17 and Treg cells and their respective cytokines in COPD patients by disease stage.

    Science.gov (United States)

    Li, Xiang-Nan; Pan, Xue; Qiu, Dong

    2014-01-01

    The typical balance between Th17 and Treg T cell subsets is altered in various autoimmune diseases. Here, inflammatory markers in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) (n=32) and stable COPD (n=36) were compared with smokers with normal lung function (n=40, control group). Flow cytometry was used to detect proportions of Th17 and Treg cells in the peripheral blood. ELISA of induced sputum samples was used to detect IL-17 (secreted by Th17 cells) and TGF-β1 (secreted by Treg cells) concentrations. The proportion of Th17 cells in peripheral blood and secreted IL-17 and TGF-β1 levels in sputum were significantly higher in acute exacerbation of COPD patients than in stable COPD and control groups (P Treg cells was lower than in stable COPD but higher than in controls. Th17 proportions were negatively correlated with Treg proportions in both acute exacerbation and stable COPD patients, and positively correlated with IL-17 levels (P Treg proportion and TGF-β1 levels (P Treg cells. Acute exacerbation of COPD is shifted toward a pro-inflammatory response, while stable COPD is shifted toward an anti-inflammatory response. This finding may provide a new direction for future clinical treatment of COPD by seeking to repair the disrupted balance in T cells.

  8. Th2/Th17细胞群与支气管哮喘机制研究%The mechanism research of Th2/Th17 cells and bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    魏燕; 向旭东

    2014-01-01

    Bronchial asthma(asthma) is a kind of chronic airway inflammatory diseases mediated by eosinophils,mast cells,T lymphocytes,neutrophils,airway epithelial cells and their cytokines[1].Classic imbalance ofTh1 Th2 cell played an important role in allergic asthma pathogenesis,Th17/IL-17 axis was confirmed with sever asthma,hormone resistant asthma,predominantly neutrophils infiltrating asthma[2].In recent years,the study found there is a a new subset of CD4+ T cells in the body which is different from Th1,Th2,Th17,Th9,called the Th2/Th17 double phenotypic effector CD4+ T cells (Th2/Th17 cells)[3-5].Found in the discussion to the pathogenesis of asthma,Th2/Th17 cells can both secrete Th2 cytokines IL-4,IL-5,IL-13 and Th17 cytokines IL-17,IL-8,IL-22,etc.And under the differentenvironment,it can produce different biological effect.This shows the Th2/Th17 cells could play a decisive role in sever asthma and process of mutual transformation between different asthma phenotypes.The aim of this review is to propose how Th2/Th17 cells function in asthma.%支气管哮喘(简称哮喘)是一种由多种细胞(如嗜酸粒细胞、肥大细胞、T淋巴细胞、中性粒细胞和气道上皮细胞等)和细胞组分参与的气道慢性炎症性疾病[1].经典的Th1/Th2细胞失衡被认为是过敏性哮喘的主要发病机制,Th17/IL-17轴被证实与重症哮喘、激素抵抗型哮喘、以中性粒细胞浸润为主的哮喘有关[2].近年来研究发现,机体内存在一种不同于目前已知的Th1、Th2、Th17、Th9等的新型CD4+T细胞,被称为Th2/Th17双表型记忆性CD4+T细胞群(简称Th2/Th17细胞群)[3-5].在哮喘发病机制的探讨中发现,Th2/Th17细胞群既能分泌Th2表型细胞因子IL-4、IL-5、IL-13,也可以分泌Th17型细胞因子IL-17、IL-8、IL-22等;且在不同的微环境下发生不一样的生物学效应,这显示了Th2/Th17细胞群可能在哮喘发生发展(特别是重症哮喘)及各亚型相互转化过程中

  9. Enhanced Th1/Th17 Functions of CD161+ CD8+ T Cells in Mucosal Tissues of Rhesus Macaques.

    Directory of Open Access Journals (Sweden)

    Namita Rout

    Full Text Available Expression of the C-type lectin-like receptor CD161 by human T cells is associated with type-17 responses, which play critical regulatory roles in immunity and inflammation at mucosal sites. However, the functions of CD161-expressing T cells in macaques, the pre-clinical model of several human diseases, remain unknown. This study examined the phenotypic and functional characteristics of CD161+ T cells in peripheral blood, mucosal tissues and lymph nodes of rhesus macaques. Majority of CD161-expressing T cells in peripheral blood and lung/intestinal mucosal tissues of rhesus macaques were found to be CD8+CD4- in phenotype. There was a significant enrichment of CD161+CD8+ T cells in the lungs and colonic mucosa (16.1%±6.6 and 16.8%±5.7 in comparison to peripheral blood (4.2%±1.2 and mesenteric lymph nodes (1.3%±0.8. Regardless of the tissue compartment, CD161+CD8+ T cells mainly comprised of γδ T cells and TCR Vα7.2+ MAIT cells (up to 80%, and displayed Th1 and Th17 cytokine responses to mitogen stimulation. Mucosal CD161+CD8+ T cells were characterized by very high expression of CD69, a recent activation marker that is preferentially expressed on tissue resident cells. Furthermore, lung and colonic mucosal CD161+CD8+ T cells showed enhanced IFN-γ, IL-17, and Perforin production in comparison to those in blood. Thus, macaque CD161+CD8+ T cells represent mucosal tissue-homing innate-like CD8+ T-cell populations with Th1/Th17 type cytokine and cytotoxic effector functions that can potentially enhance the recruitment of adaptive immune cells and control initial pathogen burden/dissemination in tissues. Analysis of their role in early immune responses to mucosal pathogens will be valuable in the design of vaccines and therapeutics.

  10. Th17细胞的分化调控与自身免疫性疾病%The differentiation and regulation of Th17 cell and autoimmune diseases

    Institute of Scientific and Technical Information of China (English)

    郭静雅; 邱玉华

    2010-01-01

    Th17细胞是最近发现的一种在分化和功能上均不同于Th1和Th2的新型CD4+T细胞亚群.该群细胞以主要分泌细胞因子IL-17而得名.IL-6、TGF-β、IL-21及IL-23等对Th17细胞的分化调控发挥重要作用.研究表明,Th17细胞可参与多种自身免疫性疾病的发生、发展与转归.%The latest revealed Th17 cell belongs to a new subgroup of CD4+T cell which differs from Th1 and Th2 on differentiation and function.The cell is so named because of its characteristic of mainly excreting cytokine IL-17.Cytokine IL-6,TGF-β,IL-21 and IL-23 all of them play important roles in differentiation and regulation of Th17 cell.Studies showed that Th17 cell can participate in the development of mutiple autoimmne diseases.

  11. IL-21 induction of CD4+ T cell differentiation into Th17 cells contributes to bleomycin-induced fibrosis in mice.

    Science.gov (United States)

    Lei, Ling; Zhong, Xiao-Ning; He, Zhi-Yi; Zhao, Cheng; Sun, Xue-Jiao

    2015-04-01

    Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs. Th17 cells and interleukin-17 (also called IL-17A) have been found to be increased in peripheral blood and skin in patients with SSc. IL-21 is a potent inducer of Th17 differentiation that is produced by activated T cells, and whose relationship with Th17 cells in SSc is unclear. Here, using a bleomycin (BLM)-induced mouse model of skin fibrosis, we detected the frequency of CD4+/IL-17+ (Th17) cells, CD4+/IL-21+ T cells and IL-21+ Th17 cells in peripheral blood, skin and lungs, as well as the serum content of IL-17A and IL-21. In addition, we assessed the differentiation of CD4+ T cells cultured from these mice into Th17 cells in response to treatment with IL-21. Compared with the control mice, Th17 cell counts and IL-17A levels were significantly increased and correlated with inflammatory and fibrotic indices in the skin and lungs of the BLM-induced fibrosis mice. Moreover, serum levels of CD4+/IL-21+ T cells, IL-21+ Th17 cells, and IL-21 were significantly increased in these mice, and correlated positively with serum levels of Th17 cells. In vitro experiments showed that IL-21 treated CD4+ T cells derived from BLM-induced mice differentiated into Th17 cells. Our results indicate that Th17 cells and IL-17A contributes to inflammatory and fibrotic processes in the skin and lungs in a BLM-induced mouse model of SSc. Moreover, the expansion of the Th17 cell population may be subsequent to IL-21 promotion of the differentiation of CD4+ T cells in these mice.

  12. The Chinese highly pathogenic porcine reproductive and respiratory syndrome virus infection suppresses Th17 cells response in vivo.

    Science.gov (United States)

    Zhang, Long; Zhou, Lei; Ge, Xinna; Guo, Xin; Han, Jun; Yang, Hanchun

    2016-06-30

    Porcine reproductive and respiratory syndrome virus (PRRSV) has been shown to immunomodulate innate and adaptive immunity of pigs. The Chinese highly pathogenic PRRSV (HP-PRRSV) infection causes severe bacterial secondary infection in pigs. However, the mechanism in relation to the bacterial secondary infection induced by HP-PRRSV remains unknown. In the present study, Th17 cells response in peripheral blood, lungs, spleens and lymph nodes of piglets were analyzed, and bacterial loads in lungs of piglets were examined upon HP-PRRSV infection. Meanwhile the changes of CD4(+) and CD8(+) T cells in peripheral blood of the inoculated piglets were analyzed. The results showed that HP-PRRSV-inoculated piglets exhibited a suppressed Th17 cells response in peripheral blood and a reduced number of Th17 cells in lungs, and higher bacterial loads in lungs, compared with low pathogenic PRRSV. Moreover, HP-PRRSV obviously resulted in severe depletion of porcine T cells in peripheral blood at the early stage of infection. These findings indicate that HP-PRRSV infection suppresses the response of Th17 cells that play an important role in combating bacterial infections, suggesting a possible correlation between the suppression of Th17 cells response in vivo and bacterial secondary infection induced by HP-PRRSV. Our present study adds a novel insight into better understanding of the pathogenesis of the Chinese HP-PRRSV.

  13. T helper 17 cells in sexually transmitted diseases%性传播疾病与Th17细胞关系的研究进展

    Institute of Scientific and Technical Information of China (English)

    章鹏飞; 季必华

    2014-01-01

    T helper 17 (Th17) cells,a new subset of CD4+ effector T cells different trom Thl and Th2 cells,are characterized by the secretion of interleukin-17 (IL-17),and associated with the pathogenesis of syphilis,gonorrhea and acquired immunodeficiency syndrome (AIDS).The number of Th17 cells is abnormal in patients with syphilis and gonorrhea,but whether Th17 cells helps to control syphilis or gonorrhea remains controversial.The proportion of Th17 cells is decreased and there is an imbalance between Th17 cells and regulatory T (Treg) cells in peripheral blood of patients with human immunodeficiency virus (HIV).To upregulate the levels of Th17 cells and maintain the balance between Th17 cells and Treg cells is essential for the host to fight against HIV infection spontaneously.%Th17细胞是近年来发现的一种不同于Th1、Th2细胞的CD4+效应性T细胞亚群,以分泌IL-17为特点.Th17细胞与梅毒、淋病及艾滋病的发病机制具有一定的相关性.Th17细胞数目在梅毒螺旋体及淋球菌感染者体内存在变化,但Th17细胞是否有利于梅毒及淋病的病情控制尚有争议.HIV感染者存在外周血Th17和Treg细胞的不平衡,Th17细胞比例较低,机体自发地控制病毒进展,需要保持Th 17/Treg的平衡,而Th17细胞水平升高有利于控制病情.

  14. T cell-derived interleukin-10 is an important regulator of the Th17 response during lethal alphavirus encephalomyelitis.

    Science.gov (United States)

    Kulcsar, Kirsten A; Griffin, Diane E

    2016-06-15

    Neuroadapted Sindbis virus infection of mice causes T cell-mediated fatal encephalomyelitis. In the absence of IL-10, pathogenic Th17 cells are increased and disease is accelerated. Lymphoid and myeloid cell contributions to IL-10 production were determined using VertX IL-10 transcriptional eGFP reporter mice. Effector and regulatory CD4(+) and CD8(+) T cells in the brain, but not the cervical lymph nodes, were the primary producers of IL-10. Th17 and Th1/Th17 cells were increased in mice that lacked T cell IL-10 production, although less than in the absence of IL-10. Morbidity and mortality were not affected suggesting an IL-10 threshold for disease exacerbation. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. GITRL modulates the activities of p38 MAPK and STAT3 to promote Th17 cell differentiation in autoimmune arthritis.

    Science.gov (United States)

    Tang, Xinyi; Tian, Jie; Ma, Jie; Wang, Jiemin; Qi, Chen; Rui, Ke; Wang, Yungang; Xu, Huaxi; Lu, Liwei; Wang, Shengjun

    2016-02-23

    The glucocorticoid-induced TNFR family-related protein (GITR) and its ligand play a critical role in the pathogenesis of autoimmune arthritis by enhancing the Th17 cell response, but their molecular mechanisms remain largely unclear. This study aims to define the role of p38 mitogen-activated protein kinases (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling in GITRL-induced Th17 cells in autoimmune arthritis. We found that the p38 phosphorylation was enhanced by GITRL in activated CD4+T cells, and the p38 inhibitor restrained the GITRL-induced Th17 cell expansion in a dose-dependent manner. Moreover, there was decreased STAT3 activity on Tyr705 and Ser727 with the p38 inhibitor in vitro. Notably, the p38 inhibitor could prevent GITRL-treated arthritis progression and markedly decrease the Th17 cell percentages. The phosphorylation of the Tyr705 site was significantly lower in the GITRL-treated CIA mice administrated with the p38 inhibitor. A significantly higher phosphorylation of p38 was detected in RA patients and had a positive relationship with the serum level of anti-cyclic citrullinated peptide (anti-CCP) antibody. Our findings have indicated that GITRL could promote Th17 cell differentiation by p38 MAPK and STAT3 signaling in autoimmune arthritis.

  16. Decidual stromal cells recruit Th17 cells into decidua to promote proliferation and invasion of human trophoblast cells by secreting IL-17.

    Science.gov (United States)

    Wu, Hai-Xia; Jin, Li-Ping; Xu, Bing; Liang, Shan-Shan; Li, Da-Jin

    2014-05-01

    T helper 17 (Th17) cells have both regulatory and protective roles in physiological conditions. The Th17 subset and the cytokine interleukin-17A (IL-17A) have been implicated in the pathogenesis of certain autoimmune diseases, several types of cancer and allograft rejection. However, the role of Th17 cells at the maternal/fetal interface remains unknown. Here, we demonstrate that Th17 cells are present in decidua and are increased in the peripheral blood of 10 clinically normal pregnancies based on intracellular cytokine analysis. Our results suggest a potential role of Th17 cells in sustaining pregnancy in humans. Furthermore, we demonstrate that decidual stromal cells (DSCs) but not trophoblast cells recruit peripheral Th17 cells into the decidua by secreting CCL2. The recruited Th17 cells promote proliferation and invasion and inhibit the apoptosis of human trophoblast cells by secreting IL-17 during the first trimester of pregnancy. These findings indicate a novel role for Th17 cells in controlling the maternal-fetal relationship and placenta development.

  17. Arctigenin Suppress Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis Through AMPK and PPAR-γ/ROR-γt Signaling.

    Science.gov (United States)

    Li, Wen; Zhang, Zhihui; Zhang, Kai; Xue, Zhenyi; Li, Yan; Zhang, Zimu; Zhang, Lijuan; Gu, Chao; Zhang, Qi; Hao, Junwei; Da, Yurong; Yao, Zhi; Kong, Ying; Zhang, Rongxin

    2016-10-01

    Arctigenin is a herb compound extract from Arctium lappa and is reported to exhibit pharmacological properties, including neuronal protection and antidiabetic, antitumor, and antioxidant properties. However, the effects of arctigenin on autoimmune inflammatory diseases of the CNS, multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE) are still unclear. In this study, we demonstrated that arctigenin-treated mice are resistant to EAE; the clinical scores of arctigenin-treated mice are significantly reduced. Histochemical assays of spinal cord sections also showed that arctigenin reduces inflammation and demyelination in mice with EAE. Furthermore, the Th1 and Th17 cells in peripheral immune organs are inhibited by arctigenin in vivo. In addition, the Th1 cytokine IFN-γ and transcription factor T-bet, as well as the Th17 cytokines IL-17A, IL-17F, and transcription factor ROR-γt are significantly suppressed upon arctigenin treatment in vitro and in vivo. Interestedly, Th17 cells are obviously inhibited in CNS of mice with EAE, while Th1 cells do not significantly change. Besides, arctigenin significantly restrains the differentiation of Th17 cells. We further demonstrate that arctigenin activates AMPK and inhibits phosphorylated p38, in addition, upregulates PPAR-γ, and finally suppresses ROR-γt. These findings suggest that arctigenin may have anti-inflammatory and immunosuppressive properties via inhibiting Th17 cells, indicating that it could be a potential therapeutic drug for multiple sclerosis or other autoimmune inflammatory diseases.

  18. Continuous time Bayesian networks identify Prdm1 as a negative regulator of TH17 cell differentiation in humans.

    Science.gov (United States)

    Acerbi, Enzo; Viganò, Elena; Poidinger, Michael; Mortellaro, Alessandra; Zelante, Teresa; Stella, Fabio

    2016-03-15

    T helper 17 (TH17) cells represent a pivotal adaptive cell subset involved in multiple immune disorders in mammalian species. Deciphering the molecular interactions regulating TH17 cell differentiation is particularly critical for novel drug target discovery designed to control maladaptive inflammatory conditions. Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling TH17 differentiation. From the network, we identified the Prdm1 gene encoding the B lymphocyte-induced maturation protein 1 as a crucial negative regulator of human TH17 cell differentiation. The results have been validated by perturbing Prdm1 expression on freshly isolated CD4(+) naïve T cells: reduction of Prdm1 expression leads to augmentation of IL-17 release. These data unravel a possible novel target to control TH17 polarization in inflammatory disorders. Furthermore, this study represents the first in vitro validation of continuous time Bayesian networks as gene network reconstruction method and as hypothesis generation tool for wet-lab biological experiments.

  19. Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment.

    Science.gov (United States)

    Andersson, Karin M E; Cavallini, Nicola Filluelo; Hu, Dan; Brisslert, Mikael; Cialic, Ron; Valadi, Hadi; Erlandsson, Malin C; Silfverswärd, Sofia; Pullerits, Rille; Kuchroo, Vijay K; Weiner, Howard L; Bokarewa, Maria I

    2015-06-04

    T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF ). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF ) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.

  20. CD161 Expression Defines a Th1/Th17 Polyfunctional Subset of Resident Memory T Lymphocytes in Bronchoalveolar Cells.

    Directory of Open Access Journals (Sweden)

    Yolanda Gonzalez

    Full Text Available Alveolar resident memory T cells (T(RM comprise a currently uncharacterized mixture of cell subpopulations. The CD3(+CD161(+ T cell subpopulation resides in the liver, intestine and skin, but it has the capacity for tissue migration; however, the presence of resident CD3(+CD161(+ T cells in the bronchoalveolar space under normal conditions has not been reported. Bronchoalveolar cells (BACs from healthy volunteers were evaluated and found that 8.6% (range 2.5%-21% of these cells were CD3(+ T lymphocytes. Within the CD3(+ population, 4.6% of the cells (2.1-11.3 expressed CD161 on the cell surface, and 74.2% of the CD161(+CD3(+ T cells expressed CD45RO. The number of CD3(+CD161(+ T cells was significantly lower in the bronchoalveolar space than in the blood (4.6% of BACs vs 8.4% of peripheral blood mononuclear cells (PBMCs; P<0.05. We also found that 2.17% of CD4(+ T lymphocytes and 1.52% of CD8(+ T lymphocytes expressed CD161. Twenty-two percent of the alveolar CD3(+CD161(+ T lymphocytes produced cytokines upon stimulation by PMA plus ionomycin, and significantly more interferon gamma (IFN-γ was produced compared with other cytokines (P = 0.05. Most alveolar CD3(+CD161(+ T cells produced interleukin-17 (IL-17 and IFN-γ simultaneously, and the percentage of these cells was significantly higher than the percentage of CD3(+CD161- T cells. Moreover, the percentage of alveolar CD3(+CD161(+ T lymphocytes that produced IFN-γ/IL-17 was significantly higher than those in the peripheral blood (p<0.05. In conclusion, Th1/Th17-CD3(+CD161(+ TRM could contribute to compartment-specific immune responses in the lung.

  1. Expansion of Th17 Cells by Human Mast Cells Is Driven by Inflammasome-Independent IL-1β.

    Science.gov (United States)

    Suurmond, Jolien; Habets, Kim L L; Dorjée, Annemarie L; Huizinga, Tom W; Toes, René E M

    2016-12-01

    Mast cells (MC) are most well known for their role in innate immune responses. However, MC are increasingly recognized as important regulators of adaptive immune responses, especially in setting the outcome of T cell responses. In this study we determined the effect of MC on cytokine production by naive and memory human Th cells. CD4(+) T cells were cultured with MC supernatant or control medium, after which cytokine production by T cells was determined. Supernatant of activated MC specifically increased the number of IL-17-producing T cells. This enhancement of Th17 cell number was specifically observed for the memory CD4(+) T cell population and not for the naive CD4(+) T cell population. The effect of MC was inhibited for ∼80% by blocking Abs to IL-1β and the rIL-1R antagonist anakinra. Importantly, secretion of active IL-1β by MC was independent of caspase activity, indicating that Th17 cell expansion by MC occurred through inflammasome-independent IL-1β. Together, these studies reveal a role for human MC in setting the outcome of T cell responses through release of caspase-independent IL-1β, and provide evidence for a novel contribution of MC in boosting the Th17 axis in mucosal immune responses. Copyright © 2016 by The American Association of Immunologists, Inc.

  2. Changes and Significance of peripheral Th17 cells and Treg cells in HBV infected patients%Th17细胞与 Treg 细胞在 HBV 感染患者中的检测意义

    Institute of Scientific and Technical Information of China (English)

    邓永佳; 张房英; 赖小丽

    2015-01-01

    Objective To investigate the changes of T helper 17 (Th17)cells and regulatory T (Treg)cells in the peripheral blood of hepatitis B virus(HBV)infected patients and their correlations with liver injury.Methods One hundred and nine cases of hepatitis B patients were chosen in our hospital from March 2010 to January 2013 and were divided into four groups in accordance with the condition of diseases.The peripheral blood of 32 asymptomatic HBV carriers (ASC group),47 chronic hepatitis B patients (CHB group),30 hepatocellular carcinoma patients (HCC group)and 30 healthy controls (control group)were collected.The percentages of Th17 and Treg cells were detected by flow cytometry.Alanine aminotransferase (ALT)and aspartate aminotransferase (AST)were detected by automatic biochemistry analyzer.Results Compared with control group,the percentages of both Treg and Th17 cells in the peripheral blood of ASC group were higher,but no statistical difference was detected (t =0.809,P >0.05 for Treg cells;t =1 .459,P >0.05 for Th17 cells, respectively).While significant increase of percentages of Treg cells and Th17 cells in CHB group and HCC group was found(t=2.988,7.569,P <0.05 for Treg cells;t=3.910,6.725,P <0.05 for Th17 cells,respectively).And Treg cells increase in HCC group was higher than that in CHB group (t=6.580,P <0.01).Treg cells and Th17 cells were correlated positively with ALT and AST(r=0.546,0.587,P <0.01 for Treg cells;r =0.546、0.617,P <0.01 for Th17 cells),and Th17 cell percentage was positively correlated with Treg cell percentage (r =0.487,P <0.01).The rate of Th17/Treg in control group was the lowest (0.15%±0.14%),while significantly higher Th17/Treg ratio in CHB group and HCC group were observed (t=2.015,5.056,P <0.05).Conclusion With the development of HBV infection,the percentages of Th17 and Treg cells increased.The destruetion of the immune balance leads to the increased of Th17 cells that induced immune injury and induce the inflammation of liver cells

  3. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues

    Energy Technology Data Exchange (ETDEWEB)

    Tong, Bei; Dou, Yannong; Wang, Ting; Yu, Juntao; Wu, Xin; Lu, Qian [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China); Chou, Guixin; Wang, Zhengtao [Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Kong, Lingyi [Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009 (China); Dai, Yue, E-mail: yuedaicpu@hotmail.com [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China); Xia, Yufeng, E-mail: yfxiacpu@126.com [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China)

    2015-01-01

    Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic–pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail. In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3{sup +} cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint. The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR. - Highlights: • Norisoboldine, administered orally, markedly attenuates the clinical signs of CIA. • Norisoboldine regulates the balance of Th17/Treg cells in the intestinal lymph node. • Norisoboldine induces the migration of Treg cells from the gut to joint.

  4. Detection of Th17 cells in peripheral blood of the patients with serofast sypilis%梅毒血清固定患者外周血Th17细胞的检测

    Institute of Scientific and Technical Information of China (English)

    刘百灵; 赵建斌

    2013-01-01

    目的 检测梅毒血清固定患者外周血Th17细胞的细胞比例和相关细胞因子的变化,初步探讨Th17细胞在梅毒血清固定现象中的作用.方法 梅毒血清固定患者30例,同时以30例健康体检人作为对照组.采用流式细胞术(Flow cytometry,FCM)检测外周血单个核细胞(peripheral blood mononuclear cells,PBMC)中Th17细胞在CD4+T细胞中的比例;采用实时定量PCR方法检测Th17细胞特异性转录因子孤独受体(Υ)t(orphan nuclear receptorgammat,ROR(Υ)t)及细胞因子IL-17mRNA的表达.结果 梅毒血清固定患者外周血Th17细胞比例及ROR(Υ)t和IL-17的表达量显著低于健康对照组(P<0.05).结论 Th17细胞的异常可能是梅毒血清固定现象形成的重要原因之一.

  5. 宫颈癌患者外周血及组织中Th17细胞、Treg细胞表达及Th17/Treg失衡的研究%Th17 cells, Treg cells and imbalance of Th17/Treg in peripheral blood and tissues of patients with cervical cancer

    Institute of Scientific and Technical Information of China (English)

    何芳; 杨慧娟

    2014-01-01

    目的 探讨宫颈癌患者外周血及组织中Th17细胞、Treg细胞表达及Th 17/Treg失衡的意义.方法 分别选取同期53例宫颈癌、25例CIN和25例子宫全切患者作为研究对象,采用流式细胞仪检测外周血和宫颈组织中Th17细胞、Treg细胞表达.结果 宫颈癌组、CIN组外周血中Th17细胞、Treg细胞表达及Th 17/Treg均显著高于对照组(P<0.05).外周血Th17细胞表达与FIGO分期呈正相关(P<0.05),Treg细胞表达与分化程度呈负相关(P<0.05).组织中Th 17/Treg与FIGO分期呈负相关(P<0.05).结论 宫颈癌患者外周血和组织中Th17细胞和Treg细胞表达均显著升高,Th17/Treg失衡在宫颈癌发生发展过程中起重要促进作用.

  6. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis.

    Directory of Open Access Journals (Sweden)

    Abdul M Tyagi

    Full Text Available Th17 cells produce IL-17, and the latter promotes bone loss in collagen-induced arthritis in mice. Blocking IL-17 action in mouse model of rheumatoid arthritis reduces disease symptoms. These observations suggest that Th17 cells may be involved in the pathogenesis of bone loss. However, the role of Th17 cell in estrogen (E2 deficiency-induced bone loss is still not very clear. We investigated the effect of E2 on Th17 differentiation in vivo and IL-17 mediated regulation of osteoclast and osteoblast differentiation. Additionally, effect of IL-17 functional block under E2 deficiency-induced bone loss was studied. In murine bone marrow cells, E2 suppressed IL-17 mediated osteoclast differentiation. IL-17 inhibited formation of mineralized nodules in osteoblasts and this effect was suppressed by E2. E2 treatment to mouse calvarial osteoblasts inhibited the IL-17-induced production of osteoclastogenic cytokines and NF-kB translocation. In ovariectomized mice, there was increase in the number of Th17 cells, transcription factors promoting Th17 cell differentiation and circulating IL-17 levels. These effects were reversed by E2 supplementation. Treatment of neutralizing IL-17 monoclonal antibody to Ovx mice mitigated the E2 deficiency-induced trabecular bone loss and reversed the decreased osteoprotegerin-to-receptor activator of nuclear factor kappa B ligand (RANKL transcript levels in long bones, increased osteoclast differentiation from the bone marrow precursor cells and decreased osteoblast differentiation from the bone marrow stromal cells. Our findings indicate that E2 deficiency leads to increased differentiation of Th17 cells with attendant up regulation of STAT3, ROR-γt and ROR-α and downregulation of Foxp3 which antagonizes Th17 cell differentiation. Increased IL-17 production in turn induces bone loss by increasing pro-osteoclastogenic cytokines including TNF-α, IL-6 and RANKL from osteoblasts and functional block of IL-17 prevents bone

  7. Th17和Treg细胞的平衡状态与肺结核的关系%Relation of the equilibrium state of Th17 and Treg cells with tuberculosis

    Institute of Scientific and Technical Information of China (English)

    李靖; 封文军; 何艳

    2012-01-01

    Th17和Treg细胞均来源于CD4+T细胞,在机体免疫应答中的作用基本相反,Th17促进免疫应答,而Treg细胞抑制免疫应答,正常情况下两者之间的平衡状态有利于保持机体免疫平衡.结核分枝杆菌感染可能打破两者之间的平衡从而导致疾病进展,而抗结核治疗可能恢复二者平衡关系.此文就Th17和Treg细胞的分化、调控和功能,以及两者在艾滋病及肺结核患者中的变化等进行综述.%Th17 and Treg cells are all derived from the CD4 + T cells.Their roles in the body' s immune response are basically opposite.Th17 cells promote the immune responses,though Treg cells suppress it.Under normal circumstances,the equilibrium state between them could maintain the immunologic balance of the body.Tuberchlosis infection may break the balance and lead to disease progression,however,anti-tuberculosis treatment may restore balance.The differentiation,regulation and function of Th17 and Treg cells,as well as the changes of Th17 and Treg in AIDS and tuberculosis patients are reviewed.

  8. Role of Th17 cell and interleukin-17 in the pathogenesis of chronic urticaria%Th17细胞和IL-17在慢性荨麻疹患者发病中的作用

    Institute of Scientific and Technical Information of China (English)

    邹循辉; 石丽君; 李利豪

    2013-01-01

    Objective To investigate the roles of Th17 cells and interleukin-17 in the pathogenesis of chronic urticaria. Methods Peripheral blood were collected from 60 chronic urticaria patients and 30 normal controls,The expression of Th17 cells were tested with flow Cytometry,and serum level of interleukin-17 was tested with ELISA. The correlation between Th17 and interleukin-17 was analyzed. Results Compared with controls,the positive rate of Th17 cells and serum level of interleukin-17 were significantly higher in the chronic urticaria patients (P<0.05), showing a positive correlation between them (r=0.896,P<0.05). Conclusions Both of Th17 cells and interleukin-17 are involved in the course of chronic urticaria.%目的 探讨Th17细胞和白细胞介素(Interleukin,IL)-17在慢性荨麻疹患者发病机制中的作用. 方法 采用流式细胞仪检测60例慢性荨麻疹患者和30例健康体检者(对照组)外周血Th17细胞的表达,双抗夹心酶联免疫吸附法检测上述研究对象外周血血清IL-17水平,并分析二者相关性. 结果 慢性荨麻疹患者Th17细胞阳性率和IL-17水平均高于对照组(P<0.05),Th17细胞与血清IL-17水平呈正相关(r=0.896,P<0.05). 结论 Th17细胞和IL-17可能参与了慢性荨麻疹患者的发病过程.

  9. Th17 cytokines and arthritis

    NARCIS (Netherlands)

    E.W. Lubberts (Erik)

    2010-01-01

    textabstractTh17 cells are implicated in human autoimmune diseases, such as rheumatoid arthritis (RA), although it has not been established whether this persistent destructive arthritis is driven by Th1 and/or Th17 cells. Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis as has b

  10. Role of Th17 cells and cytokines in the pathogenesis of kidney diseases%Th17细胞及相关细胞因子与肾脏疾病

    Institute of Scientific and Technical Information of China (English)

    盖丰丰; 曹鹏

    2012-01-01

    Th17细胞是近年来新发现的一类CD4+T细胞亚群,主要通过分泌白细胞介素17等细胞因子发挥促炎作用,参与多种自身免疫性疾病的发病过程.本文就Th17细胞及其相关细胞因子与肾脏病的关系进行综述,以期更深入地认识肾脏病的发病机制,为肾脏病诊治寻找新的靶点提供依据.%T helper 17 cells ( Th17) are a subset of T helper cells producing interleukin 17 (IL-17). They are considered developnientally distinct from Thl and Th2 cells and excessive amounts of the cell are thought to play a key role in autoimmune disease. Accumulating evidence suggests that Th17 cells and cytokines participate in human and experimental renal disease. This article reviews the progress on the role of Th17 cells and cytokines in the pathogenesis of kidney diseases.

  11. C5a regulates IL-12+ DC migration to induce pathogenic Th1 and Th17 cells in sepsis.

    Directory of Open Access Journals (Sweden)

    Ning Ma

    Full Text Available OBJECTIVE: It is well known that complement system C5a is excessively activated during the onset of sepsis. However, it is unclear whether C5a can regulate dentritic cells (DCs to stimulate adaptive immune cells such as Th1 and Th17 in sepsis. METHODS: Sepsis was induced by cecal ligation and puncture (CLP. CLP-induced sepsis was treated with anti-C5a or IL-12. IL-12(+DC, IFNγ(+Th1, and IL-17(+Th17 cells were analyzed by flow cytometry. IL-12 was measured by ELISA. RESULTS: Our studies here showed that C5a induced IL-12(+DC cell migration from the peritoneal cavity to peripheral blood and lymph nodes. Furthermore, IL-12(+DC cells induced the expansion of pathogenic IFNγ(+Th1 and IL-17(+Th17 cells in peripheral blood and lymph nodes. Moreover, IL-12, secreted by DC cells in the peritoneal cavity, is an important factor that prevents the development of sepsis. CONCLUSION: Our data suggests that C5a regulates IL-12(+DC cell migration to induce pathogenic Th1 and Th17 cells in sepsis.

  12. Candida-elicited murine Th17 cells express high Ctla-4 compared with Th1 cells and are resistant to costimulation blockade.

    Science.gov (United States)

    Krummey, Scott M; Floyd, Tamara L; Liu, Danya; Wagener, Maylene E; Song, Mingqing; Ford, Mandy L

    2014-03-01

    Effector and memory T cells may cross-react with allogeneic Ags to mediate graft rejection. Whereas the costimulation properties of Th1 cells are well studied, relatively little is known about the costimulation requirements of microbe-elicited Th17 cells. The costimulation blocker CTLA-4 Ig has been ineffective in the treatment of several Th17-driven autoimmune diseases and is associated with severe acute rejection following renal transplantation, leading us to investigate whether Th17 cells play a role in CD28/CTLA-4 blockade-resistant alloreactivity. We established an Ag-specific model in which Th1 and Th17 cells were elicited via Mycobacterium tuberculosis and Candida albicans immunization, respectively. C. albicans immunization elicited a higher frequency of Th17 cells and conferred resistance to costimulation blockade following transplantation. Compared with the M. tuberculosis group, C. albicans-elicited Th17 cells contained a higher frequency of IL-17(+)IFN-γ(+) producers and a lower frequency of IL-10(+) and IL-10(+)IL-17(+) cells. Importantly, Th17 cells differentially regulated the CD28/CTLA-4 pathway, expressing similarly high CD28 but significantly greater amounts of CTLA-4 compared with Th1 cells. Ex vivo blockade experiments demonstrated that Th17 cells are more sensitive to CTLA-4 coinhibition and therefore less susceptible to CTLA-4 Ig. These novel insights into the differential regulation of CTLA-4 coinhibition on CD4(+) T cells have implications for the immunomodulation of pathologic T cell responses during transplantation and autoimmunity.

  13. Pre-Vaccination Frequencies of Th17 Cells Correlate with Vaccine-Induced T-Cell Responses to Survivin-Derived Peptide Epitopes

    DEFF Research Database (Denmark)

    Køllgaard, Tania; Ugurel-Becker, Selma; Idorn, Manja

    2015-01-01

    Various subsets of immune regulatory cells are suggested to influence the outcome of therapeutic antigen-specific anti-tumor vaccinations. We performed an exploratory analysis of a possible correlation of pre-vaccination Th17 cells, MDSCs, and Tregs with both vaccination-induced T-cell responses...... an altered activity of immune regulatory cells. Moreover, the frequencies of Th17 cells (p=0.03) and Tregs (p=0.02) were elevated as compared to healthy donors. IL-17-secreting CD4+ T cells displayed an impact on the immunological and clinical effects of vaccination: Patients characterized by high...... frequencies of Th17 cells at pre-vaccination were more likely to develop survivin-specific T-cell reactivity post-vaccination (p=0.03). Furthermore, the frequency of Th17 (p=0.09) and Th17/IFNγ+ (p=0.19) cells associated with patient survival after vaccination. In summary, our explorative, hypothesis...

  14. Increased circulating Th17 cells and elevated serum levels of TGF-beta and IL-21 are correlated with human non-segmental vitiligo development.

    Science.gov (United States)

    Zhou, Li; Shi, Yu-Ling; Li, Kai; Hamzavi, Iltefat; Gao, Tian-Wen; Huggins, Richard H; Lim, Henry W; Mi, Qing-Sheng

    2015-05-01

    Although non-segmental vitiligo (NSV) results from the autoimmune destruction of melanocytes, the detailed immune mechanisms have not yet been fully elucidated. Th17 cells have been identified to be implicated in human autoimmune diseases. In this study, the frequencies of peripheral blood Th17 cells and serum levels of IL-17A and Th17 cell-related cytokines were examined in 45 patients with active NSV compared to 45 race-, gender-, and age-matched healthy controls. Our results showed increased circulating Th17 cell frequencies and elevated serum IL-17A, TGF-β1, and IL-21 levels in patients with NSV. Meanwhile, the increased Th17 cell frequencies are positively correlated with serum TGF-β1 level, and the body surface area of lesions is positively correlated with elevated TGF-β1 and IL-21 levels and Th17 cell frequencies. Furthermore, positive correlation was identified between Th17 and Th1 cell frequencies in patients with NSV. These results further indicate the potential involvement of Th17 cells and the collaborative contribution of Th17 and Th1 in NSV development, and suggest that the elevated serum TGF-β1 and IL-21 levels could contribute to enhanced Th17 cell differentiation in NSV.

  15. Th17 cells and its role in bronchial asthma%Th17细胞及其在支气管哮喘发病中的作用

    Institute of Scientific and Technical Information of China (English)

    杨志明; 成俊芬

    2012-01-01

    Th17 cell represent a new subset of CD4+ CD effector T cells,some factors.Such as STAT3 and RORγt as well as RORα are involved in the differentiation and regulations of the Th17 cells.Recently,researches demonstrate that Th17 cells and its related Cytokines play crucial roles in the development of bronchial asthma,which may contribute to airway inflammation of bronchial asthma,airway remodeling and hyperresponsiveness.%Th17细胞是一类新型的CD4+T细胞,STAT3、RORγt和RORα等参与了其分化调控.最近,大量研究表明,Th17及其相关的细胞因子在支气管哮喘中起着重要的作用,参与了气道炎症、气道重塑以及气道高反应性.

  16. The Th17/Treg Immune Balance in Ulcerative Colitis Patients with Two Different Chinese Syndromes: Dampness-Heat in Large Intestine and Spleen and Kidney Yang Deficiency Syndrome

    Directory of Open Access Journals (Sweden)

    Yang Gong

    2015-01-01

    Full Text Available Objective. To investigate the Th17/Treg immune balance in the ulcerative colitis (UC patients with two Chinese syndrome: dampness-heat in large intestine (DHLI and spleen and kidney Yang deficiency (SKYD. Methods. Ninety UC patients (45 were diagnosed with DHLI and 45 with SKYD syndrome and 23 healthy people were recruited. The serumIL-17 and TGF-β1 levels of these participants were measured with ELISA; the expression of IL-17 and TGF-β 1 in colonic mucosa tissue was determined with immunohistochemistry and the percentage of Th17 and Treg in peripheral blood with flow cytometry. Results. The levels of IL-17 and Th17 were significantly higher in both DHLI and SKYD groups than in healthy control group and higher in DHLI than in SKYD group (P<0.05. The levels of TGF-β1 and Treg were significantly lower in the two UC patients groups than in healthy control group; and lower in SKYD group than in DHLI group (P<0.05. Conclusions. UC with DHLI syndrome could be characterized by the elevation of Th17 and IL-17 levels, which indicated an accentuation of inflammatory reaction; UC with SKYD syndrome could be characterized by the reduction of serum Treg and TGF-β1 levels, which represented a depression of immune tolerance.

  17. Th17 and regulatory T cells contribute to the in situ immune response in skin lesions of Jorge Lobo's disease.

    Science.gov (United States)

    Kanashiro-Galo, Luciane; Pagliari, Carla; Barboza, Tania Cristina; de Brito, Arival Cardoso; Xavier, Marilia Brasil; de Oliveira, Clivia Maria Moraes; Unger, Deborah Aben Athar; Sotto, Mirian Nacagami; Quaresma, Juarez Antonio Simões; Duarte, Maria Irma Seixas

    2016-01-01

    Jorge Lobo's disease (JLD) is a chronic granulomatous mycosis described in various Latin American countries. The main objective of the present study was to investigate the possible role of Th17 and Foxp3+ Treg cells in the pathogenesis of Jorge Lobo's disease. Human skin biopsies were submitted to an immunohistochemistry protocol to detect Foxp3, interleukin (IL)-1beta, CD25, IL-6, IL-17, and IL-23. The epidermis presented acanthosis, hyperkeratosis, and frequent presence of fungi. The dermis presented inflammatory infiltrate comprising macrophages, lymphocytes, epithelioid and multinucleated cells, and an intense number of fungi. Foxp3+ Treg cells and IL-17+ cells were visualized in lymphocytes in the inflammatory infiltrate. IL-1, IL-2R (CD25), IL-6, and IL-23 were visualized in the dermis, intermingled with fungal cells, permeating or participating of the granuloma. Following IL-17, the most prominent cytokine was IL-6. IL-23 and cells expressing CD25 were present in fewer number. The comparative analysis between IL-17 and Foxp3 demonstrated a statistically significant increased number of IL-17+ cells. Th17 cells play a role in the immune response of JLD. IL-1beta and IL-6 added to the previously described increased number of TGF-beta would stimulate such pattern of response. Th17 cells could be present as an effort to modulate the local immune response; however, high levels of a Th17 profile could overcome the role of Treg cells. The unbalance between Treg/Th17 cells seems to corroborate with the less effective immune response against the fungus.

  18. Upregulated Expression of microRNA-16 Correlates with Th17/Treg Cell Imbalance in Patients with Rheumatoid Arthritis.

    Science.gov (United States)

    Wu, Yuan-Hao; Liu, Wei; Xue, Bin; Zhang, Lei; Liu, Xiao-Ya; Liu, Bin; Wang, Yi; Cai, Yue; Duan, Ran

    2016-12-01

    To explore the correlation between miR-16 expression in T cells of peripheral blood mononuclear cells (PBMCs) and Th17/Treg imbalance in rheumatoid arthritis (RA) patients. Forty RA patients were recruited as the case group and further grouped as active RA and inactive RA groups; 21 healthy individuals were selected as the control group. Th17 and Treg were measured by flow cytometry, and their related cytokines were measured by FlowCytomix. RORγt, FoxP3 mRNA, and miR-16 expression in T cells was determined by real-time quantitative polymerase chain reaction. Western blotting was performed to measure RORγt and FoxP3 protein expression. RA patients showed upregulated Th17 and RORγt mRNA and protein expression compared with the controls (all p Treg and FoxP3 mRNA and protein expression compared with inactive RA patients and controls (all p Treg-related cytokines were lower in active RA patients than in controls (all p Treg cells of PBMCs (both p Treg cells was positively related with FoxP3 mRNA expression (both p Treg cells of PBMCs in RA patients was closely associated with the expression of RORγt and FoxP3. MiR-16 may be involved in Th17/Treg imbalance of RA patients by affecting the expression of RORγt and FoxP3.

  19. Generation of engineering Th17 cells and its function evaluation%基因工程Th17细胞的研制及其功能探讨

    Institute of Scientific and Technical Information of China (English)

    张焕新; 陈翀; 曾令宇; 张滢; 徐开林

    2011-01-01

    目的 探讨并优化制备基因工程Th17细胞的方法,评估制备的工程Th17细胞是否具有同天然Th17细胞类似的表型和功能.方法 包装含RORγt基因的重组慢病毒pXZ9-RORγt和空载体对照质粒pXZ9.C57BL6小鼠CD4+ CD25 - na(i)ve T细胞体外活化36 h后依据感染慢病毒颗粒的不同及是否添加TGF-β和IL-6,分为五组:pXZ9-RORγt组、TGF-β+ IL-6组(pXZ9+ TGF-β+ IL-6组)、联合组(pXZ9-RORγt+ TGF-β+ IL-6组)、空载体对照组(pXZ9组)及空白对照组.流式细胞术检测各组IL-17A阳性细胞比例,荧光定量PCR检测各组细胞IL-17A、IL-17F、IL-21和IFN-γ表达水平.通过小鼠实验性变应性脑脊髓炎(EAE)模型评估各组细胞是否具有加重EAE的功能.结果 ①pXZ9-RORγt组、TGF-β +IL-6组和联合组均制备出工程Th17细胞,其中联合组IL-17A阳性率达(60.59±8.15)%,明显高于pXZ9-RORγt组[(40.25±5.46)%]和TGF-β+IL-6组[(14.36±5.27)%].②各组工程Th17细胞均表达IL-17A与IL-17F,而IL-21仅在给予TGF-β和IL-6时明显升高.③各组工程Th17细胞均可加重小鼠EAE.结论 成功建立了制备高效工程Th17细胞的方法,其中过表达RORγt基因与联合TGF-β和IL-6不仅可提高Th17细胞的制备效率,而且制备的工程Th17细胞在表型和功能上与天然Th17细胞相类似.%Objective To generate engineering Th17 cells from mice CD4+ CD25- naive T cells,and to evaluate whether the phenotypes or functions of these engineering cells were similar to natural Th17 cells.Methods Recombinant lentivirus carrying mouse RORγt (pXZ9-RORγt) and mock control pXZ9 were generated by co-transfected three-plasmids into 293FT packing cells.CD4 + CD25 - naǐve T cells were purified from mice spleens by magnetic activated cell sorting,and stimulated by anti-CD3ε,anti-CD28 mAb plus IL-2.The stimulated cells were further infected by pXZ9-RORγt or pXZ9 virus with or without polarization by TGF-β plus IL-6 and divided into five groups:pXZ9

  20. [Effect of Qiling Decoction combined HAART on expression levels of Treg cells and Th17 in HIV/AIDS patients].

    Science.gov (United States)

    Xu, Wen-Fang; Wu, Yong; Pan, Guo-Shao; Zhong, Jian-Ping; Lan, Shao-Bo; Chen, Xue-Fang; Lu, Qiu-Qiong

    2014-02-01

    To explore the effect of Qiling Decoction (QD) combined highly active antiretroviral treatment (HAART) on expression levels of peripheral blood Th17 and Treg cells in HIV/AIDS patients. Totally 55 HIV/AIDS patients were randomly assigned to the treatment group (28 cases) and the combination group (27 cases). Besides, 21 HIV negative patients were recruited as the healthy control group. Those in the treatment group received HARRT alone, while those in the combination group received HAART combined QD. The observation lasted for 24 weeks. Meanwhile, according to peripheral blood CD4+ T cell counts before treatment, HIV/AIDS patients were assigned to three subgroups. For patients in subgroup 1, 1 cells/microL HIV/AIDS patients at the pre-treatment baseline, week 4, 12, and 24, as well as those in the healthy control group. Compared with the healthy control group, CD4+ T cell counts and the baseline expression level of Th17 cells in the peripheral blood of HIV/AIDS patients significantly decreased, the expression level of Treg cells significantly increased P difference (P difference in the effective rate at various CD4+ T cell levels between the two groups (P > 0.05). There was no statistical difference in expression levels of Th17 and Treg cells between the combination group and the treatment group at any time point (all P >0.05). The Th17/Treg ration significantly increased in the combination group after 24 weeks of treatment, showing statistical difference when compared with the treatment group (U = 2.135, P = 0.038). QD could improve the immune balance of Th17/Treg cells, which might be one of its mechanisms for improving HIV/AIDS patients' immunity.

  1. Preferential induction of Th17 cells in vitro and in vivo by Fucogalactan from Ganoderma lucidum (Reishi).

    Science.gov (United States)

    Yoshida, Hideyuki; Suzuki, Mayu; Sakaguchi, Ryota; Tani, Ito; Kotani, Hitoshi; Shudo, Norimasa; Yoshimura, Akihiko

    2012-05-25

    The mushroom known as Reishi (Ganoderma lucidum) has been used as an herbal medicine for tumor treatment and immune system activation. Because its effects on the differentiation of effector T helper cells have not yet been fully understood, we investigated the effects of Reishi and those of its principal ingredient, β-glucan, on the activation of dendritic cells and the differentiation of Th17 cells. Reishi extracts as well as purified β-glucan (Curdran) activated DCs and caused them to produce large amounts of IL-23. β-glucan also enhanced and sustained the transcription of IL-23p19. The MEK-ERK signaling pathway positively regulates IL-23p19 transcription in β-glucan-stimulated DCs. In a mixed leukocyte reaction, Reishi-stimulated DCs preferentially induced Th17 cells. Furthermore, orally-administrated Reishi increased the percentages of Th17 cells and the transcription levels of antimicrobial peptides. Our results show that Reishi and β-glucan activate DCs to produce large amounts of IL-23, which induces Th17 differentiation both in vitro and in vivo.

  2. Th17 Cells Express Interleukin-10 Receptor and Are Controlled by Foxp3 − and Foxp3 + Regulatory CD4 + T Cells in an Interleukin-10-Dependent Manner

    National Research Council Canada - National Science Library

    Huber, Francis J; Huber, Samuel; Gagliani, Nicola; Esplugues, Enric; O'Connor, William; Chaudhry, Ashutosh; Kamanaka, Masahito; Kobayashi, Yasushi; Booth, Carmen J; Rudensky, Alexander Y; Roncarolo, Maria Grazia; Battaglia, Manuela; Flavell, Richard A

    2011-01-01

    ...+ T cells expressed interleukin-10 receptor α (IL-10Rα) in vivo. Importantly, T cell-specific blockade of IL-10 signaling led to a selective increase of IL-17A+IFN-γ⁻ (Th17) and IL-17A+IFN-γ+ (Th17+Th1) CD4...

  3. IL-4 abrogates TH17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells

    Science.gov (United States)

    Guenova, Emmanuella; Skabytska, Yuliya; Hoetzenecker, Wolfram; Weindl, Günther; Sauer, Karin; Tham, Manuela; Kim, Kyu-Won; Park, Ji-Hyeon; Seo, Ji Hae; Ignatova, Desislava; Cozzio, Antonio; Levesque, Mitchell P.; Volz, Thomas; Köberle, Martin; Kaesler, Susanne; Thomas, Peter; Mailhammer, Reinhard; Ghoreschi, Kamran; Schäkel, Knut; Amarov, Boyko; Eichner, Martin; Schaller, Martin; Clark, Rachael A.; Röcken, Martin; Biedermann, Tilo

    2015-01-01

    Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-γ–producing TH1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12–producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4–mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6- and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/TH17 responses despite simultaneous enhancement of IL-12/TH1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/TH17 responses without blocking IL-12/TH1, selective IL-4–mediated IL-23/TH17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12–dependent TH1 responses. PMID:25646481

  4. IL-26 is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and Th17 cell generation.

    Directory of Open Access Journals (Sweden)

    Murielle Corvaisier

    Full Text Available Interleukin-26 (IL-26, a member of the IL-10 cytokine family, induces the production of proinflammatory cytokines by epithelial cells. IL-26 has been also reported overexpressed in Crohn's disease, suggesting that it may be involved in the physiopathology of chronic inflammatory disorders. Here, we have analyzed the expression and role of IL-26 in rheumatoid arthritis (RA, a chronic inflammatory disorder characterized by joint synovial inflammation. We report that the concentrations of IL-26 are higher in the serums of RA patients than of healthy subjects and dramatically elevated in RA synovial fluids compared to RA serums. Immunohistochemistry reveals that synoviolin(+ fibroblast-like synoviocytes and CD68(+ macrophage-like synoviocytes are the main IL-26-producing cells in RA joints. Fibroblast-like synoviocytes from RA patients constitutively produce IL-26 and this production is upregulated by IL-1-beta and IL-17A. We have therefore investigated the role of IL-26 in the inflammatory process. Results show that IL-26 induces the production of the proinflammatory cytokines IL-1-beta, IL-6, and tumor necrosis factor (TNF-alpha by human monocytes and also upregulates the expression of numerous chemokines (mainly CCL20. Interestingly, IL-26-stimulated monocytes selectively promote the generation of RORgamma t(+ Th17 cells, through IL-1-beta secretion by monocytes. More precisely, IL-26-stimulated monocytes switch non-Th17 committed (IL-23R(- or CCR6(- CD161(- CD4(+ memory T cells into Th17 cells. Finally, synovial fluids from RA patients also induce Th17 cell generation and this effect is reduced after IL-26 depletion. These findings show that IL-26 is constitutively produced by RA synoviocytes, induces proinflammatory cytokine secretion by myeloid cells, and favors Th17 cell generation. IL-26 thereby appears as a novel proinflammatory cytokine, located upstream of the proinflammatory cascade, that may constitute a promising target to treat RA and

  5. Dehydrodiconiferyl alcohol (DHCA) modulates the differentiation of Th17 and Th1 cells and suppresses experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Lee, Junghun; Choi, Jinyong; Lee, Wonwoo; Ko, Kyeongryang; Kim, Sunyoung

    2015-12-01

    Dehydrodiconiferyl alcohol (DHCA), originally isolated from the stems of Cucurbita moschata, has previously been shown to exhibit anti-adipogenic and anti-lipogenic effects in 3T3-L1 cells and primary mouse embryonic fibroblasts (MEFs) (Lee et al., 2012). Here, we investigated whether synthetic DHCA could suppress the CD4 T helper 17 (Th17)-mediated production of the interleukin (IL)-17 protein. The results from RT-qPCR suggest that DHCA-mediated down-regulation of IL-17 occurred at the transcriptional level by suppressing the expression of RAR-related orphan receptor (ROR)γt, the master transcription factor involved in the differentiation of Th17 cells. Furthermore, such inhibition was mediated by the suppression of NF-κB activity. DHCA also inhibited the Th1-mediated production of interferon (IFN) γ by controlling the expression of a key transcription factor known to regulate the production of this cytokine, T-bet. In the mouse experimental autoimmune encephalomyelitis (EAE) model, DHCA showed significant therapeutic effects by inhibiting the infiltration of immune cells into the spinal cords, decreasing the differentiation of pathogenic Th17 and Th1 cells, suppressing the expression of various pro-inflammatory cytokines, and eventually ameliorating the clinical symptoms of EAE mice. Taken together, our data indicate that DHCA may be a potential candidate as an agent for the control of Th17 and Th1-mediated inflammatory diseases.

  6. Th1/Th17 plasticity is a marker of advanced β cell autoimmunity and impaired glucose tolerance in humans

    NARCIS (Netherlands)

    Reinert-Hartwall, Linnea; Honkanen, Jarno; Salo, Harri M; Nieminen, Janne K; Luopajärvi, Kristiina; Härkönen, Taina; Veijola, Riitta; Simell, Olli; Ilonen, Jorma; Peet, Aleksandr; Tillmann, Vallo; Knip, Mikael; Vaarala, Outi; Harmsen, Hermanus

    2015-01-01

    Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pa

  7. Changes in the expression of Th17 cell-associated cytokines in the development of rheumatic heart disease.

    Science.gov (United States)

    Wen, Yun; Zeng, Zhiyu; Gui, Chun; Li, Lang; Li, Wenting

    2015-01-01

    Autoimmunity plays a critical role in the development of rheumatic heart disease (RHD). Recent studies have linked Th17 cells to the autoimmune mechanism associated with RHD. This study aimed to investigate changes in Th17 cell-related cytokine expression in acute and chronic RHD. We established a Lewis rat model of experimental RHD, which was induced by inactivated Group A streptococci and complete Freund's adjuvant. After 7- and 24-week intervention treatments, we measured serum levels of interleukin-17 (IL-17) and IL-6, key cytokines associated with Th17 cells, using a Luminex liquichip method, and levels of IL-17 and IL-6 in heart tissues using immunohistochemical assays. Moreover, expression levels of IL-17, IL-21, IL-6, and IL-23 in mitral valve tissues of human RHD patients were also measured using immunohistochemistry. Compared with the normal control group, serum IL-17 and IL-6 concentrations were significantly increased, and the expression levels of IL-17 and IL-6 in the mitral valve were also significantly increased in 7- or 24-week RHD rats (P<.017). Compared with the control group, expression of IL-17, IL-21, IL-6, and IL-23 in mitral valve tissues was significantly increased in RHD patients (P<.05). Our study suggested that the increased expression of Th17 cell-associated cytokines might play an important role in the pathogenesis and development of RHD. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Evaluation of Th1 and Th17 cells cytokines in cell culture stimulated in women with recurrent spontaneous abortion

    Directory of Open Access Journals (Sweden)

    Y Varghaiyan

    2013-10-01

    Full Text Available Introduction: Various immunological abnormalities have been reported in women with RSA of unknown aetiologies including autoimmune abnormalities and increased cellular immunity such as elevated natural killer (NK , Th1 and Th17 cell levels. Th17 and Th1 cells play a central role during inflammation. Th1 cells product cytokines IFN-γ, IL-2 and Th17 cells mainly cytokines IL-17A, F, IL-22. The aim of this study is evaluation of Th1 and Th17 activity in women with recurrent spontaneous abortion. Methods: In this case-control study, 30 women with history of two or more abortion who at least 3 months past after last abortion considered as case group and 30 normal fertile healthy women with at least one delivery as control group. We determined the levels of IL-17A, F and IFN-γ in cell culture supernatant of peripheral blood mononuclear cells (PBMC stimulated with the mitogen phytohemagglutinin (PHA by enzyme-linked immunosorbent assay (ELISA method and compared in the two groups. The results obtained using the one-sample kolmogorov-smirnov Test, Kruskal-wallis Test and Spearman were analyzed using SPSS 16 software. Results: The level of IFN- γ in case group was significantly higher than control group (186/53±30/41 versus 88/06±21/44 pg/ml, P < 0.005. Also the level of IL-17 A, F in case group was significantly higher than control group (84/74±21/26 versus 28/41±8 pg/ml, P < 0.01. IFN-γ concentration showed positive correlation with IL-17 A, F in case group (P=0.015, r= 0.455. Conclusion: In this study the increased levels of cytokines IFN- γ and IL-17 A, F in women with recurrent spontaneous abortion shows a propensity of pro inflammation via Th17 and Th1 immunity and may be these cells play a pivotal role in rejecting fetus antigens.

  9. Generation of Th17 cells in response to intranasal infection requires TGF-β1 from dendritic cells and IL-6 from CD301b+ dendritic cells.

    Science.gov (United States)

    Linehan, Jonathan L; Dileepan, Thamotharampillai; Kashem, Sakeen W; Kaplan, Daniel H; Cleary, Patrick; Jenkins, Marc K

    2015-10-13

    Intranasal (i.n.) infections preferentially generate Th17 cells. We explored the basis for this anatomic preference by tracking polyclonal CD4(+) T cells specific for an MHC class II-bound peptide from the mucosal pathogen Streptococcus pyogenes. S. pyogenes MHC class II-bound peptide-specific CD4(+) T cells were first activated in the cervical lymph nodes following i.n. inoculation and then differentiated into Th17 cells. S. pyogenes-induced Th17 formation depended on TGF-β1 from dendritic cells and IL-6 from a CD301b(+) dendritic cell subset located in the cervical lymph nodes but not the spleen. Thus, the tendency of i.n. infection to induce Th17 cells is related to cytokine production by specialized dendritic cells that drain this site.

  10. Enhancement of CD147 on M1 macrophages induces differentiation of Th17 cells in the lung interstitial fibrosis.

    Science.gov (United States)

    Geng, Jie-jie; Zhang, Kui; Chen, Li-na; Miao, Jin-lin; Yao, Meng; Ren, Ying; Fu, Zhi-guang; Chen, Zhi-nan; Zhu, Ping

    2014-09-01

    Lung interstitial fibrosis is a chronic lung disease, and few effective therapies are available to halt or reverse the progression of the disease. In murine and human lung fibrosis, the expression of CD147 is increased. However, the role of CD147 in lung fibrosis has not been identified, and it remains to be determined whether lung fibrosis would be improved by decreasing the expression of CD147. A murine bleomycin-induced lung interstitial fibrosis model was used in the experiments, and HAb18 mAbs and CsA were administered during the induction of lung fibrosis. In our study, we found that the HAb18 mAbs markedly reduced the collagen score and down-regulated M1 macrophages and Th17 cells. In vitro, flow cytometry analysis showed that M1 macrophages induced higher Th17 differentiation than M2 macrophages. After treatment with HAb18 mAbs or after reducing the expression of CD147 by lentivirus interference in M1 macrophages, the level of Th17 cells were significantly inhibited. In conclusion, HAb18 mAbs or CsA treatment ameliorates lung interstitial fibrosis. CD147 promoted M1 macrophage and induced the differentiation of Th17 cells in lung interstitial fibrosis, perhaps by regulating some cytokines such as IL-6, IL-1β, IL-12 and IL-23. These results indicated that CD147 may play an important role in the development of lung interstitial fibrosis.

  11. Host responses to Candida albicans: Th17 cells and mucosal candidiasis

    OpenAIRE

    Conti, Heather R.; Gaffen, Sarah L.

    2010-01-01

    Candida albicans causes mucosal and disseminated candidiasis, which represent serious problems for the rapidly expanding immunocompromised population. Until recently, Th1-mediated immunity was thought to confer the primary protection, particularly for oral candidiasis. However, emerging data indicate that the newly-defined Th17 compartment appears to play the predominant role in mucosal candidiasis.

  12. Th17细胞及其在哮喘等过敏性疾病中的作用%Th17 cells and its roles in asthma and allergy diseases

    Institute of Scientific and Technical Information of China (English)

    赵灵芝

    2010-01-01

    Th17 cells were identified as an independent lineage of CD4+ T cells that secrete a distinctive set of immunoregulatory cytokines, which play an important role in the pathogenesis of a diverse group of immune-mediated diseases. Recent data in humans and mice trials suggest that as the hallmark cytokine of Th17 cells, IL-17 involved in the inducement and the inflammation of allergy, such as asthma. IL-17 induces chemokine IL-8, and prominently recruits neutrophils in the airways in severe asthma exacerbations and may contribute to airway gland hypersecretion, bronchial hyper-reactivity and airway wall remodelling in asthma. Given the strong association between excessive Th17 activity and human diseases, new therapeutic approaches targeting Th17 cells are highly promising, but the potential clinical application need further investigation.%Th17细胞作为独立的CD4+T细胞谱系,分泌一系列特有的免疫调节因子,在各种免疫介导的疾病中发挥重要作用.研究证明,Th17分泌的特征性细胞因子IL-17,参与哮喘等过敏性疾病的诱导,介导其炎症过程.IL-17诱导产生趋化因子IL-8,在严重哮喘的气道中募集中性粒细胞浸润,而且可能对哮喘息者气道腺体的高分泌、气道高反应性及气道重塑起作用.假设Th17细胞过度活化和过敏性气道炎症之间存在密切关联,那么针对Th17细胞的治疗方法将有广阔前景,但其临床应用有待进一步研究.

  13. Role of interaction between Th17 cells and commensal microbiota in the pathogenesis of inflammatory bowel disease%Th17细胞及肠道内共生菌群在炎症性肠病中的作用

    Institute of Scientific and Technical Information of China (English)

    李睿东; 韩高雄; 陶凯雄

    2011-01-01

    Inflammatory bowel disease (IBD) is an autoimmune disease whose etiology and pathogenesis remain incompletely understood. Thl7 cells can secrete cytokines interleukin-17A and interleu-kin-17F, which play an important role in the pathogenesis of IBD. Some studies have proved that reduction of IL-17A and IL-17F can attenuate intestinal mucosal inflammation. Additionally, many studies reveal that the occurrence of IBD is correlated with commensal microbiota. Commensal microbiota can alter the number of Thl7 cells in intestinal mucosa and cause abnormal intestinal mucosal immune responses. Elucidation of relationship between Thl7 cells and commensal microbiota in intestinal mucosa is important for understanding the pathogenesis of IBD.%炎症性肠病(inflammatory bowel disease,IBD)是一种以慢性肠道炎症性疾病,病因未明,肠道黏膜异常的免疫反应在发病中有着重要作用.最近发现一类辅助T淋巴细胞Th17细胞,能在肠黏膜中大量分泌IL-17A和IL-17F.减少肠道Th17细胞数量和其相关的细胞因子的表达能够缓解肠道炎症反应,预示Th17细胞在IBD发病中起到一定作用.肠道共生菌与IBD的发病也有着密切关系,肠道共生菌群的变化可能导致Th17细胞的数量发生改变引起炎症,或者通过其他机制和途径诱发免疫紊乱,从而使得炎症得以发生.本文就Th17细胞的分化与其在IBD中的作用,以及共生菌群和Th17细胞之间的相互联系作一综述.

  14. In vitro generated Th17 cells support the expansion and phenotypic stability of CD4(+)Foxp3(+) regulatory T cells in vivo.

    Science.gov (United States)

    Zhou, Qiong; Hu, Ya; Howard, O M Zack; Oppenheim, Joost J; Chen, Xin

    2014-01-01

    CD4(+) T cells stimulate immune responses through distinct patterns of cytokine produced by Th1, Th2 or Th17 cells, or inhibit immune responses through Foxp3-expressing regulatory T cells (Tregs). Paradoxically, effector T cells were recently shown to activate Tregs, however, it remains unclear which Th subset is responsible for this effect. In this study, we found that Th17 cells expressed the highest levels of TNF among in vitro generated Th subsets, and most potently promoted expansion and stabilized Foxp3 expression by Tregs when co-transferred into Rag1(-/-) mice. Both TNF and IL-2 produced by Th17 cells contributed to this effect. The stimulatory effect of Th17 cells on Tregs was largely abolished when co-transferred with TNFR2-deficient Tregs. Furthermore, Tregs deficient in TNFR2 also supported a much lower production of IL-17A and TNF expression by co-transferred Th17 cells. Thus, our data indicate that the TNF-TNFR2 pathway plays a crucial role in the reciprocal stimulatory effect of Th17 cells and Tregs. This bidirectional interaction should be taken into account when designing therapy targeting Th17 cells, Tregs, TNF and TNFR2.

  15. Assessment of Treg and Th17 contents in peripheral blood of patients with non-small cell lung cancer and analysis of their correlation with clinicopathologic characteristics

    Institute of Scientific and Technical Information of China (English)

    Jin Pu; Yuan-Yuan Zhou; Wen-Shu Ge; Hui-Lan Hong; Jing-Feng Zhang; Chong Bai

    2016-01-01

    Objective:To analyze Treg and Th17 contents in peripheral blood of patients with non-small cell lung cancer and their correlation with clinicopathologic characteristics.Methods:Peripheral blood and serum specimens were collected from patients with non-small cell lung cancer and healthy volunteers to detect Treg and Th17 contents in peripheral blood as well as CEA, TSGF, CYFRA21-1, PTX3 and HE4 contents in serum; tumor tissue and paracancer tissue were collected from lung cancer patients to detect mRNA expression of TRIM25, PKM2, Endoglin, Pin1, Stahmin and HMGA2.Results:Treg cell content and Treg/Th17 ratio in peripheral blood of patients with non-small cell lung cancer were significantly higher than those of healthy volunteers, and Th17 cell content was significantly lower than that of healthy volunteers; the higher the TNM stage and the lower the degree of differentiation, the higher the Treg cell content and Treg/Th17 ratio and the lower the Th17 cell content in peripheral blood; 1 week and 1 month after operation, Treg cell content and Treg/Th17 ratio in peripheral blood of patients with non-small cell lung cancer were lower than those before operation, and Th17 cell content was higher than that before treatment; serum CEA, TSGF, CYFRA21-1, PTX3 and HE4 contents of patients with non-small cell lung cancer were significantly higher than those of healthy volunteers and positively correlated with Treg/Th17 ratio; mRNA contents of TRIM25, PKM2, Endoglin, Pin1, Stahmin and HMGA2 in non-small cell lung cancer tissue were significantly higher than those in paracancer tissue and positively correlated with Treg/Th17 ratio.Conclusion:Increased Treg content and decreased Th17 content are related to the occurrence and development of non-small cell lung cancer.

  16. Schisandrin B inhibits Th1/Th17 differentiation and promotes regulatory T cell expansion in mouse lymphocytes.

    Science.gov (United States)

    Chen, Zhaoyang; Guo, Min; Song, Guohua; Gao, Jiping; Zhang, Yinhong; Jing, Zhijie; Liu, Tianfu; Dong, Chuan

    2016-06-01

    Schisandrin B (Sch-B), the most abundant active ingredient of the fruit of Schisandra chinensis, has been proposed to have antioxidant, anti-tumor and anti-inflammatory effects. The present study was undertaken to investigate the effect of Sch-B on differentiation of T helper cells (Th). Using mouse splenic lymphocytes stimulated with concanavalin A (Con A) in vitro and ex vivo as inflammation models, we found that Sch-B significantly inhibited secretion of Th1 and Th17 related cytokines, such as IFN-γ and IL-17. In addition, we found that Sch-B suppressed the differentiation of naive CD4+ T cells into Th1 and Th17 cells, while promoted their differentiation into the regulatory T cells (Treg) in vitro. We further found that Sch-B suppressed transcription of Th1-related T-box transcription factor, T-bet, and Th17-related transcription factor, retinoid related orphan receptor gamma t (RORγt), while enhanced transcription of Treg-related transcription factor forkhead box protein 3 (Foxp3) in naive CD4+ T cells under Th cell polarization conditions. Furthermore, the effect of Sch-B on the T cell differentiation was abrogated by heme oxygenase-1 (HO-1) inhibitor zinc protoporphyrin. Taken together, we conclude that Sch-B can modulate differentiation of naïve CD4+ T cells into specific lineages of effector cells, which may have potential benefits for treatment of autoimmune diseases.

  17. Current researches of the relationship between Th17/Treg cells and autoimmune uveitis%Th17/Treg细胞与自身免疫性葡萄膜炎的研究进展

    Institute of Scientific and Technical Information of China (English)

    张莲; 宋继科; 郭俊国; 毕宏生

    2015-01-01

    Human autoimmune uveitis is a group of common ocular inflammatory diseases caused by autoimmune disorder. It is considered an inflammatory response dominated by CD4+ T cells at present. It is well known that CD4+ T cells are divided into four subsets including Th1, Th2, Th17 and Treg cells ( CD4+ CD25+ Foxp3+regulatory T cells) . Previous studys have focused on Th1 and Th2 cells. Recent studys indicate that Th17 cells are the main factor of induction of uveitis while Treg cells are the main factor of negative regulation of uveitis. And they both play important roles in the onset and progression of uveitis. We give a review of current research in the relationship between Th17/Treg cells with autoimmune uveitis.%葡萄膜炎是一组常见的由自身免疫紊乱导致的眼部炎症性致盲性眼病,现代研究认为主要是由CD4+T 细胞介导产生。 CD4+T 细胞主要分为Th1,Th2,Th17和 Treg 细胞( CD4+CD25+Foxp3+调节性T细胞)四个亚群。以往研究主要集中在Th1, Th2细胞亚群,近年来研究表明, Th17细胞是诱导自身免疫性葡萄膜炎发病的主要原因,而Treg细胞是负向调控葡萄膜炎的主要因素。因此, Th17和 Treg 细胞在葡萄膜炎的发病及病程演变过程中发挥重要作用,本文就Th17细胞、Treg 细胞与自身免疫性葡萄膜炎的相关研究进展进行综述。

  18. Antigen-Specific Th17 Cells Are Primed by Distinct and Complementary Dendritic Cell Subsets in Oropharyngeal Candidiasis.

    Directory of Open Access Journals (Sweden)

    Kerstin Trautwein-Weidner

    2015-10-01

    Full Text Available Candida spp. can cause severe and chronic mucocutaneous and systemic infections in immunocompromised individuals. Protection from mucocutaneous candidiasis depends on T helper cells, in particular those secreting IL-17. The events regulating T cell activation and differentiation toward effector fates in response to fungal invasion in different tissues are poorly understood. Here we generated a Candida-specific TCR transgenic mouse reactive to a novel endogenous antigen that is conserved in multiple distant species of Candida, including the clinically highly relevant C. albicans and C. glabrata. Using TCR transgenic T cells in combination with an experimental model of oropharyngeal candidiasis (OPC we investigated antigen presentation and Th17 priming by different subsets of dendritic cells (DCs present in the infected oral mucosa. Candida-derived endogenous antigen accesses the draining lymph nodes and is directly presented by migratory DCs. Tissue-resident Flt3L-dependent DCs and CCR2-dependent monocyte-derived DCs collaborate in antigen presentation and T cell priming during OPC. In contrast, Langerhans cells, which are also present in the oral mucosa and have been shown to prime Th17 cells in the skin, are not required for induction of the Candida-specific T cell response upon oral challenge. This highlights the functional compartmentalization of specific DC subsets in different tissues. These data provide important new insights to our understanding of tissue-specific antifungal immunity.

  19. Soluble Tumor Necrosis Factor Receptor 1 Released by Skin-Derived Mesenchymal Stem Cells Is Critical for Inhibiting Th17 Cell Differentiation.

    Science.gov (United States)

    Ke, Fang; Zhang, Lingyun; Liu, Zhaoyuan; Yan, Sha; Xu, Zhenyao; Bai, Jing; Zhu, Huiyuan; Lou, Fangzhou; Cai, Wei; Sun, Yang; Gao, Yuanyuan; Wang, Hong; Wang, Honglin

    2016-03-01

    T helper 17 (Th17) cells play an important role in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Th17 cell differentiation from naïve T cells can be induced in vitro by the cytokines transforming growth factor β1 and interleukin-6. However, it remains unclear whether other regulatory factors control the differentiation of Th17 cells. Mesenchymal stem cells (MSCs) have emerged as a promising candidate for inhibiting Th17 cell differentiation and autoimmune diseases. Despite the fact that several molecules have been linked to the immunomodulatory function of MSCs, many other key MSC-secreted regulators that are involved in inhibiting Th17 cell polarization are ill-defined. In this study, we demonstrated that the intraperitoneal administration of skin-derived MSCs (S-MSCs) substantially ameliorated the development of EAE in mice. We found that the proinflammatory cytokine tumor necrosis factor (TNF)-α, a key mediator in the pathophysiology of MS and EAE, was capable of promoting Th17 cell differentiation. Moreover, under inflammatory conditions, we demonstrated that S-MSCs produced high amounts of soluble TNF receptor 1 (sTNFR1), which binds TNF-α and antagonizes its function. Knockdown of sTNFR1 in S-MSCs decreased their inhibitory effect on Th17 cell differentiation ex vivo and in vivo. Thus, our data identified sTNFR1 and its target TNF-α as critical regulators for Th17 cell differentiation, suggesting a previously unrecognized mechanism for MSC therapy in Th17-mediated autoimmune diseases.

  20. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis.

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    Full Text Available BACKGROUND: T-helper (Th 22 is involved in the pathogenesis of inflammatory diseases. The roles of Th22 cells in the pathophysiological of ankylosing spondylitis (AS and rheumatoid arthritis (RA remain unsettled. So we examined the frequencies of Th22 cells, Th17 cells and Th1 cells in peripheral blood (PB from patients with AS and patients with RA compared with both healthy controls as well as patients with osteoarthritis. DESIGN AND METHODS: We studied 32 AS patients, 20 RA patients, 10 OA patients and 20 healthy controls. The expression of IL-22, IL-17 and IFN-γ were examined in AS, RA, OA patients and healthy controls by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay. RESULTS: Th22 cells, Th17 cells and interleukin-22 were significantly elevated in AS and RA patients compared with OA patients and healthy controls. Moreover, Th22 cells showed positive correlation with Th17 cells as well as interleukin-22 in AS and RA patients. However, positive correlation between IL-22 and Th17 cells was only found in AS patients not in RA patients. In addition, the percentages of both Th22 cells and Th17 cells correlated positively with disease activity only in RA patients not in AS patients. CONCLUSIONS: The frequencies of both Th22 cells and Th17 cells were elevated in PB from patients with AS and patients with RA. These findings suggest that Th22 cells and Th17 cells may be implicated in the pathogenesis of AS and RA, and Th22 cells and Th17 cells may be reasonable cellular targets for therapeutic intervention.

  1. Protective contributions against invasive Streptococcus pneumoniae pneumonia of antibody and Th17-cell responses to nasopharyngeal colonisation.

    Science.gov (United States)

    Cohen, Jonathan M; Khandavilli, Suneeta; Camberlein, Emilie; Hyams, Catherine; Baxendale, Helen E; Brown, Jeremy S

    2011-01-01

    The nasopharyngeal commensal bacteria Streptococcus pneumoniae is also a frequent cause of serious infections. Nasopharyngeal colonisation with S. pneumoniae inhibits subsequent re-colonisation by inducing Th17-cell adaptive responses, whereas vaccination prevents invasive infections by inducing antibodies to S. pneumoniae capsular polysaccharides. In contrast, protection against invasive infection after nasopharyngeal colonisation with mutant S. pneumoniae strains was associated with antibody responses to protein antigens. The role of colonisation-induced Th17-cell responses during subsequent invasive infections is unknown. Using mouse models, we show that previous colonisation with S. pneumoniae protects against subsequent lethal pneumonia mainly by preventing bacteraemia with a more modest effect on local control of infection within the lung. Previous colonisation resulted in CD4-dependent increased levels of Th17-cell cytokines during subsequent infectious challenge. However, mice depleted of CD4 cells prior to challenge remained protected against bacteraemia, whereas no protection was seen in antibody deficient mice and similar protection could be achieved through passive transfer of serum. Serum from colonised mice but not antibody deficient mice promoted phagocytosis of S. pneumoniae, and previously colonised mice were able to rapidly clear S. pneumoniae from the blood after intravenous inoculation. Thus, despite priming for a Th17-cell response during subsequent infection, the protective effects of prior colonisation in this model was not dependent on CD4 cells but on rapid clearance of bacteria from the blood by antibody-mediated phagocytosis. These data suggest that whilst nasopharyngeal colonisation induces a range of immune responses, the effective protective responses depend upon the site of subsequent infection.

  2. Correlation Between the Expression of MicroRNA-301a-3p and the Proportion of Th17 Cells in Patients with Rheumatoid Arthritis.

    Science.gov (United States)

    Tang, Xinyi; Yin, Kai; Zhu, Hongsheng; Tian, Jie; Shen, Dong; Yi, Lixian; Rui, Ke; Ma, Jie; Xu, Huaxi; Wang, Shengjun

    2016-04-01

    Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation and subsequent joint destruction. Previous studies have confirmed that Th17 cells play a critical role in the pathogenesis of RA. MicroRNA (miR)-301a-3p is a regulatory factor for Th17 cells differentiation that contributes to the pathogenesis of autoimmune diseases. The purposes of this study were to identify the alteration of Th17 cells and analyze the correlation between the expression of the miR-301a-3p and the proportion of Th17 cells in RA patients. The results showed that the frequency of Th17 cells and the expression of transcription factors (RORγt and STAT3) significantly increased in the peripheral blood mononuclear cells (PBMCs) from RA patients, and the associated proinflammatory cytokines were also upregulated. We also observed that the expression of protein inhibitor of activated STAT3 (PIAS3), the main cellular inhibitor of STAT3, was attenuated in RA patients and negatively correlated with the percentage of Th17 cells in RA. Interestingly, miR-301a-3p, an inhibitor of PIAS3 expression, was overexpressed in the PBMCs from RA patients and positively correlated with the frequency of Th17 cells in patients with RA. Taken together, these data indicated that miR-301a-3p and Th17 cells were augmented in peripheral blood, which may play an important role in the process of RA.

  3. TNFα Promotes Th17 Cell Differentiation through IL-6 and IL-1β Produced by Monocytes in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Yingxia Zheng

    2014-01-01

    Full Text Available TNFα plays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Th17 cells were accumulated in synovial fluid, which was attributable to TNFα aberrantly produced in rheumatoid synovium. Interestingly, TNFα cannot induce IL-17 production of CD4+ T cells directly, but through the monocytes high levels of IL-1β and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFα was shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4+ T cells when cultured with CD14+ monocytes. Treatment with an approved TNFα blocking antibody showed marked reduction in the levels of IL-6, IL-1β, and IL-17 and the expression level of STAT3 phosphorylation in relation to Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFα in the pathogenic Th17 cell differentiation in rheumatoid arthritis.

  4. Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance

    Directory of Open Access Journals (Sweden)

    Yan Zhou

    2016-01-01

    Full Text Available It is well known that dendritic cells (DCs play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs, a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG- specific experimental autoimmune encephalomyelitis (EAE model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS. Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs. Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS.

  5. The ratio of circulating regulatory T cells (Tregs)/Th17 cells is associated with acute allograft rejection in liver transplantation.

    Science.gov (United States)

    Wang, Ying; Zhang, Min; Liu, Zhen-Wen; Ren, Wei-Guo; Shi, Yan-Chao; Sun, Yan-Ling; Wang, Hong-Bo; Jin, Lei; Wang, Fu-Sheng; Shi, Ming

    2014-01-01

    CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) and Th17 cells are known to be involved in the alloreactive responses in organ transplantation, but little is known about the relationship between Tregs and Th17 cells in the context of liver alloresponse. Here, we investigated whether the circulating Tregs/Th17 ratio is associated with acute allograft rejection in liver transplantation. In present study, thirty-eight patients who received liver transplant were enrolled. The patients were divided into two groups: acute allograft rejection group (Gr-AR) (n = 16) and stable allograft liver function group (Gr-SF) (n = 22). The frequencies of circulating Tregs and circulating Th17 cells, as well as Tregs/Th17 ratio were determined using flow cytometry. The association between Tregs/Th17 ratio and acute allograft rejection was then analyzed. Our results showed that the frequency of circulating Tregs was significantly decreased, whereas the frequency of circulating Th17 cells was significantly increased in liver allograft recipients who developed acute rejection. Tregs/Th17 ratio had a negative correlation with liver damage indices and the score of rejection activity index (RAI) after liver transplantation. In addition, the percentages of CTLA-4(+), HLA-DR(+), Ki67(+), and IL-10(+) Tregs were higher in Gr-SF group than in Gr-AR group. Our results suggested that the ratio of circulating Tregs/Th17 cells is associated with acute allograft rejection, thus the ratio may serve as an alternative marker for the diagnosis of acute rejection.

  6. The Ratio of Circulating Regulatory T Cells (Tregs)/Th17 Cells Is Associated with Acute Allograft Rejection in Liver Transplantation

    Science.gov (United States)

    Liu, Zhen-Wen; Ren, Wei-Guo; Shi, Yan-Chao; Sun, Yan-Ling; Wang, Hong-Bo; Jin, Lei; Wang, Fu-Sheng; Shi, Ming

    2014-01-01

    CD4+CD25+FoxP3+ regulatory T cells (Tregs) and Th17 cells are known to be involved in the alloreactive responses in organ transplantation, but little is known about the relationship between Tregs and Th17 cells in the context of liver alloresponse. Here, we investigated whether the circulating Tregs/Th17 ratio is associated with acute allograft rejection in liver transplantation. In present study, thirty-eight patients who received liver transplant were enrolled. The patients were divided into two groups: acute allograft rejection group (Gr-AR) (n = 16) and stable allograft liver function group (Gr-SF) (n = 22). The frequencies of circulating Tregs and circulating Th17 cells, as well as Tregs/Th17 ratio were determined using flow cytometry. The association between Tregs/Th17 ratio and acute allograft rejection was then analyzed. Our results showed that the frequency of circulating Tregs was significantly decreased, whereas the frequency of circulating Th17 cells was significantly increased in liver allograft recipients who developed acute rejection. Tregs/Th17 ratio had a negative correlation with liver damage indices and the score of rejection activity index (RAI) after liver transplantation. In addition, the percentages of CTLA-4+, HLA-DR+, Ki67+, and IL-10+ Tregs were higher in Gr-SF group than in Gr-AR group. Our results suggested that the ratio of circulating Tregs/Th17 cells is associated with acute allograft rejection, thus the ratio may serve as an alternative marker for the diagnosis of acute rejection. PMID:25372875

  7. The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor γt (RORγt) in Th17 cells.

    Science.gov (United States)

    Han, Lei; Yang, Jing; Wang, Xiuwen; Wu, Qingsi; Yin, Shuying; Li, Zhiyuan; Zhang, Jing; Xing, Yue; Chen, Zuojia; Tsun, Andy; Li, Dan; Piccioni, Miranda; Zhang, Yu; Guo, Qiang; Jiang, Lindi; Bao, Liming; Lv, Ling; Li, Bin

    2014-09-12

    Stable retinoic acid-related orphan nuclear receptor γt (RORγt) expression is pivotal for the development and function of Th17 cells. Here we demonstrate that expression of the transcription factor RORγt can be regulated through deubiquitination, which prevents proteasome-mediated degradation. We establish that USP17 stabilizes RORγt protein expression by reducing RORγt polyubiquitination at its Lys-360 residue. In contrast, knockdown of endogenous USP17 in Th17 cells resulted in decreased RORγt protein levels and down-regulation of Th17-related genes. Furthermore, USP17 expression was up-regulated in CD4(+) T cells from systemic lupus erythematosus patients. Our data reveal a molecular mechanism in which RORγt expression in Th17 cells can be positively regulated by USP17, thereby modulating Th17 cell functions.

  8. Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver.

    Science.gov (United States)

    Rau, Monika; Schilling, Anne-Kristin; Meertens, Jan; Hering, Ilona; Weiss, Johannes; Jurowich, Christian; Kudlich, Theodor; Hermanns, Heike M; Bantel, Heike; Beyersdorf, Niklas; Geier, Andreas

    2016-01-01

    Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4(+) effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4(+)CD45RA(+)CD25(++)) and higher frequencies of IFN-γ(+) and/or IL-4(+) cells were detected among CD4(+) T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17(+) cells among intrahepatic CD4(+) T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17(+) cells among intrahepatic CD4(+) T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.

  9. Dietary n-3 polyunsaturated fatty acids (PUFA decrease obesity-associated Th17 cell-mediated inflammation during colitis.

    Directory of Open Access Journals (Sweden)

    Jennifer M Monk

    Full Text Available Clinical and experimental evidence suggests that obesity-associated inflammation increases disease activity during colitis, attributed in part to the effects of Th17 cells. Using a model of concurrent obesity and colitis, we monitored changes in critical immune cell subsets and inflammatory biomarker expression in three key tissues: visceral adipose tissue, colon (local inflammatory site and spleen (systemic inflammatory site, and we hypothesized that n-3 PUFA would reduce the percentage of inflammatory immune cell subsets and suppress inflammatory gene expression, thereby improving the disease phenotype. Obesity was induced in C57BL/6 mice by feeding a high fat (HF diet (59.2% kcal alone or an isocaloric HF diet supplemented with fish oil (HF-FO for 12 weeks. Colitis was induced via a 2.5% trinitrobenzene sulfonic acid (TNBS enema. The HF-FO diet improved the obese phenotype by reducing i serum hormone concentrations (leptin and resistin, ii adipose tissue mRNA expression of inflammatory cytokines (MCP-1, IFNγ, IL-6, IL17F and IL-21 and iii total (F4/80⁺ CD11b⁺ and inflammatory adipose tissue M1 (F4/80⁺ CD11c⁺ macrophage content compared to HF (P<0.05. In addition, the HF-FO diet reduced both colitis-associated disease severity and colonic mRNA expression of the Th17 cell master transcription factor (RORγτ and critical cytokines (IL-6, IL-17A, IL-17F, IL-21, IL-23 and IFNγ versus HF (P<0.05. Compared to HF, the percentage of both splenic Th17 and Th1 cells were reduced by the HF-FO group (P<0.05. Under ex vivo polarizing conditions, the percentage of HF-FO derived CD4⁺ T cells that reached Th17 cell effector status was suppressed (P = 0.05. Collectively, these results indicate that n-3 PUFA suppress Th1/Th17 cells and inflammatory macrophage subsets and reconfigure the inflammatory gene expression profile in diverse tissue sites in obese mice following the induction of colitis.

  10. Treg/Th17细胞及相关细胞因子在Graves眼病中的作用及机制%Role of Treg/Th17 cells and related cytokines in Graves' ophthalmopathy

    Institute of Scientific and Technical Information of China (English)

    吕蒙; 沈洁; 李章芳; 赵德福; 陈志; 万亨; 郝宝珺

    2014-01-01

    Objective To explore the role of CD4+CD25+Foxp3+Treg/CD4+IL-17A+Th17 cells and the related cytokines in Graves' ophthalmopathy. Methods Based on clinical activity scores (CAS), we divided patients with untreated Graves' ophthal-mopathy into active group (AGO group with CAS≥3 (15 cases) and non-active group (NGO group) with CAS<3 (15 cases), with another 15 patients with untreated Graves' disease free of eye symptoms (GD group) and 15 normal subjects as controls. Peripheral venous blood Treg/Th17 cell ratio was determined using flow cytometry. RT-PCR was used to detect the mRNA expression levels of Treg-specific transcription factor Foxp3 and Th17-specific transcription factor RORγt. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of Th17 cell-related cytokines (IL-17A, IL-23, and IL-6) and Treg-related cytokines (TGF-β, IL-10, and IL-35). Results Compared with the normal subjects, the patients in GD, NGO, AGO groups all showed significantly increased Th17 cell count (P<0.05), which was the highest in AGO group. RT-PCR results revealed significantly increased RORγt in GD, NGO, and AGO groups, also the highest in AGO group. Serum IL-17A, IL-23, and IL-6 levels all showed significant increments in GD, NGO, and AGO groups (P<0.05), especially in AGO group. Among the Treg-related cytokines, TGF-βand IL-35 levels decreased (P<0.05) but IL-10 increased significantly (P<0.05) in GD, NGO, AGO groups. Conclusion Decreased immunosuppressive capacity of Treg cells can be an important factor in the pathogenesis of Graves' ophthalmopathy. Th17 cells may also participate in the occurrence and progression of Graves' ophthalmopathy and can serve along with related cytokines as novel indicators of the disease activity. Impaired Treg/Th17 balance may importantly contribute to the occurrence of Graves' ophthalmopathy.%目的:探讨CD4+CD25+Foxp3+Treg/CD4+IL-17A+Th17细胞及相关细胞因子在Graves眼病中的作用及机制。方法根据临

  11. Decreased ratio of Treg cells to Th17 cells correlates with HBV DNA suppression in chronic hepatitis B patients undergoing entecavir treatment.

    Directory of Open Access Journals (Sweden)

    Ji-Yuan Zhang

    Full Text Available BACKGROUND: Treatment with nucleotide analogs is known to be effective in inhibiting HBV replication; however, patients with chronic hepatitis B (CHB often show a wide range of clinical responses to these drugs. Therefore, the identification of an early immunologic marker associated with the clinical outcomes in such cases is critical for the improved clinical management. In our study, we aimed to investigate whether the viral load in CHB patients affected the ratio of the number of regulatory T cells (Tregs to the number of interleukin-17-producing helper (Th17 cells. Further, we evaluated the clinical implications of the alterations in this ratio. METHODOLOGY/PRINCIPAL FINDINGS: Nine patients seropositive for hepatitis B e antigen received entecavir monotherapy for 12 months and the percentages of Tregs and Th17 cells as well as the HBV-specific IL-17 productions in these patients were longitudinally analyzed. The entecavir-induced suppression of HBV replication was accompanied by a rapid increase in the number of Th17 cells, together with a decrease in Treg cells, which lead to a significant reduction of Treg/Th17 ratios. In addition, peripheral blood mononuclear cells (PBMCs exhibited a decreased IL-17 production upon stimulation with the HBV core antigen in vitro. CONCLUSIONS: The inhibition of viral replication results in an increase in Th17 cells and concomitant decrease in Treg cells. This imbalance of Treg cells to Th17 cells might have an important role in HBV persistence during entecavir treatment.

  12. Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C.

    Directory of Open Access Journals (Sweden)

    Hassen Kared

    Full Text Available Loss of CD4 T cell help correlates with virus persistence during acute hepatitis C virus (HCV infection, but the underlying mechanism(s remain unknown. We developed a combined proliferation/intracellular cytokine staining assay to monitor expansion of HCV-specific CD4 T cells and helper cytokines expression patterns during acute infections with different outcomes. We demonstrate that acute resolving HCV is characterized by strong Th1/Th17 responses with specific expansion of IL-21-producing CD4 T cells and increased IL-21 levels in plasma. In contrast, viral persistence was associated with lower frequencies of IL-21-producing CD4 T cells, reduced proliferation and increased expression of the inhibitory receptors T cell immunoglobulin and mucin-domain-containing-molecule-3 (Tim-3, programmed death 1 (PD-1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4 on HCV-specific CD8 T cells. Progression to persistent infection was accompanied by increased plasma levels of the Tim-3 ligand Galectin-9 (Gal-9 and expansion of Gal-9 expressing regulatory T cells (Tregs. In vitro supplementation of Tim-3(high HCV-specific CD8 T cells with IL-21 enhanced their proliferation and prevented Gal-9 induced apoptosis. siRNA-mediated knockdown of Gal-9 in Treg cells rescued IL-21 production by HCV-specific CD4 T cells. We propose that failure of CD4 T cell help during acute HCV is partially due to an imbalance between Th17 and Treg cells whereby exhaustion of both CD4 and CD8 T cells through the Tim-3/Gal-9 pathway may be limited by IL-21 producing Th17 cells or enhanced by Gal-9 producing Tregs.

  13. A study of the changes of Th17 cells and IL-23 in patients with Guillain-Barré syndrome

    Directory of Open Access Journals (Sweden)

    Gai-ping HE

    2014-06-01

    Full Text Available Guillain-Barré syndrome (GBS is an acute autoimmune-mediated inflammatory neuropathy. In this paper, the percentage of Th17 in peripheral blood lymphocyte and the level of IL-23 in serum and cerebrospinal fluid (CSF of patients with GBS were detected. Twenty-five patients with GBS and 20 controls were analyzed. The percentage of Th17 cells in patients with GBS was (4.86 ± 0.60%, which was higher than that in controls [(2.71 ± 0.54%; t = 2.616, P = 0.012]. Serum IL-23 increased in patients with GBS [(111.80 ± 13.84 pg/ml vs (72.55 ± 8.19 pg/ml; t = 2.300, P = 0.026]. The level of IL-23 in serum and CSF from patients with GBS before therapy [(110.50 ± 15.66 and (102.30 ± 7.52 pg/ml] declined to normal after therapy [(74.13 ± 6.18 and (72.92 ± 12.09 pg/ml], and the difference was statistically significant (t = 2.557, P = 0.022; t = 1.422, P = 0.046. Th17 cells and IL-23 increased in patients with GBS, indicating that they may involve in the pathogenesis of GBS. doi: 10.3969/j.issn.1672-6731.2014.06.012

  14. Th1、Th17细胞对小鼠视网膜星形细胞的杀伤作用%Interaction between mouse retinal astrocyte and antigen specific Th1 and Th17 Cells

    Institute of Scientific and Technical Information of China (English)

    崔彦; 毕宏生; Deming Sun

    2012-01-01

    light for mouse after immunization whereas it is prominent for B10R Ⅲ. Objective This study was to observe the killing effect of interphotoreceptor retinoid binding protein (IRBP) 1-20-specific T cells on mouse retinal astrocyte.Th1 and Th17 cells effect in the EAU mechanism was discussed.Methods B10RllⅢ mice and C57BL/6 mice were immunized with IRBP 161-180 and IRBP 1-20 in complete Freund adjuvant (CFA).The infiltrating cells of diseased B10R Ⅲ eyes were analyzed by flow cytometry.IRBP 1-20-specific T cells were isolated from the drainage lymph node and spleen and cultured in IL-2 or IL-23 for Th1 and Th17 cells polarization,respectively.Th1 and Th17 cells cultured for 5 days were seeded on the mouse retinal astrocyte monolayer pretreated with gamma interferon.Cell interaction was observed and the quantity of TNF-α was tested by ELISA.Every test was repeated 6 times and the mean was calculated.The maintenance of experimental animals complied with the Statement of ARVO. Results There were lots of infiltrating cells in the eyes of B10Rm mice after immunization,including 9.5% IFNγ+ cells,5.1% IL-17+cells and 41.4% CD45+ cells.Six days after IRBP1-20 stimulation and cultured by IL-2 and IL-23,44.0% and 8.0% cells were IFNγ+,and 1.0% and 26.0% cells were IL17+.Twentyfour hours after the interaction between Th1 or Th17 and retinal astrocyte,retinal astrocyte died and detached.The killing effect of Th17 was stronger than Th1.48 hours after co-culture of Th1 or Th17T cells with astrocytes,the concentrations of TNF-α were ( 500± 10 ) and ( 801 ±24 μg/L) μg/L,respectively,with a significant statistical difference (t =-20.36,P =0.00). Conclusions Both Th1 and Th17 can kill retinal astrocyte,but Th17 plays a key role in the EAU pathogenesis process.The killing effect is caused by intercellular contact and interaction under the induction of cytokines.

  15. Synthesis of Th17 cytokines in the culture of peripheral blood mononuclear cells stimulated with Borrelia burgdorferi sensu lato

    Directory of Open Access Journals (Sweden)

    Sambor Grygorczuk

    2016-06-01

    Full Text Available [b]Introduction and objective. [/b]Th17 lymphocytes and their cytokines, interleukin 17A (IL-17A, IL-17F and IL-22, participate in the response to extracellular bacteria and in the autoimmunity and may be engaged in the pathogenesis of Lyme borreliosis. Concentrations were measured of IL-17A, IL-17F and IL-22 in the supernatant of the peripheral blood mononuclear cells (PBMC culture stimulated with [i]Borrelia burgdorferi sensu lato[/i] ([i]B. burgdorferi[/i]. [b]Materials and method.[/b] The study group consisted of 13 patients with early disseminated and late Lyme borreliosis and a control group of 7 healthy persons. PBMC cultures were stimulated for 48 hours with [i]B. burgdorferi [/i]spirochetes of three pathogenic species: [i]B. burgdorferi[/i] sensu stricto, B. afzelii or B. garinii, in the multiplicity of infection 10:1. Concentrations of Th17 cytokines IL-17A, IL-17F and IL-22, as well as Th2/immunoregulatory cytokine IL-10 were measured with ELISA assays. [b]Results. [/b]Expression of IL-17A, IL-17F and IL-22 increased under stimulation, simultaneously with the increased IL-10 expression. Concentration of IL-17F tended to be lower in early neuroborreliosis than in late Lyme borreliosis and than in controls. [i]B. afzelii[/i] elicited higher expression of IL-17A than the other two species. [b]Conclusions.[/b] IL-17A, IL-17F and IL-22 are synthesized simultaneously by PBMC stimulated with [i]B. burgdorferi[/i]. There is no antagonism between Th17 response and IL-10 expression. The role of Th17 cytokines seems to differ depending on the clinical stage of Lyme borreliosis and on the [i]B. burgdorferi[/i] species.

  16. In vivo delivery of interleukin-35 relieves coxsackievirus-B3-induced viral myocarditis by inhibiting Th17 cells.

    Science.gov (United States)

    Hu, Yadong; Dong, Chunsheng; Yue, Yan; Xiong, Sidong

    2014-09-01

    Interleukin (IL)-35 is a new member of the IL-12 cytokine family. The suppressive role of IL-35 in the immune response to parasitic and bacterial infections and in autoimmunity has been demonstrated in terms of its anti-inflammatory properties. However, the functional role of IL-35 in viral myocarditis has not been investigated. In this study, IL-35 expression was measured in heart tissues with coxsackievirus B3 (CVB3)-induced myocarditis. It was significantly reduced in the late stage of viral infection and correlated negatively with disease severity. To examine the therapeutic role of IL-35 in viral myocarditis, an IL-35-expressing plasmid (pIL-35-FC) was packaged with polyethyleneimine and delivered intraperitoneally to BALB/c male mice before and after CVB3 infection. The severity of myocarditis was assessed 7 days after infection. The in vivo delivery of IL-35 significantly ameliorated the severity of viral myocarditis, reflected in an increased survival rate and increased bodyweights, and reduced serum creatine kinase (CK) and CK-MB activities, cardiac pathological scores, and viral replication. We also show that the overexpression of IL-35 reduced splenic Th17 cells and Th17-related proinflammatory cytokines in heart tissues. In conclusion, our data indicate that IL-35 effectively protects the myocardium from the pathogenesis of CVB3-induced viral myocarditis, which may be attributable to reduced Th17 production. This suggests that supplementation with IL-35 could be a novel therapeutic treatment for viral myocarditis.

  17. The transcription factor Th-POK negatively regulates Th17 differentiation in Vα14i NKT cells.

    Science.gov (United States)

    Engel, Isaac; Zhao, Meng; Kappes, Dietmar; Taniuchi, Ichiro; Kronenberg, Mitchell

    2012-11-29

    The majority of mouse Vα14 invariant natural killer T (Vα14i NKT) cells produce several cytokines, including IFNγ and IL-4, very rapidly after activation. A subset of these cells, known as NKT17 cells, however, differentiates in the thymus to preferentially produce IL-17. Here, we show that the transcription factor-known as T helper, Poxviruses, and Zinc-finger and Krüppel family, (Th-POK)-represses the formation of NKT17 cells. Vα14i NKT cells from Th-POK-mutant helper deficient (hd/hd) mice have increased transcripts of genes normally expressed by Th17 and NKT17 cells, and even heterozygosity for this mutation leads to dramatically increased numbers of Vα14i NKT cells that are poised to express IL-17, especially in the thymus and lymph nodes. In addition, using gene reporter mice, we demonstrate that NKT17 cells from wild-type mice express lower amounts of Th-POK than the majority population of Vα14i NKT cells. We also show that retroviral transduction of Th-POK represses the expression of the Th17 master regulator RORγT in Vα14i NKT-cell lines. Our data suggest that NKT17-cell differentiation is intrinsically regulated by Th-POK activity, with only low levels of Th-POK permissive for the differentiation of NKT17 cells.

  18. Clinical Significance of IL-23 Regulating IL-17A and/or IL-17F Positive Th17 Cells in Chronic Periodontitis

    Directory of Open Access Journals (Sweden)

    Zhenhua Luo

    2014-01-01

    Full Text Available Objective. To investigate the expression level and clinical significance of (IL-17A+ and/or IL-17F+ Th17 cells under IL-23 regulation in patients of chronic periodontitis (CP and healthy controls (HC. Materials and Methods. The whole peripheral blood samples were collected from 30 CP patients and 25 healthy controls. Flow cytometry was used to test the (IL-17A+ and/or IL-17F+ Th17 expression level. Recombinant human IL-23 (rhIL-23 was used to detect Th17 differentiation and expansion. Correlation coefficient analysis between Th17 expression level and clinical parameters was analyzed by SPSS software. Results. Flow cytometry results showed that IL-17A+IL-17F− and IL-17A−IL-17F+ Th17 were both increased in CP group than in HC group (P < 0.01, while, under recombinant human IL-23 (rhIL-23 stimulation, the number of IL-17A+IL-17F− Th17 cells was significantly increased in both CP and HC groups (P < 0.01. Interestingly, IL-17A−IL-17F+ Th17 cells were only increased in CP group after rhIL-23 stimulation. Additionally, correlation coefficient analysis showed significant correlation between IL-17A+IL-17F− Th17 cell and attachment loss or probing depth (P < 0.05. Conclusions. This study indicates that both the IL-17A+IL-17F− and IL-17A−IL-17F+ Th17 cells may be involved in pathogenesis of periodontitis. The role of these Th17 cells in the disease pathogenesis needs to be further investigated.

  19. Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation.

    Science.gov (United States)

    Jones, Lindsay L; Alli, Rajshekhar; Li, Bofeng; Geiger, Terrence L

    2016-04-01

    How a large number of cytokines differentially signal through a small number of signal transduction pathways is not well resolved. This is particularly true for IL-6 and IL-10, which act primarily through STAT3 yet induce dissimilar transcriptional programs leading alternatively to pro- and anti-inflammatory effects. Kinetic differences in signaling, sustained to IL-10 and transient to IL-6, are critical to this in macrophages. T cells are also key targets of IL-6 and IL-10, yet how differential signaling in these cells leads to divergent cellular fates is unclear. We show that, unlike for macrophages, signal duration cannot explain the distinct effects of these cytokines in T cells. Rather, naive, activated, activated-rested, and memory CD4(+) T cells differentially express IL-6 and IL-10 receptors in an activation state-dependent manner, and this impacts downstream cytokine effects. We show a dominant role for STAT3 in IL-6-mediated Th17 subset maturation. IL-10 cannot support Th17 differentiation because of insufficient cytokine receptivity rather than signal quality. Enforced expression of IL-10Rα on naive T cells permits an IL-10-generated STAT3 signal equivalent to that of IL-6 and equally capable of promoting Th17 formation. Similarly, naive T cell IL-10Rα expression also allows IL-10 to mimic the effects of IL-6 on both Th1/Th2 skewing and Tfh cell differentiation. Our results demonstrate a key role for the regulation of receptor expression rather than signal quality or duration in differentiating the functional outcomes of IL-6 and IL-10 signaling, and identify distinct signaling properties of these cytokines in T cells compared with myeloid cells.

  20. Rebamipide suppresses collagen-induced arthritis through reciprocal regulation of th17/treg cell differentiation and heme oxygenase 1 induction.

    Science.gov (United States)

    Moon, Su-Jin; Park, Jin-Sil; Woo, Yun-Ju; Lim, Mi-Ae; Kim, Sung-Min; Lee, Seon-Yeong; Kim, Eun-Kyung; Lee, Hee Jin; Lee, Weon Sun; Park, Sang-Hi; Jeong, Jeong-Hee; Park, Sung-Hwan; Kim, Ho-Youn; Cho, Mi-La; Min, Jun-Ki

    2014-04-01

    Rebamipide, a gastroprotective agent, has the ability to scavenge reactive oxygen radicals. Increased oxidative stress is implicated in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to investigate the impact of rebamipide on the development of arthritis and the pathophysiologic mechanisms by which rebamipide attenuates arthritis severity in a murine model of RA. Collagen-induced arthritis (CIA) was induced in DBA/1J mice. Anti-type II collagen antibody titers and interleukin-17 (IL-17) levels were determined using enzyme-linked immunosorbent assay. The expression of transcription factors was analyzed by immunostaining and Western blotting. Frequencies of IL-17-producing CD4+ T cells (Th17 cells) and CD4+CD25+FoxP3+ Treg cells were analyzed by flow cytometry. Rebamipide reduced the clinical arthritis score and severity of histologic inflammation and cartilage destruction in a dose-dependent manner. The joints isolated from rebamipide-treated mice with CIA showed decreased expression of nitrotyrosine, an oxidative stress marker. Rebamipide-treated mice showed lower circulating levels of type II collagen-specific IgG, IgG1, and IgG2a. Whereas the number of Th17 cells in spleens was decreased in rebamipide-treated mice with CIA, a significant increase in the number of Treg cells in spleens was observed. In vitro, rebamipide inhibited Th17 cell differentiation through STAT-3/retinoic acid receptor-related orphan nuclear receptor γt and reciprocally induced Treg cell differentiation through FoxP3. Rebamipide increased Nrf2 nuclear activities in murine CD4+ T cells and LBRM-33 murine T lymphoma cells. Heme oxygenase 1 (HO-1) expression in the spleens was markedly increased in rebamipide-treated mice. The inhibitory effects of rebamipide on joint inflammation are associated with recovery from an imbalance between Th17 cells and Treg cells and with activation of an Nrf2/HO-1 antioxidant pathway. Copyright © 2014 by the American College of

  1. Graves病患者外周血中Th17细胞及相关细胞因子的表达%Expression of Th17 cells and related cytokines in peripheral blood of patients with Graves′disease

    Institute of Scientific and Technical Information of China (English)

    李红林; 邓之奎; 郑云会; 刘艳秋; 刘小宁; 杨士军; 陆卫军; 高美华

    2016-01-01

    目的:研究Graves病患者外周血中Th17细胞及IL-17、IL-23的表达水平并探讨其临床意义。方法:用流式细胞仪检测29例Graves病患者治疗前后( GD组,GD缓解组)和29名健康对照者( NC组)外周血PBMC中CD4+IL-17+T细胞比例,用ELISA法检测血清中IL-17和IL-23浓度,用电化学发光法检测血清游离三碘甲状腺原氨酸( FT3)、游离甲状腺素(FT4)、促甲状腺激素(TSH)水平,用放射受体分析法测定抗促甲状腺激素受体抗体(TrAb)水平。结果:3组之间年龄、性别差异均无统计学意义( F=0.0075,P>0.05;χ2=0.4213,P>0.05)。 GD组和GD缓解组Th17比例、IL-17、IL-23的水平显著高于NC组,差异有统计学意义( P均<0.05)。 GD缓解组的Th17比例、IL-23浓度显著低于GD组,但GD缓解组IL-17浓度与GD组的差异无统计学意义( P>0.05)。 Th17比例、IL-17、IL-23与FT3、FT4、TrAb均呈正相关( r值依次为:0.5882、0.3372、0.3710;0.5496、0.2875、0.3427;0.3610、0.4208、0.3308;P均<0.05)。 Th17比例、IL-17、IL-23与TSH均呈负相关( r值依次为-0.3197、-0.4728、-0.4282;P均<0.05)。结论:Th17细胞及其相关细胞因子IL-17、IL-23在GD患者外周血中均高表达;并与GD患者的甲功4项指标具有不同程度的相关性。 Th17细胞及相关细胞因子IL-17、IL-23能够作为GD的生物学标记物。%Objective:To explore the proportions of Th17 cells in the peripheral blood and levels of IL-17,IL-23 in the serum of patients with Graves′disease ( GD ) and their clinical significance.Methods: We studied 29 patients with GD ( GD group ) , and reevaluated the GD group after therapy ( euthyroid GD group ).29 gender-and age-matched volunteers were selected as the normal control ( NC group).The proportions of Th17 cells were investigated by flow cytometry.The levels of IL-23,IL-17 in the serums were measured by ELISA

  2. Th17/Treg细胞失衡与再生障碍性贫血研究进展%Recent Progress of Study on Imbalance of Th17/Treg Cells in Aplastic Anemia——Review

    Institute of Scientific and Technical Information of China (English)

    杨友卫; 郑智茵; 姚红章

    2012-01-01

    再生障碍性贫血( aplastic anemia,AA)是一种以效应T细胞功能亢进导致造血组织损伤为特征的自身免疫性疾病.近年来研究发现,AA与Th17细胞数量增加及Treg细胞数量减少密切相关,且Th17和Treg细胞功能上相互拮抗.动物实验表明,IL-17抗体靶向治疗及Treg细胞回输治疗均可改善免疫介导的AA小鼠骨髓衰竭状态.本文就Th17/Treg细胞与AA关系最新研究进展作一综述,旨在进一步探讨AA发病机制,为临床治疗提供新思路.本综述讨论的主要问题有:Th1 7/Treg细胞一般生物学特性,Th17/Treg细胞平衡的调节及相关细胞因子,Th17/Treg细胞与再生障碍性贫血关系等.%Aplastic anemia (AA) is an autoimmune disease characterized by destruction of hematopoietic tissue resulting in hyperfunction of effector T-lymphocytes. Recent studies indicate that Thl7 and Treg cells are functionally antagonistic each other, and the increase of Thl7 cells and decrease of Treg cells are closely related with AA. In vivo experiments showed that both anti-IL-17 treatment and Treg cell infusion can protect against immune-mediated bone marrow failure in mouse with AA. This review summarizes the recent progress of study on imbalance of Thl7/ Treg cells in AA, so as to explore the pathogenesis of AA and provide approach to clinical treatment. The main problems that are discussed in this review include biological characteristics of Thl7/Treg cells, the regulation of Thl7/Treg cell balance and related cytokines, the relationship between Thl7/Treg cells and AA.

  3. Human periodontal ligament cells facilitate leukocyte recruitment and are influenced in their immunomodulatory function by Th17 cytokine release.

    Science.gov (United States)

    Konermann, A; Beyer, M; Deschner, J; Allam, J P; Novak, N; Winter, J; Jepsen, S; Jäger, A

    2012-01-01

    The objective of this in vitro study was to examine the immunomodulatory impact of human periodontal ligament (PDL) cells on the nature and magnitude of the leukocyte infiltrate in periodontal inflammation, particularly with regard to Th17 cells. PDL cells were challenged with pro-inflammatory cytokines (IL-1ß, IL-17A, and IFN-γ) and analyzed for the expression of cytokines involved in periodontal immunoinflammatory processes (IL-6, MIP-3 alpha, IL-23A, TGFß1, IDO, and CD274). In order to further investigate a direct involvement of PDL cells in leukocyte function, co-culture experiments were conducted. The expression of the immunomodulatory cytokines studied was significantly increased under pro-inflammatory conditions in PDL cells. Although PDL cells did not stimulate leukocyte proliferation or Th17 differentiation, these cells induced the recruitment of leukocytes. The results of our study suggest that PDL cells might be involved in chronic inflammatory mechanisms in periodontal tissues and thus in the transition to an adaptive immune response in periodontitis.

  4. Expression of tyrosine hydroxylase in CD4+ T cells contributes to alleviation of Th17/Treg imbalance in collagen-induced arthritis.

    Science.gov (United States)

    Wang, Xiao-Qin; Liu, Yan; Cai, Huan-Huan; Peng, Yu-Ping; Qiu, Yi-Hua

    2016-07-20

    Tyrosine hydroxylase (TH), a rate-limiting enzyme for the synthesis of catecholamines, is expressed in T lymphocytes. However, the role of T cell-expressed TH in rheumatoid arthritis (RA) is less clear. Herein, we aimed to show the contribution of TH expression by CD4(+) T cells to alleviation of helper T (Th)17/regulatory T (Treg) imbalance in collagen-induced arthritis (CIA), a mouse model of RA. CIA was prepared by intradermal injection of collagen type II (CII) at tail base of DBA1/J mice. Expression of TH in the spleen and the ankle joints was measured by real-time polymerase chain reaction and Western blot analysis. Percentages of TH-expressing Th17 and Treg cells in splenic CD4(+) T cells were determined by flow cytometry. Overexpression and knockdown of TH gene in CD4(+) T cells were taken to evaluate effects of TH on Th17 and Treg cells in CIA. TH expression was upregulated in both the inflamed tissues (spleen and ankle joints) and the CD4(+) T cells of CIA mice. In splenic CD4(+) T cells, the cells expressing TH were increased during CIA. These cells that expressed more TH in CIA were mainly Th17 cells rather than Treg cells. TH gene overexpression in CD4(+) T cells from CIA mice reduced Th17 cell percentage as well as Th17-related transcription factor and cytokine expression and secretion, whereas TH gene knockdown enhanced the Th17 cell activity. In contrast, TH gene overexpression increased Treg-related cytokine expression and secretion in CD4(+) T cells of CIA mice, while TH gene knockdown decreased the Treg cell changes. Collectively, these findings show that CIA induces TH expression in CD4(+) T cells, particularly in Th17 cells, and suggest that the increased TH expression during CIA represents an anti-inflammatory mechanism.

  5. Detection of Th17/Treg cell balance in peripheral blood of patients with Henoch-Sch(o)nlein purpura%过敏性紫癜患者外周血Th17/Treg细胞平衡性检测

    Institute of Scientific and Technical Information of China (English)

    马蕾; 李晓红; 张玉杰; 张俊花

    2010-01-01

    Objective To assess the role of Th 17/Treg cell imbalance in the pathogenesis of HenochSch(o)nlein purpura (HSP). Methods Peripheral blood was obtained from 59 children with HSP and 38 ageand sex-matched healthy subjects. Flow cytometric analysis (FCM) was performed to detect the percentage of CD4+IL17+ T (Th17) cells and CD4+CD25+ Foxp3+ T (Treg) cells, real-time RT-PCR to measure the mRNA expressions of RORγt and Foxp3, which are specific transcription factors of Th17 and Treg cells, respectively.Results Patients with HSP showed a significant increase in the percentage of Th17 cells and mRNA level of RORγt (1.87% ± 0.56% vs 0.39% ± 0.15%, 7.71 ± 1.95 vs 1.49 ± 0.57, both P< 0.01) and a statistical decrease in the percentage of Treg cells and mRNA level of Foxp3 ( 1.63% ± 0.44% vs 5.04% ± 1.44%, 0.34 ±0.11 vs 1.71 ± 0.69, both P < 0.01 ) compared with the normal controls. No significant difference was observed in the percentage of Th17 or Treg cells or the mRNA levels of RORγt or Foxp3 among patients with different types of HSP. Conclusion In patients with HSP, there is a change in the pecentage of Th17/Treg cells and expression of their transcription factors, which may lead to immune imbalance and contribute to the development of HSP.%目的 探讨Th17细胞/Treg细胞(CD4+CD25+Foxp3+T细胞)失衡在过敏性紫癜(HSP)发病机制中的作用.方法 采用流式细胞仪检测59例HSP患儿外周血Th17细胞和Treg细胞的比例、实时定量RT-PCR检测Th17细胞与Treg细胞转录因子RORγt、Foxp3 mRNA的表达.同时以38例性别、年龄匹配的健康儿童做对照.结果 HSP组外周血Th17细胞比例(CD4+IL-17+/CD4+T细胞,1.87%±0.56%)及RORγt mRNA表达量(7.71±1.95),均显著高于正常人对照组(CD4+IL-17+/CD4+T细胞:0.39%±0.15%,P<0.01;RORγt mRNA:1.49±0.57,P<0.01);HSP组外周血Treg细胞比例(CD4+CD25+Foxp3+/CD4+T细胞,1.63%±0.44%)及Foxp3 mRNA的表达量(0.34±0.11),均明显低于正常人对照组(CD4+CD

  6. Periplocoside A prevents experimental autoimmune encephalomyelitis by suppressing IL-17 production and inhibits differentiation of Th17 cells

    Institute of Scientific and Technical Information of China (English)

    Jing ZHANG; Jia NI; Zhen-hua CHEN; Xin LI; Ru-jun ZHANG; Wei TANG; Wei-min ZHAO; Yi-fu YANG; Jian-ping ZUO

    2009-01-01

    Aim: The aim of this study was to determine the therapeutic effect of Periplocoside A (PSA), a natural product isolated from the tradi-tional Chinese herbal medicine Periploca sepium Bge, in MOG35-55 (myelin oligodendrocyte glycoprotein 35-55)-induced experimental autoimmune encephalomyelitis (EAE).Methods: Female C57BL/6 mice immunized with MOG35-55 were treated with (50 mg/kg or 25 mg/kg) or without PSA following immu-nization and continuously throughout the study. The degree of CNS inflammation was evaluated by H&E staining. Anti-MOG-specific recall responses were analyzed by [3H]-Thymidine incorporation, ELISA, and RT-PCR. The proportion of IL-17-producing T cells was mea-sured by flow cytometry.Results: Oral administration of PSA significantly reduced the incidence and severity of EAE, which closely paralleled the inhibition of MOG35-55-specific IL-17 production. Importantly, PSA inhibited the transcription of IL-17 mRNA and RORyt. Further studies examin-ing intracellular staining and adoptive transfer EAE validated the direct suppressive effect of PSA on Th17 cells. In vitro studies also showed that PSA significantly inhibited the differentiation of Th17 cells from murine purified CD4+ T cells in a dose-dependent manner.Conclusion: PSA ameliorated EAE by suppressing IL-17 production and inhibited the differentiation of Th17 cells in vitro. Our results provide new insight into the potential mechanisms underlying the immunosuppressive and anti-inflammatory effects of PSA.

  7. RANKL expression on Th17 cells in rheumatoid arthritis and its significance to clinic%类风湿关节炎患者Th17细胞膜上RANKL的表达及意义

    Institute of Scientific and Technical Information of China (English)

    范璐; 陈海燕; 韩捷; 周洁如

    2011-01-01

    目的 探讨类风湿关节(rheumatoid arthritis,RA)患者外周血和关节液中Th17细胞膜上RANKL的表达水平与RA病情活动程度指标CRP、ESR、RF及DAS28评分的关系.方法 用流式细胞术及RT-PCR方法检测RA患者外周血和关节液中Th17细胞膜上RANKL的表达水平.结果 RA患者外周血Th17细胞膜上RANKL表达明显高于健康对照组(P<0.05),RA患者关节液中Th17细胞膜上RANKL表达高于RA外周血(P<0.05),RA患者外周血Th17细胞膜上RANKL表达与DAS28评分呈正相关性(r=0.36,P<0.05).RT-PCR结果提示RA患者CD4+T上RANKL表达较健康对照组升高(P<0.05).CD4+T细胞RANKL mRNA水平与IL-17 mRNA水平呈显著正相关(r=0.63,P<0.001).结论 Th17细胞膜上RANKL表达明显升高,且与病情活动程度显著相关,提示Th17细胞可能参与RA骨破坏过程,在RA的破骨免疫致病机制中可能起重要作用.%Objective To study the expression of blood and synovial fluid RANKL on Thl7 cells in patient with rheumatoid arthritis by analyzing the correlations between their expression level and the indexes reflecting RA disease and to elaborate the relationship between Thl7 cells and bone destruction.Methods Expression of RANKL on Thl7 cells from RA and control group was evaluated by flow cytometry and RT-PCR.Results Expression of RANKL on Thl7 cells was higher in RA blood than that in control group ( P < 0.05 ), and it was higher in RA synovial fluid (P < 0.05 ).There was a significantly positive correlation between expression of RANKL on Thl7 cells in peripheral blood of RA and DAS28 ( r= 0.36, P < 0.05 ).Results from RT-PCR indicated that RANKL on CD4 + T cells was higher than that in control group ( P < 0.05 ).A positive correlation was also found between RANKL mRNA and IL-17 mRNA on CD4 +T cell.Conclusion RANKL on Thl7 cells overexpresses in RA blood and synovial fluid, and has a significantly positive correlation with DAS28 in RA patients.Thl7 cells may be involved in the process

  8. An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients.

    Science.gov (United States)

    Wei, Ping; Hu, Guo-Hua; Kang, Hou-Yong; Yao, Hong-Bing; Kou, Wei; Liu, Hong; Zhang, Cheng; Hong, Su-Ling

    2014-05-01

    A predominant Th17 population is a marker of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR) exhibits strong immunomodulation potential via regulation of the differentiation of T lymphocytes and dendritic cells (DCs) after activation by its ligand, such as 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). The aim of this study was to analyze the effect of AhR on Th17 differentiation by investigating the action of ITE on DCs and CD4(+) T cells from patients with AR. In all, 26 AR patients and 12 healthy controls were included in this study. The expression of interleukin (IL)-1β, IL-6, IL-10, and IL-17 in the culture supernatant and the presence of Th17 cells in CD4(+) T cells and DC-CD4(+) T-cell co-culture system were measured before and after treatment with ITE. We show that ITE significantly induced cell secretion of IL-10 and inhibited IL-1β and IL-6 production in DCs, and promoted IL-10 production and suppressed IL-17 expression in CD4(+) T cells in vitro. It also suppressed the expansion of Th17 cells in vitro. Our work demonstrates that ITE acts on DCs and CD4(+) T cells to inhibit the Th17 response that suppresses AR; the AhR-DC-Th17 axis may be an important pathway in the treatment of AR. ITE, a nontoxic AhR ligand, attenuated the Th17 response; thus, it appears to be a promising therapeutic candidate for suppressing the inflammatory responses associated with AR.

  9. Th17细胞在慢性乙型肝炎及其重症化中的变化%The changes of Th17 cells in the pathogenesis and aggravation of chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    杨波; 赵彩彦; 王亚东; 车宏浩; 阎文昭; 赵萌

    2012-01-01

    Objective To explore the changes of Th17 cells in the pathogenesis and aggravation of chronic hepatitis B (CHB).Methods Thirty-two CHB patients,44 hepatitis B virus (HBV)related acute-on-chronic liver [ailure (ACLF) patients and 20 healthy controls (HC) were involved in our research. The frequencies of circulating Th17 cells were detected by flow cyrometry. The interleukin 17 (IL-17) mRNA expressions in the peripheral blood mononuclear cells (PBMC) were detected by quantitative real-time polymerase chain reaction (PCR).Immunohistochemical staining was performed to determine the expressions of IL-17+ cells in the liver tissues.The serum IL-17 concentrations were detected by enzyme-linked immunosorhent assay (ELISA),and the dynamic changes in ACLF patients with different prognosis were also observed.Normal distribution data were used by analysis of variance and non-normal distribution data were used by Kruskal-Wallis H test or Mann-Whitney U test.Results In CHB,ACLF and healthy control groups,Th17 cells frequencies in PBMC were (1.47 ± 0.60) %,(3.20 ± 1.08) % and (0.86 ± 0.43) %,respectively ; IL-17 mRNA were 4.32±11.77,18.32±8.21 and 1.00,respectively; IL-17+ cells in the liver tissues were (10.6±4.8),(21.1±6.6) and (0.5±0.2)/high power field; the level of IL-17 in serum were (15.88±6.51),(35.03±11.54) and (10.04±4.06) ng/L,respectively (all P<0.05).Moreover,the frequencies of circulating Th17 cells and the levels of serum IL-17 in medium-stage and end-stage ACLF patients were higher than that in early-stage ACLF patients (both P < 0.01). In ACLF patients,the circulating Th17 cells frequencies were positively correlated with international normalized ratio (INR,r=0.44,P<0.01) and model of end-stage liver disease (MELD) score (r=0.44,P<0.01).And the frequencies of circulating Th17 cells were positively associated with the serum alanine transaminase (ALT) levels in CHB patients (r=0.51,P<0.01).Moreover,the survival ACLF patients had an

  10. Advances in the Research on T helper 17 Cells and Tumor Immunity%Th17细胞与肿瘤免疫的研究进展

    Institute of Scientific and Technical Information of China (English)

    何宋兵

    2012-01-01

    Th17细胞是一类与Th1、Th2及Treg细胞不同的新型效应CD4+T细胞,研究已证实Th17细胞在感染、炎症、自身免疫性疾病及移植物抗宿主病中具有关键的致病作用.近来研究发现Th17细胞同样存在于肿瘤微环境中,并与炎症相关性肿瘤的发生有一定关系,但目前对Thl7细胞在肿瘤微环境中的分化发育条件、免疫调控机制及具体功能效应尚不完全清楚.本文将对Th17细胞及其相关细胞因子与肿瘤免疫相关性的研究进展作一简要综述.%Th17 cells have recently been classified as a new effector T-cell subset which is distinct from Th1, Th2 and Treg subsets. Since Th17 cells were found, studies confirmed that these cells had critical roles in infection, inflammation, autoimmune diseases, and graft versus host disease. Moreover, Th17 cells have been recently found in some human cancers, but the differentiation and development condition, regulation mechanisms and functional effects of Th17 cells remains controversial. This review summarizes recent findings regarding the correlation of Th17 cells and malignant tumor related cytokines with tumor immunity.

  11. Differential effects of peptidoglycan recognition proteins on experimental atopic and contact dermatitis mediated by Treg and Th17 cells.

    Science.gov (United States)

    Park, Shin Yong; Gupta, Dipika; Kim, Chang H; Dziarski, Roman

    2011-01-01

    Skin protects the body from the environment and is an important component of the innate and adaptive immune systems. Atopic dermatitis and contact dermatitis are among the most frequent inflammatory skin diseases and are both determined by multigenic predisposition, environmental factors, and aberrant immune response. Peptidoglycan Recognition Proteins (Pglyrps) are expressed in the skin and we report here that they modulate sensitivity to experimentally-induced atopic dermatitis and contact dermatitis. Pglyrp3(-/-) and Pglyrp4(-/-) mice (but not Pglyrp2(-/-) mice) develop more severe oxazolone-induced atopic dermatitis than wild type (WT) mice. The common mechanism underlying this increased sensitivity of Pglyrp3(-/-) and Pglyrp4(-/-) mice to atopic dermatitis is reduced recruitment of Treg cells to the skin and enhanced production and activation Th17 cells in Pglyrp3(-/-) and Pglyrp4(-/-) mice, which results in more severe inflammation and keratinocyte proliferation. This mechanism is supported by decreased inflammation in Pglyrp3(-/-) mice following in vivo induction of Treg cells by vitamin D or after neutralization of IL-17. By contrast, Pglyrp1(-/-) mice develop less severe oxazolone-induced atopic dermatitis and also oxazolone-induced contact dermatitis than WT mice. Thus, Pglyrp3 and Pglyrp4 limit over-activation of Th17 cells by promoting accumulation of Treg cells at the site of chronic inflammation, which protects the skin from exaggerated inflammatory response to cell activators and allergens, whereas Pglyrp1 has an opposite pro-inflammatory effect in the skin.

  12. Generation of IL-8 and IL-9 Producing CD4+ T Cells Is Affected by Th17 Polarizing Conditions and AHR Ligands

    Directory of Open Access Journals (Sweden)

    Michaela Gasch

    2014-01-01

    Full Text Available The T helper cell subsets Th1, Th2, Th17, and Treg play an important role in immune cell homeostasis, in host defense, and in immunological disorders. Recently, much attention has been paid to Th17 cells which seem to play an important role in the early phase of the adoptive immune response and autoimmune disease. When generating Th17 cells under in vitro conditions the amount of IL-17A producing cells hardly exceeds 20% while the nature of the remaining T cells is poorly characterized. As engagement of the aryl hydrocarbon receptor (AHR has also been postulated to modulate the differentiation of T helper cells into Th17 cells with regard to the IL-17A expression we ask how far do Th17 polarizing conditions in combination with ligand induced AHR activation have an effect on the production of other T helper cell cytokines. We found that a high proportion of T helper cells cultured under Th17 polarizing conditions are IL-8 and IL-9 single producing cells and that AHR activation results in an upregulation of IL-8 and a downregulation of IL-9 production. Thus, we have identified IL-8 and IL-9 producing T helper cells which are subject to regulation by the engagement of the AHR.

  13. Cholera Toxin Promotes Th17 Cell Differentiation by Modulating Expression of Polarizing Cytokines and the Antigen-Presenting Potential of Dendritic Cells.

    Directory of Open Access Journals (Sweden)

    Jung-Ok Kang

    Full Text Available Cholera toxin (CT, an exotoxin produced by Vibrio cholera, acts as a mucosal adjuvant. In a previous study, we showed that CT skews differentiation of CD4 T cells to IL-17-producing Th17 cells. Here, we found that intranasal administration of CT induced migration of migratory dendritic cell (DC populations, CD103+ DCs and CD11bhi DCs, to the lung draining mediastinal lymph nodes (medLN. Among those DC subsets, CD11bhi DCs that were relatively immature had a major role in Th17 cell differentiation after administration of CT. CT-treated BMDCs showed reduced expression of MHC class II and CD86, similar to CD11bhi DCs in medLN, and these BMDCs promoted Th17 cell differentiation more potently than other BMDCs expressing higher levels of MHC class II and CD86. By analyzing the expression of activation markers such as CD25 and CD69, proliferation and IL-2 production, we determined that CT-treated BMDCs showed diminished antigen-presenting potential to CD4+ T cells compared with normal BMDCs. We also found that CT-stimulated BMDCs promote activin A expression as well as IL-6 and IL-1β, and activin A had a synergic role with TGF-β1 in CT-mediated Th17 cell differentiation. Taken together, our results suggest that CT-stimulated DCs promote Th17 cell differentiation by not only modulating antigen-presenting potential but also inducing Th polarizing cytokines.

  14. Cholera Toxin Promotes Th17 Cell Differentiation by Modulating Expression of Polarizing Cytokines and the Antigen-Presenting Potential of Dendritic Cells

    Science.gov (United States)

    Kang, Jung-Ok; Lee, Jee-Boong

    2016-01-01

    Cholera toxin (CT), an exotoxin produced by Vibrio cholera, acts as a mucosal adjuvant. In a previous study, we showed that CT skews differentiation of CD4 T cells to IL-17-producing Th17 cells. Here, we found that intranasal administration of CT induced migration of migratory dendritic cell (DC) populations, CD103+ DCs and CD11bhi DCs, to the lung draining mediastinal lymph nodes (medLN). Among those DC subsets, CD11bhi DCs that were relatively immature had a major role in Th17 cell differentiation after administration of CT. CT-treated BMDCs showed reduced expression of MHC class II and CD86, similar to CD11bhi DCs in medLN, and these BMDCs promoted Th17 cell differentiation more potently than other BMDCs expressing higher levels of MHC class II and CD86. By analyzing the expression of activation markers such as CD25 and CD69, proliferation and IL-2 production, we determined that CT-treated BMDCs showed diminished antigen-presenting potential to CD4+ T cells compared with normal BMDCs. We also found that CT-stimulated BMDCs promote activin A expression as well as IL-6 and IL-1β, and activin A had a synergic role with TGF-β1 in CT-mediated Th17 cell differentiation. Taken together, our results suggest that CT-stimulated DCs promote Th17 cell differentiation by not only modulating antigen-presenting potential but also inducing Th polarizing cytokines. PMID:27271559

  15. Decreased expression of IL-27 and its correlation with Th1 and Th17 cells in progressive multiple sclerosis.

    Science.gov (United States)

    Tang, Shao-can; Fan, Xiao-hua; Pan, Qing-min; Sun, Qiang-san; Liu, Yu

    2015-01-15

    Progressive multiple sclerosis (MS) is an immune-mediated demyelinating disease in which both imbalanced T helper (Th) subsets and aberrant cytokine profiles have been found. Interleukin-27 (IL-27), a cytokine with pro-inflammatory and anti-inflammatory effects, plays pleiotropic roles in immunomodulation. In the present study, plasma levels of IL-27, interferon-gamma (IFN-γ), IL-17 and frequencies of peripheral Th1, Th17 cells were determined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry in 45 progressive MS and 25 healthy controls. mRNA expression levels of IL-27, IFN-γ, T-bet, IL-17 and RAR-related orphan receptor gamma t (RORγt) in peripheral blood mononuclear cells (PBMCs) were also quantified by real-time polymerase chain reaction. Plasma and mRNA levels of IL-27 in progressive MS patients were significantly lower than those in healthy controls, while plasma concentrations of IL-17, frequencies of circulating Th17, and mRNA expression levels of IL-17 as well as RORγt were all increased remarkably compared with healthy controls. No statistical significance was observed in IFN-γ and T-bet mRNA expression or plasma IFN-γ levels between progressive MS patients and healthy controls. Moreover, plasma levels of IL-27 were found to be negatively correlated to the percentages of circulating Th17 or plasma IL-17 concentrations in patients with progressive MS. Our data showed that progressive MS patients had decreased plasma and mRNA expression levels of IL-27, suggesting that it might be involved in the pathophysiological process of MS.

  16. Defining the functional states of Th17 cells [v1; ref status: indexed, http://f1000r.es/51y

    Directory of Open Access Journals (Sweden)

    Youjin Lee

    2015-05-01

    Full Text Available The molecular mechanisms governing T helper (Th cell differentiation and function have revealed a complex network of transcriptional and protein regulators. Cytokines not only initiate the differentiation of CD4 Th cells into subsets but also influence the identity, plasticity and effector function of a T cell. Of the subsets, Th17 cells, named for producing interleukin 17 (IL-17 as their signature cytokine, secrete a cohort of other cytokines, including IL-22, IL-21, IL-10, IL-9, IFNγ, and GM-CSF.  In recent years, Th17 cells have emerged as key players in host defense against both extracellular pathogens and fungal infections, but they have also been implicated as one of the main drivers in the pathogenesis of autoimmunity, likely mediated in part by the cytokines that they produce. Advances in high throughput genomic sequencing have revealed unexpected heterogeneity in Th17 cells and, as a consequence, may have tremendous impact on our understanding of their functional diversity. The assortment in gene expression may also identify different functional states of Th17 cells. This review aims to understand the interplay between the cytokine regulators that drive Th17 cell differentiation and functional states in Th17 cells.

  17. Role of Treg and TH17 cells of the gastric mucosa in children with Helicobacter pylori gastritis.

    Science.gov (United States)

    Gil, Joo Hyun; Seo, Jeong Wan; Cho, Min-Sun; Ahn, Jung-Hyuck; Sung, Hye Youn

    2014-02-01

    The aim of the present study was to examine the expression of FOXP3, interleukin (IL)-10, transforming growth factor (TGF)-β1, IL-17A, and T helper 17 (TH17) cells/FOXP3+ regulatory T (Treg) cells balance in the gastric mucosa of children with Helicobacter pylori infection, in relation to the gastric histopathology. Antral mucosal biopsies were obtained from 20 children with H pylori(+) gastritis and 20 age- and sex-matched normal controls. Histopathology was assessed by the updated Sydney classification. Gene expression of FOXP3, IL-10, and TGF-β1 was analyzed by quantitative real-time polymerase chain reaction. Immunohistochemical staining for FOXP3+ Treg and TH17 cells was performed. The gene expression levels of FOXP3, TGF-β1, and IL-10 messenger RNA (mRNA) and the number of FOXP3+ Treg were significantly higher in the H pylori(+) gastritis group than in the control group (P gastritis group (P gastritis group (P gastritis group than in the control group (P gastritis group (P gastritis group (P gastritis.

  18. Th1-Th17 cells contribute to the development of uropathogenic Escherichia coli-induced chronic pelvic pain.

    Directory of Open Access Journals (Sweden)

    Marsha L Quick

    Full Text Available The etiology of chronic prostatitis/chronic pelvic pain syndrome in men is unknown but may involve microbes and autoimmune mechanisms. We developed an infection model of chronic pelvic pain in NOD/ShiLtJ (NOD mice with a clinical Escherichia coli isolate (CP-1 from a patient with chronic pelvic pain. We investigated pain mechanisms in NOD mice and compared it to C57BL/6 (B6 mice, a strain resistant to CP-1-induced pain. Adoptive transfer of CD4+ T cells, but not serum, from CP-1-infected NOD mice was sufficient to induce chronic pelvic pain. CD4+ T cells in CP-1-infected NOD mice expressed IFN-γ and IL-17A but not IL-4, consistent with a Th1/Th17 immune signature. Adoptive transfer of ex-vivo expanded IFN-γ or IL-17A-expressing cells was sufficient to induce pelvic pain in naïve NOD recipients. Pelvic pain was not abolished in NOD-IFN-γ-KO mice but was associated with an enhanced IL-17A immune response to CP1 infection. These findings demonstrate a novel role for Th1 and Th17-mediated adaptive immune mechanisms in chronic pelvic pain.

  19. [Immunomodulation of Uncaria tomentosa over dendritic cells, il-12 and profile TH1/TH2/TH17 in breast cancer].

    Science.gov (United States)

    Núñez, César; Lozada-Requena, Iván; Ysmodes, Tíndara; Zegarra, Daniel; Saldaña, Fatima; Aguilar, José

    2015-10-01

    Objetives. This study aimed to research the in vitro immunomodulatory effects of an Uncaria tomentosa hydroalcoholic extract standardized (5.03%, pentacyclic oxindole alkaloids) (UT-POA) on the immunophenotype of dendritic cells (DC) subsets, Th1, Th2, Th17 and IL-12 cytokines from patients with stage II breast cancer (BCII) and healthy women (H). Blood of 11 H and 7 BCII was obtained, PBMC were isolated and cultured for 2h with/without various concentrations of UT-POA and stimulated or not with LPS for 24h. PBMC were labeled with specific antibodies for DC and in the supernatant we measured Th1/Th2/Th17 cytokines, both by flow cytometry. Furthermore IL-12 was measured by ELISA. UT-POA did not alter DC or accessory molecules expression in BCII. However, H exhibited a decrease in the percentage of mDC (myeloid DC) and an increase in HLA-DR and CD86 expression at 1000 μg/mL. IL-12 secretion was modified only in the H group, increasing p70 subunit and decreasing p40 subunit. UT-POA increased Th1 (IFN-γ and IL-2), Th2 (IL-4) and Th17 (IL-17) secretion in both groups. UT-POA increased the production of cytokines related with anti-tumoral response at concentrations of 500-1000 μg/mL. This positive effect should be evaluated not only systemically but also in the tumor microenvironment in further studies. UT-POA may be a useful phytochemical in chemoprevention and in the alternative use in cancer therapies.

  20. Th17细胞与Treg细胞在支气管哮喘发病机制中的研究进展%Th17 cell and CD4 + CD25 + Treg in iathogenesis of asthma

    Institute of Scientific and Technical Information of China (English)

    姚斌

    2012-01-01

    近年来,众多研究发现支气管哮喘的发病机制已不能单纯用Th1/Th2平衡理论来解释,CD4+ CD25+调节性T细胞和Th17细胞及其细胞因子IL-10、IL-17、转化生长因子-β等与支气管哮喘发病明显相关.由于Th17细胞与CD4+ CD25+调节性T细胞在功能上相互拮抗,而在分化上密切相关,因此这两种细胞的免疫失衡也是支气管哮喘发病的重要原因.糖皮质激素可通过维甲酸相关孤核受体γt信号途径降低IL-17的表达,还可以通过诱导转录因子Foxp3的表达调控CD4+ CD25+调节性T细胞的分化和功能.%Many studies have suggested that pathogenesis of asthma could no longer be interpreted merely by “Th1/Th2 balance” theory.CD4 + CD25 + Treg and Th17 cells,as well as their cytokines such as IL-10,transforming growth factor-β,and IL-17,account for asthma.CD4 + CD25 + Treg and Th17 are functionally antagonistic to each other,and also go with each other during their differentiation.Therefore,immunity-unbalance of CD4 + CD25 + Treg and Th17 is one of the most important factors that triggers asthma.Glucocorticoid has been shown to down regulate IL-17 expression by retinoic acid receptors γt signaling pathway,and regulate differentiation and function of CD4 + CD25 + Treg by inducing expression of transcription factor Foxp3,all of these are immuno-mechanisms of glucocorticoid in asthma treatment.

  1. Pre-Vaccination Frequencies of Th17 Cells Correlate with Vaccine-Induced T-Cell Responses to Survivin-Derived Peptide Epitopes.

    Science.gov (United States)

    Køllgaard, Tania; Ugurel-Becker, Selma; Idorn, Manja; Andersen, Mads Hald; Becker, Jürgen C; Straten, Per Thor

    2015-01-01

    Various subsets of immune regulatory cells are suggested to influence the outcome of therapeutic antigen-specific anti-tumor vaccinations. We performed an exploratory analysis of a possible correlation of pre-vaccination Th17 cells, MDSCs, and Tregs with both vaccination-induced T-cell responses as well as clinical outcome in metastatic melanoma patients vaccinated with survivin-derived peptides. Notably, we observed dysfunctional Th1 and cytotoxic T cells, i.e. down-regulation of the CD3ζchain (p=0.001) and an impaired IFNγ-production (p=0.001) in patients compared to healthy donors, suggesting an altered activity of immune regulatory cells. Moreover, the frequencies of Th17 cells (p=0.03) and Tregs (p=0.02) were elevated as compared to healthy donors. IL-17-secreting CD4+ T cells displayed an impact on the immunological and clinical effects of vaccination: Patients characterized by high frequencies of Th17 cells at pre-vaccination were more likely to develop survivin-specific T-cell reactivity post-vaccination (p=0.03). Furthermore, the frequency of Th17 (p=0.09) and Th17/IFNγ+ (p=0.19) cells associated with patient survival after vaccination. In summary, our explorative, hypothesis-generating study demonstrated that immune regulatory cells, in particular Th17 cells, play a relevant role for generation of the vaccine-induced anti-tumor immunity in cancer patients, hence warranting further investigation to test for validity as predictive biomarkers.

  2. Th17 cells express interleukin-10 receptor and are controlled by Foxp3− and Foxp3+ regulatory CD4+ T cells in an interleukin-10 dependent manner

    OpenAIRE

    Huber, Samuel; GAGLIANI, Nicola; Esplugues, Enric; O’Connor, William; Huber, Francis J.; Chaudhry, Ashutosh; Kamanaka, Masahito; Kobayashi, Yasushi; Booth, Carmen J.; Rudensky, Alexander Y.; Battaglia, Manuela; Roncarolo, Maria Grazia; Flavell, Richard A.

    2011-01-01

    T helper 17 (Th17) cells are important for host defense against extra-cellular microorganisms. However they are also implicated in autoimmune and chronic inflammatory diseases, and as such need to be tightly regulated. The mechanisms that directly control committed pathogenic Th17 cells in vivo remain unclear. We showed here that IL-17A-producing CD4+ T cells expressed interleukin-10 receptor α (IL-10Rα) in vivo. Importantly, T cell specific blockade of IL-10 signaling led to a selective incr...

  3. 老年代谢综合征患者趾臂指数与Th17细胞及相关细胞因子的相关性%Association between toe brachial index and Th17 cells and Th17-associated cytokines in old metabolic syndrome patients

    Institute of Scientific and Technical Information of China (English)

    刘振东; 董元丽; 路方红; 赵颖馨; 孙尚文; 王舒健; 王琳

    2011-01-01

    Objective To investigate the correlations between toe brachial index (TBI) and Thl7 cells and Thl7-associated cyto-kines in old metabolic syndrome patients. Methods According to the standard of metabolic syndrome presented by Chinese Diabetes Society in. 2004, 161 metabolic syndrome patients were eligible recruited. TBI was observed using VP-1000 automatic atherosclerosis analyzer, and then the patients were divided into normal TBI group and lower TBI group, respectively. Frequencies of peripheral blood Thl7 cells were detected using flow cytometry. And ELISA was used to test serum IL-17, IL-6 and TNF-a. Results The frequency of peripheral blood Thl7 cells in lower TBI group was higher than that in normal TBI group (J = 7. 116, P < 0. 01). Levels of serum IL-17, IL-6 and TNF-a in lower TBI group were elevated than those in normal TBI group ( P < 0. 01). Thl7 cells frequency, IL-17, IL-6 and TNF-a were negatively correlated with TBI ( r = - 0. 443, - 0.485, - 0. 348 and - 0. 429, P < 0. 001). Multiple linear regression analysis showed that Th 17 cells frequency, IL-17, IL-6 and TNF-a were risk factors of TBI. Conclusions TBI is associated with Thl7 cells and Thl7-associated cytokines in old metabolic syndrome patients.%目的 探讨老年代谢综合征患者趾臂指数(TBI)与Th17细胞及其与细胞因子白细胞介素-17(IL-17)、白细胞介素-6(IL-6)及肿瘤坏死因子α(TNF-α)的相关性.方法 依据2004年中国糖尿病学会(CDS)提出的标准入选161例代谢综合征患者,应用全自动动脉硬化测定仪VP1000测定患者的TGBI,将患者分为TBI正常组和TBI降低组.采用流式细胞检测技术检测患者外周血中Th17细胞水平,并采用ELISA法检测所有高血压患者的血清IL-17、IL-6及TNF-α浓度水平.结果 TBI降低组外周血Th17细胞比例明显高于TBI正常组(t=7.116,P<0.01).TBI降低组Th17细胞因子IL-17、IL-6及TNF-α血清浓度较TBI正常组显著升高(P<0.01).相关及回归分析显示,TBI与外周血Th

  4. Hypothyroidism in Noninterferon Treated-HCV Infected Individuals Is Associated with Abnormalities in the Regulation of Th17 Cells.

    Science.gov (United States)

    Salazar, Luis A; Garcia-Samper, Xóchitl; Suarez-Carpio, Rafael; Jimenez-Martínez, María C; Rendón-Huerta, Erika P; Masso, Felipe A; Fortoul, Teresa I; Montaño, Luis F

    2010-01-01

    HCV-Ag-specific TH17 cells secrete IL17, a cytokine involved in autoimmune diseases and regulated by IL10 and TGF-b. 5-12% of patients with chronic HCV infection have hypothyroidism. We evaluated the role of these cytokines in this patients by determining serum concentration of TsH, T3, free T4, IL2, IL10, IL12, IL17, TGF-b, anti-TG, TPO, CCP, GBM, and cardiolipin antibodies in 87 chronically noninterferon treated HCV-infected patients. 20 patients (group A) had elevated TsH values (>5 μUI/ml) whereas the remaining 67 (group B) had normal values. The percentage of anti-TPO, TG, GBM, and cardiolipin antibodies in group A patients (33%, 41%, 5% and 5%, resp.) as well as IL17, IL2 and TGF-b concentrations (25 ± 23 pg/ml, 643 ± 572 pg/ml, and 618 ± 221 pg/ml, resp.) were significantly higher than group B. Abnormal Th17 regulation mediated by IL-2 and low TGF-b concentrations is associated with hypothyroidism in chronically-infected HCV patients.

  5. Hypothyroidism in Noninterferon Treated-HCV Infected Individuals Is Associated with Abnormalities in the Regulation of Th17 Cells

    Directory of Open Access Journals (Sweden)

    Luis A. Salazar

    2010-01-01

    Full Text Available HCV-Ag-specific TH17 cells secrete IL17, a cytokine involved in autoimmune diseases and regulated by IL10 and TGF-b. 5–12% of patients with chronic HCV infection have hypothyroidism. We evaluated the role of these cytokines in this patients by determining serum concentration of TsH, T3, free T4, IL2, IL10, IL12, IL17, TGF-b, anti-TG, TPO, CCP, GBM, and cardiolipin antibodies in 87 chronically noninterferon treated HCV-infected patients. 20 patients (group A had elevated TsH values (>5 μUI/ml whereas the remaining 67 (group B had normal values. The percentage of anti-TPO, TG, GBM, and cardiolipin antibodies in group A patients (33%, 41%, 5% and 5%, resp. as well as IL17, IL2 and TGF-b concentrations (25±23 pg/ml, 643±572 pg/ml, and 618±221 pg/ml, resp. were significantly higher than group B. Abnormal Th17 regulation mediated by IL-2 and low TGF-b concentrations is associated with hypothyroidism in chronically-infected HCV patients.

  6. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway.

    Science.gov (United States)

    Anipindi, Varun C; Bagri, Puja; Roth, Kristy; Dizzell, Sara E; Nguyen, Philip V; Shaler, Christopher R; Chu, Derek K; Jiménez-Saiz, Rodrigo; Liang, Hong; Swift, Stephanie; Nazli, Aisha; Kafka, Jessica K; Bramson, Jonathan; Xing, Zhou; Jordana, Manel; Wan, Yonghong; Snider, Denis P; Stampfli, Martin R; Kaushic, Charu

    2016-05-01

    Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway.

  7. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway

    Science.gov (United States)

    Anipindi, Varun C.; Dizzell, Sara E.; Nguyen, Philip V.; Shaler, Christopher R.; Chu, Derek K.; Jiménez-Saiz, Rodrigo; Liang, Hong; Swift, Stephanie; Nazli, Aisha; Kafka, Jessica K.; Bramson, Jonathan; Xing, Zhou; Jordana, Manel; Wan, Yonghong; Snider, Denis P.; Stampfli, Martin R.; Kaushic, Charu

    2016-01-01

    Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway. PMID:27148737

  8. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway.

    Directory of Open Access Journals (Sweden)

    Varun C Anipindi

    2016-05-01

    Full Text Available Clinical and experimental studies have shown that estradiol (E2 confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway.

  9. 桥本甲状腺炎和Graves病患者Th17细胞的检测及意义%Detection and significance of the alteration of Th17 cells in patients with Hashimoto's thyroiditis and Graves' disease

    Institute of Scientific and Technical Information of China (English)

    赵建宇; 温言; 王清

    2012-01-01

    目的 探讨自身免疫性甲状腺病(桥本甲状腺炎和Graves病)患者外周血Th17细胞的水平及意义.方法 收集桥本甲状腺炎(HT)和Graves病患者及健康对照组各30例,检测各组外周血Th17/CD4+ T细胞百分率及甲状腺自身抗体水平.结果 自身免疫性甲状腺病(桥本甲状腺炎和Graves病)患者外周血Th17/CD4+ T细胞百分率较正常对照组升高,差异有统计学意义(P<0.05;P<0.01),且桥本甲状腺炎患者升高更为明显.同时发现桥本甲状腺炎患者外周血Th17/CD4+ T细胞百分率与Tg-Ab呈显著的正相关性(r=0.737,P<0.01),与TPO-Ab无显著相关性(r=-0.107,P=0.654).结论 Th17细胞与自身免疫性甲状腺病的发生发展可能有关,Th17/CD4+ T细胞的检测可以考虑做为自身免疫性甲状腺病的诊断依据之一,尤其是对桥本甲状腺炎的诊断意义更大.%Objective To investigate the alteration and its significance of Thl7 cells in peripheral blood of the patients with Autoimmune thyroid disease (Hashimoto's thyroiditis and Graves' disease). Methods Collection of Hashimoto's thyroiditis (HT) and Graves' patients and healthy control group, 30 cases were detected in peripheral blood Thl7/ CD4+ Tccll percentage and the level of thyroid autoantibodics. Results The peripheral blood Thl7/CD4+ T cells in patients with Autoimmune thyroid disease (Hashimoto's thyroiditis and Graves' disease) was higher than the normal control group, difference was statistically significant, (P<0. 05;P<0. 01), the increase is more significantly in patients with Hashimoto's thyroiditis. Thl7/CD4+ Tccll percentage and Tg-Ab was a significant positive correlation in Hashimoto's thyroiditis paticnts(r = 0. 737, P<0. 01) , and TPO-Ab was no significant corrclation(r= -0. 107, P = 0. 654). Conclusion Thl7cclls may be related to the development of Autoimmune thyroid disease. Detection of Thl7/CD4+ T cells can be considered as one of the diagnosis of Autoimmune thyroid disease. The

  10. Advancement of T helper17 cells in bronchiolitis%Th17与毛细支气管炎的研究进展

    Institute of Scientific and Technical Information of China (English)

    张国辉

    2013-01-01

    Bronchiolitis is a common lower respiratory infection disease in children younger than two years old.The main pathogen of bronchiolitis is respiratory syncytial virus,which is also associated with the asthma.By now,it is still unknown about the pathogenesis of bronchiolitis.Recent findings provide that T helper17(Th17) cells play an important role in bronchiolitis.This review summarizes the progresses of regulation of Th17 cells development,Th17 cells function,and the relationship between Th17 cells and bronchiolitis.%毛细支气管炎(毛支)是2岁以下小儿常见的下呼吸道感染性疾病,主要病原体是呼吸道合胞病毒,是需住院治疗的常见呼吸道疾病,且与哮喘的发病密切相关.目前毛支的发病机制尚未完全阐明,近年来发现T辅助性17细胞(Th17)在其发病中占有重要地位.该文就近年来对Th17在毛支发病机制方面的研究进展作一综述.

  11. Radical-containing particles activate dendritic cells and enhance Th17 inflammation in a mouse model of asthma.

    Science.gov (United States)

    Wang, Pingli; Thevenot, Paul; Saravia, Jordy; Ahlert, Terry; Cormier, Stephania A

    2011-11-01

    We identified a previously unrecognized component of airborne particulate matter (PM) formed in combustion and thermal processes, namely, environmentally persistent free radicals (EPFRs). The pulmonary health effects of EPFRs are currently unknown. In the present study, we used a model EPFR-containing pollutant-particle system referred to as MCP230. We evaluated the effects of MCP230 on the phenotype and function of bone marrow-derived dendritic cells (BMDCs) in vitro and lung dendritic cells (DCs) in vivo, and the subsequent T-cell response. We also investigated the adjuvant role of MCP230 on airway inflammation in a mouse model of asthma. MCP230 decreased intracellular reduced glutathione (GSH) and the GSH/oxidized glutathione ratio in BMDCs, and up-regulated the expression of costimulatory molecules CD80 and CD86 on DCs. The maturation of DCs was blocked by inhibiting oxidative stress or the uptake of MCP230. BMDCs exposed to MCP230 increased their antigen-specific T-cell proliferation in vitro. In a model of asthma, exposure to MCP230 exacerbated pulmonary inflammation, which was attributed to the increase of neutrophils and macrophages but not eosinophils. This result correlated with an increase in Th17 cells and cytokines, compared with non-MCP230-treated but ovalbumin (OVA)-challenged mice. The percentage of Th2 cells was comparable between OVA and OVA + MCP230 mice. Our data demonstrate that combustion-generated, EPFR-containing PM directly induced the maturation of DCs in an uptake-dependent and oxidative stress-dependent manner. Furthermore, EPFR-containing PM induced a Th17-biased phenotype in lung, accompanied by significant pulmonary neutrophilia. Exposure to EPFR-containing PM may constitute an important and unrecognized risk factor in the exacerbation and development of a severe asthma phenotype in humans.

  12. Th17 Pathway As a Target for Multipotent Stromal Cell Therapy in Dogs: Implications for Translational Research

    National Research Council Canada - National Science Library

    Kol, A; Walker, N J; Nordstrom, M; Borjesson, D L

    2016-01-01

    Detrimental Th17 driven inflammatory and autoimmune disease such as Crohn's disease, graft versus host disease and multiple sclerosis remain a significant cause of morbidity and mortality worldwide...

  13. Clinical expressions of related cytokines of Th17 cell in rheumatoid arthritis patients%类风湿性关节炎患者Th17细胞相关细胞因子的临床表达

    Institute of Scientific and Technical Information of China (English)

    陆扬光; 余志辉; 郑明江

    2015-01-01

    目的:探讨 Th17细胞相关细胞因子白介素-17(IL-17)、白介素-6(IL-6)、白介素-23(IL-23)在类风湿性关节炎(RA)发病中的表达。方法用酶联免疫吸附法(ELISA)检测活动组(35例RA患者)、缓解组(35例RA 患者)及对照组(30例健康人)血清 IL-17、IL-6、IL-23的水平,并分析它们与活动度和实验室指标的关系。结果活动组和缓解组血清IL-23、IL-6水平均明显高于对照组(P0.05)。RA患者血清IL-17、IL-6和IL-23水平之间互为正相关关系。结论Th17细胞相关细胞因子IL-17、IL-6、IL-23均在RA 的发生、发展过程中起着重要作用,并可作为RA活动参考指标。%Objective To investigate expressions of related cytokines interleukin-17 (IL-17), interleukin-6 (IL-6), interleukin-23 (IL-23) of Th17 cell in rheumatoid arthritis (RA).Methods Enzyme-linked immuno sorbent assay (ELISA) was applied in serum IL-17, IL-6, IL-23 levels in activity group (35 RA patients), relief group (35 RA patients), and control group (30 healthy people). Analysis was made on their relationship with activity and laboratory index.Results The activity group and relief group had much higher serum IL-23 and IL-6 levels than the control group (P0.05). Serum IL-17, IL-6, and IL-23 levels had positive correlations with every other one in RA patients.Conclusion Related cytokines IL-17, IL-6, IL-23 of Th17 cell all play important roles in occurrence and development of RA, and those can act as referring indicators for RA activity.

  14. Interleukin-25 Mediates Transcriptional Control of PD-L1 via STAT3 in Multipotent Human Mesenchymal Stromal Cells (hMSCs to Suppress Th17 Responses

    Directory of Open Access Journals (Sweden)

    Wei-Bei Wang

    2015-09-01

    Full Text Available Multipotent human mesenchymal stromal cells (hMSCs harbor immunomodulatory properties that are therapeutically relevant. One of the most clinically important populations of leukocytes is the interleukin-17A (IL-17A-secreting T (Th17 lymphocytes. However, mechanisms of hMSC and Th17 cell interactions are incompletely resolved. We found that, along with Th1 responses, hMSCs strongly suppressed Th17 responses and this required both IL-25—also known as IL-17E—as well as programmed death ligand-1 (PD-L1, a potent cell surface ligand for tolerance induction. Knockdown of IL-25 expression in hMSCs abrogated Th17 suppression in vitro and in vivo. However, IL-25 alone was insufficient to significantly suppress Th17 responses, which also required surface PD-L1 expression. Critically, IL-25 upregulated PD-L1 surface expression through the signaling pathways of JNK and STAT3, with STAT3 found to constitutively occupy the proximal region of the PD-L1 promoter. Our findings demonstrate the complexities of hMSC-mediated Th17 suppression, and highlight the IL-25/STAT3/PD-L1 axis as a candidate therapeutic target.

  15. An A2B Adenosine Receptor Agonist Promotes Th17 Autoimmune Responses in Experimental Autoimmune Uveitis (EAU) via Dendritic Cell Activation.

    Science.gov (United States)

    Chen, Mingjiazi; Liang, Dongchun; Zuo, Aijun; Shao, Hui; Kaplan, Henry J; Sun, Deming

    2015-01-01

    We have recently reported that, although adenosine receptor (AR) agonists have a suppressive effect on Th1 autoreactive T cells, their effect on Th17 autoreactive T cells and γδ T cells is stimulatory and this effect is mainly mediated via A2A adenosine receptors (A2ARs). In this study, we further demonstrate that treatment of C57BL/6 (B6) mice with a selective A2B adenosine receptor (A2BR) agonist greatly enhanced the development of experimental autoimmune uveitis (EAU), whereas treatment with an A2BR antagonist significantly ameliorated severity of EAU. The A2BR agonist-treated mice showed augmented Th17, but not Th1, responses. Mechanistic studies showed that the A2BR agonist-induced enhancement of the Th17 response was significantly lower when TCR-δ-/- mice received the same treatment and that transfer of γδ T cells into TCR-δ-/- mice partially restored this effect. We also showed that dendritic cells (DCs) from A2BR agonist-treated mice showed a significantly increased ability to activate γδ T cells and Th17 autoreactive T cells. Thus, our previous studies have shown that, in EAU, activated γδ T cells possess greatly increased ability to enhance Th17 autoimmune responses. In the present study, we showed that exposure of DCs to A2BR agonist facilitated γδ T cell activation, leading to augmented Th17 responses and progressive EAU development. Our results further support our previous finding that AR agonists have distinct effects on Th1 and Th17 autoimmune responses.

  16. Th17 and treg cells innovate the TH1/TH2 concept and allergy research.

    Science.gov (United States)

    Schmidt-Weber, C B

    2008-01-01

    Allergic reactions are caused by harmless allergens, which are recognized by the specific immune system. Allergen-specific T cells are assumed to play a key role in the sensitization phase and in immunological memory. Current immunological concepts suggest that asymptomatic T-cell memory cells also exist, tagging the allergen as harmless and preventing an inappropriate response and thus allergic symptoms. Proinflammatory T cells mediate allergic inflammation by exceeding the induction of IgE and competing with other T-cell subsets. Therefore, molecular mechanisms leading to pro- or anti-inflammatory T-cell memory cells appear as the key mechanism in allergy.

  17. Sexual dimorphism in an animal model of Sjögren's syndrome: a potential role for Th17 cells

    Directory of Open Access Journals (Sweden)

    Alexandria Voigt

    2015-11-01

    Full Text Available Sjögren's syndrome is a complex autoimmune disease with an array of diverse immunological, genetic and environmental etiologies, making identification of the precise autoimmune mechanism difficult to define. One of the most distinctive aspects of Sjögren's syndrome is the high sexual dimorphism with women affected 10-20 times more than men. It is nearly impossible to study the sexual dimorphic development of Sjögren's syndrome in human patients; therefore it is pertinent to develop an appropriate animal model which resembles human disease. The data indicated that female C57BL/6.NOD-Aec1Aec2 mice developed an earlier onset of sialadenitis with a higher composition of CD3+ T cells and a 10-fold increase in glandular infiltration of Th17 cells at the onset of clinical disease compared to male mice. Inflammatory Th17 cells of female mice exhibited a stronger proliferation in response to disease-specific antigen than their male counterpart. At the clinical disease stage, altered autoantibody patterns can be detected in females whereas they are seldom observed in male C57BL/6.NOD-Aec1Aec2 mice. Interestingly, male C57BL/6.NOD-Aec1Aec2 mice developed an earlier loss of secretory function, despite the fact that female C57BL/6.NOD-Aec1Aec2 mice exhibited a more rapid secretory loss. This data indicates the strong sexual dimorphism in the SjS-susceptible C57BL/6.NOD-Aec1Aec2 animal model, making it an appropriate animal model to examine human disease.

  18. Fatigue favors in vitro Th1 and Th17-like cell expansion and reduces corticoid sensitivity in MS patients.

    Science.gov (United States)

    Alvarenga-Filho, Hélcio; Salles, Marisa; Hygino, Joana; Ferreira, Thais B; Sacramento, Priscila M; Monteiro, Clarice; Vasconcelos, Claudia Cristina F; Alvarenga, Regina Maria Papais; Bento, Cleonice A M

    2017-02-15

    Fatigue is a common "ghost" symptom in patients with multiple sclerosis (MS), an autoimmune disease mediated by T cells that target myelin antigens of the central nervous system. As fatigue has been associated with inflammatory states, its occurrence may negatively impact MS progression. The aim of this study was to evaluate the impact of fatigue on the cytokine profile of patients with relapsing-remitting (RR) MS. For our study, blood were collected from MS patients in clinical remission phase with (n=15) and without (n=15) fatigue. Cytokines were detected by ELISA in the plasma and supernatant collected from anti-CD3/anti-CD28-activated T cells or LPS-stimulated monocytes. In some wells, different doses of hydrocortisone (HC) were added at the beginning of the culture. Here, peripheral levels of IL-6 and TNF-α, as well as in vitro production of cytokines related to Th17 (IL-6, IL-17, IL-22, and GM-CSF) or Th1 (IFN-γ) phenotypes, were elevated in fatigued patients and their levels were associated with fatigue severity. The same phenomenon was observed between the production of IL-6, TNF-α, IL-1β, and IL-23 by monocytes and fatigue. Moreover, HC was less efficient in inhibiting in vitro inflammatory cytokine production in patients with fatigue, mainly those produced by both CD8(+) T cells and monocytes. Our data, although preliminary, suggests that the occurrence of fatigue, by favoring the in vitro production of Th1/Th17-related cytokines and corticoid resistance, may negatively impact the course of MS.

  19. Correlation of Th17 cells and CD4+CD25+ regulatory T cells with clinical parameters in patients with systemic sclerosis

    Institute of Scientific and Technical Information of China (English)

    Jiang Nan; Li Mengtao; Zeng Xiaofeng

    2014-01-01

    Background Systemic sclerosis (SSc) is an autoimmune disease that has three major components:inflammation,fibrosis,and vasculopathy.T-helper 17 cell (Th17) and regulatory T cell (Treg) are considered to be critical for autoimmune disease pathogenesis.The role of Th17 and Treg in SSc is still unclear.The aim of this study was to detect the presence of Th17s and CD4+CD25+ Tregs in peripheral blood samples from SSc patients and to investigate the possible roles of these two T cell subsets in SSc pathogenesis.Methods Th17s (CD4 and IL-17 positive) and CD4+CD25+ Tregs (CD4,CD25 and Foxp3 positive) in the peripheral blood mononuclear cells of 53 SSc patients and 27 healthy controls were counted by flow cytometry.The differences between SSc and control patients were analyzed.Clinical parameters,including disease duration,duration of the second symptoms,Modified Rodnan Skin Score (MRSS),anti-topoisomerase I antibody,anti-U1 ribonucleoprotein (RNP) antibody,systemic involvements,pulmonary function test (PFT) and high resolution computed tomography (HRCT) score were prospectively collected following EUSTAR (EULAR scleroderma trial and research group) protocols.The correlations between the experimental and clinical data were investigated.Results The ratio of Th17 in SSc patients was significantly elevated compared to healthy controls (8.74% vs.4.41%,P <0.001).The amount of Th17 was positively correlated with disease duration (R=0.531,P=0.013) and duration of the second symptoms (R=0.505,P=0.023).The ratio of CD4+CD25+ Treg in SSc patients also significantly differed from the healthy controls (3.04% vs.2.24%,P=0.018).Elevated Tregs were more frequently observed in patients with a high interstitial lung disease (ILD) score on computed tomography (24/36) compared with patients with normal ILD scores (4/12,P=0.043).Elevated Tregs were also more often observed in patients with low carbon monoxide diffusing capacity (DLCO) (24/34) compared with patients with normal DLCO

  20. Immunomodulatory Effects of Th17/Treg Cells in Inflammatory Arthropathy%Th17/Treg细胞在炎性关节病的免疫调节作用

    Institute of Scientific and Technical Information of China (English)

    贾捷婷; 李慧; 李国青; 魏华; 张育

    2011-01-01

    There is a large class of rheumatic diseases which have main manifestation of peripheral arthritis. We could call them inflammatory arthropathy, including rheumatoid arthritis ( RA) , spondyloarthropathy ( SpA) and its related arthritis such as ankylosing spondylitis ( AS) , psoriatic arthritis ( PsA ) and inflammatory bowel disease associated arthritis and so on. Immune cells play an important role in their pathogenesis. In recent years, the T help cell 17 (Thl7) has been found, which mainly secretes IL-17 and mediates inflammatory response. The regulatory T cells (Treg) have immunosuppressive effects. Thl7 and Treg cells are closely related in their differentiation process and a variety of cytokines involved. The balance of Thl7/Treg cells are important in maintenance of normal immune response and preventing from autoimmune diseases. This paper does a review about the relationship between Thl7/Treg cells and the common inflammatory arthropathy.%炎性关节病包括一大类以外周关节炎为主要表现的风湿性疾病,如类风湿关节炎(rheumatoid arthritis,RA)、脊柱关节病(spondyloarthropathy,SpA)及其相关的关节炎,如强直性脊柱炎(ankylosing spondylitis,AS)、银屑病关节炎(psoriaticarthritis,PsA)和炎症性肠病关节炎等.免疫细胞在他们的发病过程中起了重要作用.近年又发现了一种以分泌IL-17为主的辅助性T细胞17(T help cell 17,Th17),其介导炎症反应.调节性T细胞(regulatoryT cells,Treg)是一类具有免疫抑制作用的T细胞哑群.Th17与Treg细胞在分化过程中是密切相关的,多种细胞因子参与了他们的发育分化过程,Th17/Treg细胞的平衡对维持正常免疫应答、防止自身免疫性疾病具有重要意义.

  1. The Treg/Th17 axis: A dynamic balance regulated by the gut microbiome

    Directory of Open Access Journals (Sweden)

    Sara eOmenetti

    2015-12-01

    Full Text Available T-helper 17 (Th17 and T-regulatory (Treg cells are frequently found at barrier surfaces, particularly within the intestinal mucosa, where they function to protect the host from pathogenic microorganisms and to restrain excessive effector T-cell responses, respectively. Despite their differing functional properties, Th17 cells and Tregs share similar developmental requirements. In fact, the fate of antigen-naïve T-cells to either Th17 or Treg lineages is finely regulated by key mediators, including TGFβ, IL-6 and all-trans retinoic acid (RA. Importantly, the intestinal microbiome also provides immunostimulatory signals, which can activate innate, and downstream adaptive, immune responses. Specific components of the gut microbiome have been implicated in the production of proinflammatory cytokines by innate immune cells, such as IL-6, IL-23, IL-1β, and the subsequent generation and expansion of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of intestinal Tregs that can actively induce mucosal tolerance. As such, dysbiosis of the gut microbiome may not solely represent a consequence of gut inflammation, but rather shape the Treg/Th17 commitment and influence susceptibility to inflammatory bowel disease (IBD. In this review, we discuss Treg and Th17 cell plasticity, its dynamic regulation by the microbiome, and highlight its impact on intestinal homeostasis and disease.

  2. T-cell vaccination leads to suppression of intrapancreatic Th17 cells through Stat3-mediated RORγt inhibition in autoimmune diabetes

    Institute of Scientific and Technical Information of China (English)

    Min Wang; Liu Yang; Xiaoyan Sheng; Weilei Chen; Haiqing Tang; Hongguang Sheng; Beili Xi

    2011-01-01

    Immunization with inactivated autoreactive T cells is an effective therapeutic approach to ameliorating autoimmune diseases,while the underlying mechanisms that regulate autoreactive T cells are not completely understood.This study tested the hypothesis that T-cell vaccination (TCV) inhibits autoimmune diabetes in mice through the suppression of Th17 cells.The results showed that TCV treatment decreased hyperglycemia in type 1 diabetes (T1D) induced by multiple low-dose streptozotocin (MLD-STZ) as compared with the controls,preserved the number of healthy pancreatic islets and increased the production of insulin in the islets.Further study revealed that TCV significantly decreased the production of both interleukin (IL)-17 and IL-23 in intrapancreatic infiltrating lymphocytes (IPL) through marked inhibition of mRNA level of retinoic acid-related orphan receptor γt (RORγt) and signal transducer and activator of transcription 3 (Stat3) phosphorylation.The role of TCV-induced Th17 suppression was further validated in adoptive transfer experiments with polarized Th17 cells in subdiabetogenic mice,which was similar to the effect of anti-IL-17 antibody treatment.Collectively our study shows that intrapancreatic Th17 cell suppression and healthy islet preservation play an important role in the treatment of T1D by TCV.

  3. Th17 cells mediate inflammation in a novel model of spontaneous experimental autoimmune lacrimal keratoconjunctivitis with neural damage.

    Science.gov (United States)

    Seo, Kyoung Yul; Kitamura, Kazuya; Han, Soo Jung; Kelsall, Brian

    2017-09-25

    Dry eye disease (DED) affects one third of population worldwide. In prior studies, experimental autoimmune lacrimal keratoconjunctivitis (EALK) induced by desiccating stress in mice has been used as a model of DED. This model is complicated by a requirement for exogenous epithelial cell injury and the administration of anticholinergic agents that have broad immunological effects. We sought to develop a novel mouse model of EALK, and to demonstrate the responsible immunological pathogenic mechanisms. CD4+CD45RB(high) naïve T cells with and without CD4+CD45RB(lo)CD25+ regulatory T cells were adoptively transferred to C57BL/10 RAG2(-/-) mice. The eyes, draining lymph nodes, lacrimal glands and surrounding tissues of mice that spontaneously developed keratoconjuctivitis were evaluated for histopathological changes, cellular infiltration, and cytokine production in tissues and by isolated cells. Furthermore, the integrity of corneal nerves was evaluated by whole tissue immunofluorescence imaging. Gene-deficient naïve T cells or RAG2-hosts were evaluated to assess the roles of IFN-γ, IL-17A and IL-23 in disease pathogenesis. Finally, cytokine levels were determined in the tears of patients with DED. EALK spontaneously developed in C57BL/10 RAG2(-/-) mice following adoptive of CD4+CD45RB(high) naïve T cells characterized by the infiltration of CD4(+) T cells, macrophages, and neutrophils. In addition to lacrimal keratoconjunctivitis, mice also developed damage to the corneal nerve, which connects components of lacrimal functional unit (LFU). Pathogenic T cell differentiation was dependent on IL-23p40 and controlled by co-transferred CD4+CD45RB(lo)CD25(+) regulatory T cells (Tregs). Th17 rather than Th1 CD4+ cells were primarily responsible for EALK even though both IL-17 and IFN-γ were increased in inflammatory tissues likely due to their ability to drive the expression of CXC chemokines within the cornea, and the subsequent influx of myeloid cells. Consistent with

  4. Elevated Th22 as well as Th17 cells associated with therapeutic outcome and clinical stage are potential targets in patients with multiple myeloma.

    Science.gov (United States)

    Wang, Min; Chen, Ping; Jia, Yan; He, Na; Li, Daqi; Ji, Chunyan; Ma, Daoxin

    2015-07-20

    T helper (Th) cell imbalance plays important roles in tumor development and their effects in Multiple myeloma (MM) remain unclear. In the present study, we investigated the levels and clinical significance of Th22, Th17 and Th1 cells in patients with MM. Th subsets were examined by flow cytometry. Plasma IL-22, IL-17A and IFN-γ concentrations were measured by ELISA. AHR and RORC mRNA expression was examined by RT-PCR. Here, we found that the frequency of Th22 cells was significantly elevated in peripheral blood (PB) and bone marrow (BM) of newly-diagnosed MM patients, and recovered in complete remission patients after chemotherapy. The circulating Th17 cells accompanied by IL-17A levels were also up-regulated in MM patients and decreased after remission. We also found that there was a significantly positive correlation between Th22 and Th17 cells in MM patients. Moreover, the frequencies of Th22 and Th17 cells were higher in stage III than in stage I+II of MM. Our data demonstrated that Th22 and Th17 cells might be important therapeutic targets in multiple myeloma and could facilitate the effect of antitumor immunotherapy.

  5. Treg/Th17 polarization by distinct subsets of breast cancer cells is dictated by the interaction with mesenchymal stem cells

    OpenAIRE

    Patel, Shyam A.; Dave, Meneka A.; Bliss, Sarah A.; Giec-Ujda, Agata B.; Bryan, Margarette; Pliner, Lillian F.; Rameshwar, Pranela

    2014-01-01

    Breast cancer (BC) cells (BCCs) exist within a hierarchy beginning with cancer stem cells (CSCs). Unsorted BCCs interact with mesenchymal stem cells (MSCs) to induce regulatory T cells (Tregs). This study investigated how distinct BCC subsets interacted with MSCs to polarize T-cell response, Tregs versus T helper 17 (Th17). This study tested BC initiating cells (CSCs) and the relatively more mature early and late BC progenitors. CSCs interacted with the highest avidity to MSCs. This interacti...

  6. Induction of Th17 Lymphocytes and Treg Cells by Monocyte-Derived Dendritic Cells in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus

    Science.gov (United States)

    Estrada-Capetillo, Lizbeth; Hernández-Castro, Berenice; Monsiváis-Urenda, Adriana; Alvarez-Quiroga, Crisol; Layseca-Espinosa, Esther; Abud-Mendoza, Carlos; Baranda, Lourdes; Urzainqui, Ana; Sánchez-Madrid, Francisco; González-Amaro, Roberto

    2013-01-01

    Dendritic cells (DCs) have a key role in the regulation of immune response. We herein explored, in patients with inflammatory diseases, the role of monocyte derived DC's (mo-DCs) on the generation of Th17 and T regulatory (Treg) lymphocytes. Peripheral blood was obtained from thirty-five patients with rheumatoid arthritis (RA), twelve with systemic lupus erythematosus (SLE), and twenty healthy subjects. Mo-DCs were generated under standard (IL-4/GM-CSF) or tolerogenic (IL-4/GM-CSF plus recombinant P-selectin or PD-1 or IL-10) conditions, and their ability to induce Th17 and Treg lymphocytes was tested. We detected that mo-DCs from patients with RA showed an enhanced release of IL-6 and IL-23 as well as an increased capability to induce Th17 cells. Although mo-DCs from SLE patients also released high levels of IL-6/IL-23, it did not show an increased ability to induce Th17 lymphocytes. In addition, mo-DCs, from patients with RA and SLE generated under the engagement of PSGL-1, showed a defective capability to induce Foxp3+ Treg cells. A similar phenomenon was observed in SLE, when DC's cells were generated under PDL-1 engagement. Our data indicate that DCs from patients with rheumatic inflammatory disease show an aberrant function that may have an important role in the pathogenesis of these conditions. PMID:24288552

  7. Induction of Th17 Lymphocytes and Treg Cells by Monocyte-Derived Dendritic Cells in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Lizbeth Estrada-Capetillo

    2013-01-01

    Full Text Available Dendritic cells (DCs have a key role in the regulation of immune response. We herein explored, in patients with inflammatory diseases, the role of monocyte derived DC’s (mo-DCs on the generation of Th17 and T regulatory (Treg lymphocytes. Peripheral blood was obtained from thirty-five patients with rheumatoid arthritis (RA, twelve with systemic lupus erythematosus (SLE, and twenty healthy subjects. Mo-DCs were generated under standard (IL-4/GM-CSF or tolerogenic (IL-4/GM-CSF plus recombinant P-selectin or PD-1 or IL-10 conditions, and their ability to induce Th17 and Treg lymphocytes was tested. We detected that mo-DCs from patients with RA showed an enhanced release of IL-6 and IL-23 as well as an increased capability to induce Th17 cells. Although mo-DCs from SLE patients also released high levels of IL-6/IL-23, it did not show an increased ability to induce Th17 lymphocytes. In addition, mo-DCs, from patients with RA and SLE generated under the engagement of PSGL-1, showed a defective capability to induce Foxp3+ Treg cells. A similar phenomenon was observed in SLE, when DC’s cells were generated under PDL-1 engagement. Our data indicate that DCs from patients with rheumatic inflammatory disease show an aberrant function that may have an important role in the pathogenesis of these conditions.

  8. 辅助性T细胞17(Th17)的特征及其在自身免疫性疾病中的作用%The features of T helper 17 cell (Th17) and its function in autoimmune diease

    Institute of Scientific and Technical Information of China (English)

    唐冰; 陈萍

    2012-01-01

    CD4+ T helper cells (Th) were divided into regulatory T cells,Th1 ,Th2 and Th17 cells. Th17 cells were identified recently as a subtype of Th cells which mainly produce important pro-inflammatory cytokines, IL-17A and IL-17F. This paper reviewed the key cytokines for Th17 cells differentiation and maintenance, the interaction of Th17 cells with other immune cells and the role of Th17 cells in autoimmune diseases, and also dicussed the relation between IL-23 related to Th17 and IL-12 related to Th1, as well as the effect of dendritic cells on Th17 differentiation. Th17 cell is essential to many autoimmune diseases, so the study on it will help to understand the mechanism of these diseases,and further contribute to clinic therapy.%辅助性T细胞分为调节性T细胞、Th1、Th2和Th17亚型.Th17细胞是新近发现的一个细胞亚群,其分泌的IL-17A和IL-17F是重要的致炎因子.本文综述了Thl7分化和维持所需的微环境、Th17与其他主要免疫细胞的相互作用及Thl7对自身免疫性疾病的影响,重点阐述了Th17相关的IL-23与Th1相关的IL-12之间的关系、树突状细胞对Th17分化的影响及Th17细胞对各种常见自身免疫性疾病的影响,通过对Thl7细胞的深入研究将有助于认识自身免疫性疾病及进一步寻找新的治疗靶点.

  9. Curcumin attenuates allergic airway inflammation by regulation of CD4+CD25+ regulatory T cells (Tregs)/Th17 balance in ovalbumin-sensitized mice.

    Science.gov (United States)

    Ma, Chunhua; Ma, Zhanqiang; Fu, Qiang; Ma, Shiping

    2013-06-01

    The present study aimed to determine the protective effects and the underlying mechanisms of curcumin on ovalbumin (OVA)-induced allergic inflammation in a mouse model of allergic asthma. Asthma mice model was established by ovalbumin. A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg/kg), and curcumin (50 mg/kg, 100 mg/kg, 200 mg/kg). Airway resistance (Raw) was measured by the forced oscillation technique, differential cell count in BAL fluid (BALF) was measured by Wright-Giemsa staining, histological assessment was measured by hematoxylin and eosin (HE) staining, BALF levels of Treg/Th17 cytokines were measured by enzyme-linked immunosorbent assay, Treg cells and Th17 cells were evaluated by flow cytometry (FCM). Our study demonstrated that curcumin inhibited OVA-induced increases in eosinophil count; interleukin (IL)-17A level were recovered in bronchoalveolar lavage fluid increased IL-10 level in bronchoalveolar lavage fluid. Histological studies demonstrated that curcumin substantially inhibited OVA-induced eosinophilia in lung tissue. Flow cytometry (FCM) studies demonstrated that curcumin remarkably inhibited Th17 cells and significantly increased Treg cells. The results in vivo show ovalbumin-induced significantly broke Treg/Th17 balance; curcumin treatments markedly attenuated the inflammatory in asthma model by regulating Treg/Th17 balance. Our findings support the possible use of curcumin as a therapeutic drug for patients with allergic asthma. Copyright © 2013. Published by Elsevier B.V.

  10. 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H17 cells to protect against experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Jae-Hoon Chang

    Full Text Available BACKGROUND: Vitamin D(3, the most physiologically relevant form of vitamin D, is an essential organic compound that has been shown to have a crucial effect on the immune responses. Vitamin D(3 ameliorates the onset of the experimental autoimmune encephalomyelitis (EAE; however, the direct effect of vitamin D(3 on T cells is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In an in vitro system using cells from mice, the active form of vitamin D(3 (1,25-dihydroxyvitamin D(3 suppresses both interleukin (IL-17-producing T cells (T(H17 and regulatory T cells (Treg differentiation via a vitamin D receptor signal. The ability of 1,25-dihydroxyvitamin D(3 (1,25(OH(2D(3 to reduce the amount of IL-2 regulates the generation of Treg cells, but not T(H17 cells. Under T(H17-polarizing conditions, 1,25(OH(2D(3 helps to increase the numbers of IL-10-producing T cells, but 1,25(OH(2D(3's negative regulation of T(H17 development is still defined in the IL-10(-/- T cells. Although the STAT1 signal reciprocally affects the secretion of IL-10 and IL-17, 1,25(OH(2D(3 inhibits IL-17 production in STAT1(-/- T cells. Most interestingly, 1,25(OH(2D(3 negatively regulates CCR6 expression which might be essential for T(H17 cells to enter the central nervous system and initiate EAE. CONCLUSIONS/SIGNIFICANCE: Our present results in an experimental murine model suggest that 1,25(OH(2D(3 can directly regulate T cell differentiation and could be applied in preventive and therapeutic strategies for T(H17-mediated autoimmune diseases.

  11. CD4+ Th17 cells discriminate clinical types and constitute a third subset of non Th1, Non Th2 T cells in human leprosy.

    Directory of Open Access Journals (Sweden)

    Chaman Saini

    Full Text Available BACKGROUND: Patients with localized tuberculoid and generalized lepromatous leprosy show respectively Th1 and Th2 cytokine profile. Additionally, other patients in both types of leprosy also show a non discriminating Th0 cytokine profile with both interferon-γ and IL-4. The present study investigated the role of Th17 cells which appear to be a distinct subtype of Th subtypes in 19 tuberculoid and 18 lepromatous leprosy patients. Five healthy subjects with long term exposure to infection and 4 skin biopsies from healthy subjects undergoing cosmetic surgery were used as controls. METHODOLOGY/PRINCIPLE FINDINGS: An array of Th17 related primers for cytokines, chemokines and transcription factors was used in real time reverse transcribed PCR to evaluate gene expression, ELISA for cytokine secretion in the supernatants of antigen stimulated PBMC cultures and flow cytometry for establishing the phenotype of the IL-17, IL-21 producing cells. CONCLUSIONS/SIGNIFICANCE: IL-17 isoforms showed significantly higher expression and release in supernatants of antigen stimulated PBMC cultures and dermal lesions of healthy contacts and tuberculoid leprosy as compared to lepromatous leprosy (p<0.003. This was further confirmed by Th17 associated transcription factor RORC, cytokines IL-21, IL-22, and IL-23, chemokines MMP13, CCL20, CCL22. Of interest was the association of IL-23R and not IL-6R with IL-17(+ cells. The Th17 cells were CD4(+ CCR6(+ confirming their effector cell lineage. Polarized Th1 cytokines were seen in 3/7 tuberculoid and Th2 cytokines in 5/10 lepromatous leprosy patients. Of importance was the higher association of Th17 pathway factors with the non-polarized Th0 types as compared to the polarized Th1 and Th2 (p<0.01. Our study draws attention to a third type of effector Th cell that may play a role in leprosy.

  12. CD4+ Th17 Cells Discriminate Clinical Types and Constitute a Third Subset of Non Th1, Non Th2 T Cells in Human Leprosy

    Science.gov (United States)

    Saini, Chaman; Ramesh, V.; Nath, Indira

    2013-01-01

    Background Patients with localized tuberculoid and generalized lepromatous leprosy show respectively Th1 and Th2 cytokine profile. Additionally, other patients in both types of leprosy also show a non discriminating Th0 cytokine profile with both interferon-γ and IL-4. The present study investigated the role of Th17 cells which appear to be a distinct subtype of Th subtypes in 19 tuberculoid and 18 lepromatous leprosy patients. Five healthy subjects with long term exposure to infection and 4 skin biopsies from healthy subjects undergoing cosmetic surgery were used as controls. Methodology/Principle Findings An array of Th17 related primers for cytokines, chemokines and transcription factors was used in real time reverse transcribed PCR to evaluate gene expression, ELISA for cytokine secretion in the supernatants of antigen stimulated PBMC cultures and flow cytometry for establishing the phenotype of the IL-17, IL-21 producing cells. Conclusions/Significance IL-17 isoforms showed significantly higher expression and release in supernatants of antigen stimulated PBMC cultures and dermal lesions of healthy contacts and tuberculoid leprosy as compared to lepromatous leprosy (p<0.003). This was further confirmed by Th17 associated transcription factor RORC, cytokines IL-21, IL-22, and IL-23, chemokines MMP13, CCL20, CCL22. Of interest was the association of IL-23R and not IL-6R with IL-17+ cells. The Th17 cells were CD4+ CCR6+ confirming their effector cell lineage. Polarized Th1 cytokines were seen in 3/7 tuberculoid and Th2 cytokines in 5/10 lepromatous leprosy patients. Of importance was the higher association of Th17 pathway factors with the non-polarized Th0 types as compared to the polarized Th1 and Th2 (p<0.01). Our study draws attention to a third type of effector Th cell that may play a role in leprosy. PMID:23936569

  13. The anti-CD20 antibody rituximab reduces the Th17 cell response

    NARCIS (Netherlands)

    Veerdonk, F.L. van de; Lauwerys, B.; Marijnissen, R.J.; Timmermans, K.; Padova, F.E. Di; Koenders, M.M.J.F.; Gutierrez-Roelens, I.; Durez, P.; Netea, M.G.; Meer, J.W. van der; Berg, W.B. van den; Joosten, L.A.B.

    2011-01-01

    OBJECTIVE: Rituximab has been shown to be successful in the treatment of rheumatoid arthritis (RA), and this unexpected finding indicates that B cells have an important role in this disease. The present study was undertaken to investigate the mechanism of action of rituximab in RA. METHODS: Twelve p

  14. SLA-PGN-primed dendritic cell-based vaccination induces Th17-mediated protective immunity against experimental visceral leishmaniasis: a crucial role of PKCβ.

    Science.gov (United States)

    Jawed, Junaid Jibran; Majumder, Saikat; Bandyopadhyay, Syamdas; Biswas, Satabdi; Parveen, Shabina; Majumdar, Subrata

    2016-07-01

    Emergence of drug resistance during visceral leishmaniasis (VL) is a major obstacle imposed during successful therapy. An effective vaccine strategy against this disease is therefore necessary. Our present study exploited the SLA (soluble leishmanial antigen) and PGN (peptidoglycan) stimulated bone marrow-derived dendritic cells (DCs) as a suitable vaccine candidate during experimental VL. SLA-PGN-stimulated DCs showed a significant decrease in hepatic and splenic parasite burden, which were associated with increased production of nitric oxide and pro-inflammatory cytokines such as IL-12, IFN-γ and IL-17. Elevated level of IL-17 was accompanied with the generation of more Th17 cells. Further studies on DC provided the evidence that these SLA-PGN-stimulated DCs played an important role in providing necessary cytokines such as IL-6, IL-23 and TGF-β for the generation of Th17 cells. Interestingly, inhibition of protein kinase C-β (PKCβ) in DCs led to decreased production of Th17 polarizing cytokines, causing reduction of the Th17 population size. Altogether, our finding highlighted the important role of DC-based PKCβ in regulation of the function and generation of Th17 cells. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6.

    Science.gov (United States)

    Saini, Chaman; Siddiqui, Anisuddin; Ramesh, Venkatesh; Nath, Indira

    2016-04-01

    50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR) and Type 2/ Erythema Nodosum Leprosum (ENL) reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs) have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions. Quantitative reverse transcribed PCR (qPCR), flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients. Patients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation.

  16. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6.

    Directory of Open Access Journals (Sweden)

    Chaman Saini

    2016-04-01

    Full Text Available 50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR and Type 2/ Erythema Nodosum Leprosum (ENL reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions.Quantitative reverse transcribed PCR (qPCR, flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients.Patients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation.

  17. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6

    Science.gov (United States)

    Saini, Chaman; Siddiqui, Anisuddin; Ramesh, Venkatesh; Nath, Indira

    2016-01-01

    Background 50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR) and Type 2/ Erythema Nodosum Leprosum (ENL) reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs) have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions. Methodology and Principle Findings Quantitative reverse transcribed PCR (qPCR), flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients. Conclusions Patients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation. PMID:27035913

  18. The aryl hydrocarbon receptor:a regulator of Th17 and Treg cell development in disease

    Institute of Scientific and Technical Information of China (English)

    Peggy P Ho; Lawrence Steinman

    2008-01-01

    @@ The aryl hydrocarbon receptor (AhR)was discovered almost 30 years ago as a specific binding site for the halogenated polycyclic aromatic hydrocarbon,2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD),an environmental toxin (as reviewed in [1]).Within the last decade,AhR was found to have a basic helixloop-helix and function as a ligand-activated transcription factor.Located in the cytoplasm of most cells,AhR forms a receptor complex with several proteins including the chaperone protein hsp90 (a 90kDa heat shock protein).

  19. Immunization with Escherichia coli outer membrane vesicles protects bacteria-induced lethality via Th1 and Th17 cell responses.

    Science.gov (United States)

    Kim, Oh Youn; Hong, Bok Sil; Park, Kyong-Su; Yoon, Yae Jin; Choi, Seng Jin; Lee, Won Hee; Roh, Tae-Young; Lötvall, Jan; Kim, Yoon-Keun; Gho, Yong Song

    2013-04-15

    Outer membrane vesicles (OMVs), secreted from Gram-negative bacteria, are spherical nanometer-sized proteolipids enriched with outer membrane proteins. OMVs, also known as extracellular vesicles, have gained interests for use as nonliving complex vaccines and have been examined for immune-stimulating effects. However, the detailed mechanism on how OMVs elicit the vaccination effect has not been studied extensively. In this study, we investigated the immunological mechanism governing the protective immune response of OMV vaccines. Immunization with Escherichia coli-derived OMVs prevented bacteria-induced lethality and OMV-induced systemic inflammatory response syndrome. As verified by adoptive transfer and gene-knockout studies, the protective effect of OMV immunization was found to be primarily by the stimulation of T cell immunity rather than B cell immunity, especially by the OMV-Ag-specific production of IFN-γ and IL-17 from T cells. By testing the bacteria-killing ability of macrophages, we also demonstrated that IFN-γ and IL-17 production is the main factor promoting bacterial clearances. Our findings reveal that E. coli-derived OMV immunization effectively protects bacteria-induced lethality and OMV-induced systemic inflammatory response syndrome primarily via Th1 and Th17 cell responses. This study therefore provides a new perspective on the immunological detail regarding OMV vaccination.

  20. Tetrandrine ameliorates collagen-induced arthritis in mice by restoring the balance between Th17 and Treg cells via the aryl hydrocarbon receptor.

    Science.gov (United States)

    Yuan, Xusheng; Tong, Bei; Dou, Yannong; Wu, Xin; Wei, Zhifeng; Dai, Yue

    2016-02-01

    Tetrandrine is an alkaloid constituent of the root of Stephania tetrandra S. Moore. The long-term clinical uses of tetrandrine for treatments of rheumatalgia and arthralgia as well as the inhibition of rat adjuvant-induced arthritis imply that tetrandrine may have therapeutic potential in rheumatoid arthritis (RA). Here, we explored its anti-RA mechanism in collagen-induced arthritis (CIA) in relation to the balance between T helper (Th) 17 cells and regulatory T (Treg) cells. DBA/1 mice were immunized with chicken type II collagen and were orally administered tetrandrine for 14 consecutive days. Then, the mice were sacrificed, their joints were removed for histological analysis, and spleens and mesenteric lymph nodes (MLNs) were removed to examine the Th17 and Treg cells. Tetrandrine markedly alleviated the severity of arthritis, reduced the serum levels of pro-inflammatory cytokines, and restored the Th17/Treg balance, as demonstrated by the serum levels of their related cytokines (IL-17 and IL-10) and the proportion of each cell type. Tetrandrine inhibited Th17 cell differentiation and induced Treg cell differentiation in vitro . Notably, aryl hydrocarbon receptor (AhR) was proven to play a crucial role in tetrandrine-mediated T cell differentiation. The correlation between AhR activation, regulation of Th17/Treg and amelioration of arthritis by tetrandrine was verified in the CIA mice. Moreover, tetrandrine might be a ligand of AhR because it facilitated the expression of the AhR target gene cytochrome P450 1A1 (CYP1A1) and the activation of its downstream signaling pathways. Taken together, tetrandrine exerts its anti-arthritis efficacy by restoring Th17/Treg balance via AhR.

  1. Involvement of P2X7 receptor signaling on regulating the differentiation of Th17 cells and type II collagen-induced arthritis in mice

    Science.gov (United States)

    Fan, Zhi-Dan; Zhang, Ya-Yuan; Guo, Yi-Hong; Huang, Na; Ma, Hui-Hui; Huang, Hui; Yu, Hai-Guo

    2016-01-01

    Interleukin (IL)-17 producing T helper (Th17) cells are major effector cells in the pathogenesis of rheumatoid arthritis (RA). The P2X7 receptor (P2X7R) has emerged as a potential site in the regulation of inflammation in RA but little is known of its functional role on the differentiation of Th17 cells. This study investigates the in vitro and in vivo effects of P2X7R on Th17 cell differentiation during type II collagen (CII) induced experimental arthritis model. In CII-treated dendritic cells (DCs) and DC/CD4+ T coculture system, pretreatment with pharmacological antagonists of P2X7R (Suramin and A-438079) caused strong inhibition of production of Th17-promoting cytokines (IL-1β, TGF-β1, IL-23p19 and IL-6). Exposure to CII induced the elevation of mRNAs encoding retinoic acid receptor-related orphan receptor α and γt, which were abolished by pretreatment with P2X7R antagonists. Furthermore, blocking P2X7R signaling abolished the CII-mediated increase in IL-17A. Blockade of P2X7R remarkably inhibited hind paw swelling and ameliorated pathological changes in ankle joint of the collagen-induced arthritis mice. Thus, we demonstrated a novel function for P2X7R signaling in regulating CII-induced differentiation of Th17 cells. P2X7R signaling facilitates the development of the sophisticated network of DC-derived cytokines that favors a Th17 phenotype. PMID:27775097

  2. Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling.

    Science.gov (United States)

    Pasztoi, Maria; Bonifacius, Agnes; Pezoldt, Joern; Kulkarni, Devesha; Niemz, Jana; Yang, Juhao; Teich, René; Hajek, Janina; Pisano, Fabio; Rohde, Manfred; Dersch, Petra; Huehn, Jochen

    2017-04-04

    Adaptive immunity critically contributes to control acute infection with enteropathogenic Yersinia pseudotuberculosis; however, the role of CD4(+) T cell subsets in establishing infection and allowing pathogen persistence remains elusive. Here, we assessed the modulatory capacity of Y. pseudotuberculosis on CD4(+) T cell differentiation. Using in vivo assays, we report that infection with Y. pseudotuberculosis resulted in enhanced priming of IL-17-producing T cells (Th17 cells), whereas induction of Foxp3(+) regulatory T cells (Tregs) was severely disrupted in gut-draining mesenteric lymph nodes (mLNs), in line with altered frequencies of tolerogenic and proinflammatory dendritic cell (DC) subsets within mLNs. Additionally, by using a DC-free in vitro system, we could demonstrate that Y. pseudotuberculosis can directly modulate T cell receptor (TCR) downstream signaling within naïve CD4(+) T cells and Tregs via injection of effector molecules through the type III secretion system, thereby affecting their functional properties. Importantly, modulation of naïve CD4(+) T cells by Y. pseudotuberculosis resulted in an enhanced Th17 differentiation and decreased induction of Foxp3(+) Tregs in vitro. These findings shed light to the adjustment of the Th17-Treg axis in response to acute Y. pseudotuberculosis infection and highlight the direct modulation of CD4(+) T cell subsets by altering their TCR downstream signaling.

  3. Immunization of Mice with a Live Transconjugant Shigella Hybrid Strain Induced Th1 and Th17 Cell-Mediated Immune Responses and Confirmed Passive Protection Against Heterologous Shigellae.

    Science.gov (United States)

    Nag, D; Koley, H; Sinha, R; Mukherjee, P; Sarkar, C; Withey, J H; Gachhui, R

    2016-02-01

    An avirulent, live transconjugant Shigella hybrid (LTSHΔstx) strain was constructed in our earlier study by introducing a plasmid vector, pPR1347, into a Shiga toxin gene deleted Shigella dysenteriae 1. Three successive oral administrations of LTSHΔstx to female adult mice produced comprehensive passive heterologous protection in their offspring against challenge with wild-type shigellae. Production of NO and different cytokines such asIL-12p70, IL-1β and IL-23 in peritoneal mice macrophages indicated that LTSHΔstx induced innate and adaptive immunity in mice. Furthermore, production of IFN-γ, IL-10 and IL-17 in LTSH-primed splenic CD4+ T cell suggested that LTSHΔstx may induce Th1 and Th17 cell-mediated immune responses. Exponential increase of the serum IgG and IgA titre against whole shigellae was observed in immunized adult mice during and after the immunization with the highest peak on day 35. Antigen-specific sIgA was also determined from intestinal lavage of immunized mice. The stomach extracts of neonates from immunized mice, mainly containing mother's milk, contained significant levels of anti-LTSHΔstx immunoglobulin. These studies suggest that the LTSHΔstx could be a new live oral vaccine candidate against shigellosis in the near future.

  4. Effects of exposure to extremely low-frequency electromagnetic fields on the differentiation of Th17 T cells and regulatory T cells.

    Science.gov (United States)

    Lee, Yun-Jung; Hyung, Kyeong Eun; Yoo, Jong-Sun; Jang, Ye Won; Kim, Soo Jeong; Lee, Do Ik; Lee, Sang Joon; Park, So-Young; Jeong, Ji Hoon; Hwang, Kwang Woo

    2016-10-01

    The potential risks that electromagnetic fields (EMF) pose to human physiology have been debated for several decades, especially considering that EMF is almost omnipresent and some occupations involve regular exposure to particularly strong fields. In the present study, the effects of 60 Hz 0.3 mT EMF on CD4+ T cells were evaluated. Production of T cell related cytokines, IFN-γ and IL-2, was not altered in CD4+ T cells that were exposed to EMF, and cell proliferation was also unaffected. The expression of genes present in a subset of Th17 cells was upregulated following EMF exposure, and the production of effector cytokines of the IL-17A subset also increased. To determine signaling pathways that underlie these effects, phosphorylation of STAT3 and SMAD3, downstream molecules of cytokines critical for Th17 induction, was analyzed. Increased SMAD3 phosphorylation level in cells exposed to EMF, suggesting that SMAD3 may be at least in part causing the increased Th17 cell production. Differentiation of Treg, another CD4+ T cell subset induced by SMAD3 signaling, was also elevated following EMF exposure. These results suggest that 60 Hz 0.3 mT EMF exposure amplifies TGF-β signaling and increases the generation of specific T cell subsets.

  5. Identification of protective pneumococcal T(H17 antigens from the soluble fraction of a killed whole cell vaccine.

    Directory of Open Access Journals (Sweden)

    Kristin L Moffitt

    Full Text Available Mucosal or parenteral immunization with a killed unencapsulated pneumococcal whole cell antigen (WCA with an adjuvant protects mice from colonization by a T(H17 CD4+ cell-mediated mechanism. Using preparative SDS gels, we separated the soluble proteins that compose the WCA in order to identify fractions that were immunogenic and protective. We screened these fractions for their ability to stimulate IL-17A secretion from splenocytes obtained from mice immunized with WCA and adjuvant. We identified 12 proteins within the stimulatory fractions by mass spectrometry; these proteins were then cloned, recombinantly expressed and purified using an Escherichia coli expression system. The ability of these proteins to induce IL-17A secretion was then evaluated by stimulation of mouse splenocytes. Of the four most stimulatory proteins, three were protective in a mouse pneumococcal serotype 6B colonization model. This work thus describes a method for identifying immunogenic proteins from the soluble fraction of pneumococcus and shows that several of the proteins identified protect mice from colonization when used as mucosal vaccines. We propose that, by providing protection against pneumococcal colonization, one or more of these proteins may serve as components of a multivalent pneumococcal vaccine.

  6. Induction of regulatory T cells in Th1-/Th17-driven experimental autoimmune encephalomyelitis by zinc administration.

    Science.gov (United States)

    Rosenkranz, Eva; Maywald, Martina; Hilgers, Ralf-Dieter; Brieger, Anne; Clarner, Tim; Kipp, Markus; Plümäkers, Birgit; Meyer, Sören; Schwerdtle, Tanja; Rink, Lothar

    2016-03-01

    The essential trace element zinc is indispensable for proper immune function as zinc deficiency accompanies immune defects and dysregulations like allergies, autoimmunity and an increased presence of transplant rejection. This point to the importance of the physiological and dietary control of zinc levels for a functioning immune system. This study investigates the capacity of zinc to induce immune tolerance. The beneficial impact of physiological zinc supplementation of 6 μg/day (0.3mg/kg body weight) or 30 μg/day (1.5mg/kg body weight) on murine experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis with a Th1/Th17 (Th, T helper) cell-dominated immunopathogenesis, was analyzed. Zinc administration diminished EAE scores in C57BL/6 mice in vivo (Pzinc supplementation seems to be capable to induce tolerance in unwanted immune reactions by increasing iTreg cells. This makes zinc a promising future tool for treating autoimmune diseases without suppressing the immune system.

  7. 原因不明性复发性流产患者Th17/Treg细胞失衡及主动免疫治疗效果%Imbalance of Th17/Treg Cells in Patients with Unexplained Recurrent Spontaneous Abortion and Curative Effect of Lymphocyte Active Im-munotherapy

    Institute of Scientific and Technical Information of China (English)

    郑艳萍; 杨菁

    2015-01-01

    Objective To investigate the proportions of Th17/Treg in the peripheral blood of patients with unexplained recurrent spontaneous abortion ( URSA) and the effect of lymphocyte ac-tive immunotherapy on the balance of Th17/Treg.Methods Flow cytometry was applied to detect the proportion of Th17/Treg in the peripheral blood of 28 URSA patients ( experimental group) and 30 normal early pregnant women ( control group ) .Then changes in Th17/Treg levels were further assessed in URSA patients who received lymphocyte active immunotherapy.The pregnancy outcomes were followed up.Results The proportion of Th17 cells was significantly higher in URSA group than that in control group, while Treg cell proportion was obviously lower in URSA group ( P <0.05 ) .The ratio of Th17/Treg favored a Th17 shift in URSA group ( P<0.05 ) .After immuno-therapy, the proportion of Th17 cells decreased while Treg cells increased.The ratio of Th17/Treg was recognized with a Treg shift.Follow up of pregnancy suggested a success rate of 73.9% in the experimental grop.Conclusion There is an imbalance of Th17/Treg in URSA.Lymphocyte active immunotherapy is effective for URSA by improving the imbalance of Th17/Treg.%目的:探讨原因不明性复发性流产患者外周血中Th17/Treg细胞水平,及淋巴细胞主动免疫治疗对Th17/Treg平衡的影响。方法应用流式细胞术检测28例原因不明性复发性流产( unexplained recurrent spontaneous abortion, URSA)患者和30例正常妊娠早期妇女外周血中Th17/Treg细胞的比例;对自愿接受免疫治疗的23名URSA患者行淋巴细胞主动免疫治疗,检测治疗后患者外周血Th17/Treg水平的变化,并对妊娠结局进行随访。结果 URSA患者外周血中Th17细胞比例显著高于对照组,而Treg细胞比例则明显低于对照组, Th17/Treg的比值较对照组升高( P<0.05);经主动免疫治疗后, Th17细胞比例下降, Treg细胞比例上升, Th17/Treg比

  8. Analysis of TGF-β1 and TGF-β3 as regulators of encephalitogenic Th17 cells: Implications for multiple sclerosis.

    Science.gov (United States)

    Lee, Priscilla W; Yang, Yuhong; Racke, Michael K; Lovett-Racke, Amy E

    2015-05-01

    The phenotype of the CD4(+) T cells that mediate the CNS pathology in multiple sclerosis is still unclear, and yet a vital question for developing therapies. One of the conundrums is the role of TGF-β in the development of encephalitogenic Th17 cells. In the present study, TGF-β1 and TGF-β3 were directly compared in their capacity to promote the differentiation of myelin-specific Th17 cells that could induce experimental autoimmune encephalomyelitis (EAE). Myelin-specific CD4(+) T cell receptor transgenic cells differentiated with antigen in the presence of IL-6+TGF-β1 or IL-6+TGF-β3 generated T cells that produced robust amounts of IL-17, but were incapable of inducing EAE when transferred into mice. Further analysis of these non-encephalitogenic Th17 cells found that they expressed lower amounts of GM-CSF or IL-23R, both molecules necessary for encephalitogenicity. Thus, TGF-β, irrespective of isoform, negatively regulates the differentiation of encephalitogenic Th17 cells.

  9. BATF: Bringing (in) Another Th17-regulating Factor

    Institute of Scientific and Technical Information of China (English)

    Gustavo J. Martinez; Chen Dong

    2009-01-01

    T helper (Th) 17 cells are a recently identified subset of T cells that regulate tissue inflammation, and RORγt and RORα have been shown to be Th17-specific transcription factors that mediate Th17 cell generation. A new study of Batf-deficient mice shows that this AP-1 family transcription factor also regulates Th17 cell differentiation by binding to Th17-associated gene promoters and by maintaining RORa and RORgt expression, shedding new lights on current clinical modulation of Th17 cell function in inflammatory diseases.

  10. 非小细胞肺癌患者外周血Foxp3+调节性T细胞和Th17的检测与临床意义%The detection and significance of Foxp3+ regulatory T cells, Th17 in peripheral blood of non-small cell lung cancer patients

    Institute of Scientific and Technical Information of China (English)

    李莎; 李岩; 梁婧; 刘晓琳

    2012-01-01

    Objective To detect the Foxp3+ regulatory T cells (TrFoxp3+),Th17,TrFoxp3+/Th17 and related cell factors level in peripheral blood of non-small cell lung cancer(NSCLC) patients,and to explore the relationships about TrFoxp3+,Th17 with occurrence and development of lung cancer and whether there are imbalance of TrFoxp3+/Th17.Methods The proportions of TrFoxp3+,Th17 cells and the level of related cell factors such as TGF-β,IL-17,IL-23 were determined respectively by flow cytometry and ELISA in peripheral blood of 18 healthy people and 26 patients with NSCLC.Results The proportions of TrFoxp3+,Th17 and TrFoxp3+/Th17 in peripheral blood with NSCLC were higher than healthy controls(P <0.05).The proportion of Th17 cells from NSCLC patients was positively correlated with that of TrFoxp3+(r =0.81,P<0.05).Comparing TrFoxp3+/Th17 among different TNM stages in NSCLC patients:TrFoxp3+/Th17 of in Ⅳ stage was obvious higher than that of in Ⅰ-Ⅱ stage,Ⅲ stage(P<0.05).The level of TGF-β,IL-17,IL-23 was higher in NSCLC patients than that in healthy controls,the ratio of TGF-β in the advanced stage group/healthy controls was higher in the early and middle group/healthy controls (P<0.05).Conclusion TrFoxp3+,Th17 and TrFoxp3+/Th17 in NSCLC patients were higher than healthy people,moreover TrFoxp3+/Th17 in advanced stage increased significantly.The results may imply that there are certain relationships between the imbalance of TrFoxp3+/Th17 and immunosuppression and occurrence and development of NSCLC as well as the regulation of their cytokines.%目的 通过检测非小细胞肺癌(NSCLC)患者外周血Foxp3+调节性T细胞(TrFoxp3+)、Th17细胞、TrFoxp3+/Th17及相关细胞因子水平,探讨TrFoxp3+、Th17细胞在肺癌发生发展中的相互作用以及是否存在TrFoxp3+/Th17失衡.方法 采用流式细胞术和酶联免疫吸附法(ELISA)分别检测18例健康人、26例NSCLC患者外周血中TrFoxp3+、Th17细胞占CD4+T细胞的比例,以及转

  11. Rapamycin ameliorates experimental autoimmune uveoretinitis by inhibiting Th1/Th2/Th17 cells and upregulating CD4+CD25+ Foxp3 regulatory T cells

    Institute of Scientific and Technical Information of China (English)

    Li-Fei; Yuan; Guang-Da; Li; Xin-Jun; Ren; Hong; Nian; Xiao-Rong; Li; Xiao-Min; Zhang

    2015-01-01

    · AIM: To determine the effects of rapamycin on experimental autoimmune uveoretinitis(EAU) and investigate of role of rapamycin on T cell subsets in the disease.·METHODS: EAU was induced in rats using peptides1169 to 1191 of the interphotoreceptor binding protein(IRBP). Rapamycin(0.2 mg/kg/d) was administrated by intraperitoneal injection for a consecutive 7d after immunization. Th1/Th2/Th17 cytokines, TGF-β1, and IL-6produced by lymphocyteswere measured by ELISA, while Th17 cells and CD4 +CD25 + regulatory T cells(Tregs)from rat spleen were detected by flow cytometry.·RESULTS: Intraperitoneal treatment immediately after immunization dramatically ameliorated the clinical course of EAU. Clinical responses were associated with reduced retinal inflammatory cell infiltration and tissue destruction. Rapamycin induced suppression of Th1/Th2/Th17 cytokines, including IFN-γ, IL-2, IL-17, IL-4, and IL-10 release from T lymphocytes of EAU rats, in vitro.Rapamycin also significantly increased TGF-β1production but had no effect on IL-6 productionof T lymphocytes from EAU rats in vitro. Furthermore,rapamycin decreased the ratio of Th17 cells/CD4 +T cells and upregulated Tregs in EAU, as detected by flow cytometry.·CONCLUSION: Rapamycin effectively interferes with T cell mediated autoimmune uveitis by inhibiting antigen-specific T cell functions and enhancing Tregs in EAU.Rapamycin is a promising new alternative as an adjunct corticosteroid-sparing agent for treating uveitis.

  12. Coincident diabetes mellitus modulates Th1-, Th2-, and Th17-cell responses in latent tuberculosis in an IL-10- and TGF-β-dependent manner.

    Science.gov (United States)

    Kumar, Nathella Pavan; Moideen, Kadar; George, Parakkal Jovvian; Dolla, Chandrakumar; Kumaran, Paul; Babu, Subash

    2016-02-01

    Type 2 diabetes mellitus (DM) is a risk factor for the development of active tuberculosis (TB), although its role in the TB-induced responses in latent TB (LTB) is not well understood. Since Th1, Th2, and Th17 responses are important in immunity to LTB, we postulated that coincident DM could alter the function of these CD4(+) T-cell subsets. To this end, we examined mycobacteria-induced immune responses in the whole blood of individuals with LTB-DM and compared them with responses of individuals without DM (LTB-NDM). T-cell responses from LTB-DM are characterized by diminished frequencies of mono- and dual-functional CD4(+) Th1, Th2, and Th17 cells at baseline and following stimulation with mycobacterial antigens-purified protein derivative, early secreted antigen-6, and culture filtrate protein-10. This modulation was at least partially dependent on IL-10 and TGF-β, since neutralization of either cytokine resulted in significantly increased frequencies of Th1 and Th2 cells but not Th17 cells in LTB-DM but not LTB individuals. LTB-DM is therefore characterized by diminished frequencies of Th1, Th2, and Th17 cells, indicating that DM alters the immune response in latent TB leading to a suboptimal induction of protective CD4(+) T-cell responses, thereby providing a potential mechanism for increased susceptibility to active disease.

  13. Ratio of Circulating IFNγ (+) "Th17 Cells" in Memory Th Cells Is Inversely Correlated with the Titer of Anti-CCP Antibodies in Early-Onset Rheumatoid Arthritis Patients Based on Flow Cytometry Methods of the Human Immunology Project.

    Science.gov (United States)

    Kotake, Shigeru; Nanke, Yuki; Yago, Toru; Kawamoto, Manabu; Kobashigawa, Tsuyoshi; Yamanaka, Hisashi

    2016-01-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic joint inflammation characterized by activated T cells. IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. However, it remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we validated the methods of the Human Immunology Project using only the cell-surface marker through measuring the actual expression of IL-17 and IFNγ. We also evaluated the expression of CD161 in human Th17 cells. We then tried to identify Th17 cells, IL-17(+)Th17 cells, and IFNγ (+)Th17 cells in the peripheral blood of early-onset RA patients using the standardized method of the Human Immunology Project. Our findings validated the method and the expression of CD161. The ratio of IFNγ (+)Th17 cells in memory T cells was inversely correlated to the titers of anti-CCP antibodies in the early-onset RA patients. These findings suggest that Th17 cells play important roles in the early phase of RA and that anti-IL-17 antibodies should be administered to patients with early phase RA, especially those with high titers of CCP antibodies.

  14. Suppressive IL-17A(+)Foxp3(+) and ex-Th17 IL-17A(neg)Foxp3(+) Treg cells are a source of tumour-associated Treg cells.

    Science.gov (United States)

    Downs-Canner, Stephanie; Berkey, Sara; Delgoffe, Greg M; Edwards, Robert P; Curiel, Tyler; Odunsi, Kunle; Bartlett, David L; Obermajer, Nataša

    2017-03-14

    Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Treg imbalance is associated with inflammatory immunosuppression in cancer. Here we show that Th17 cells are a source of tumour-induced Foxp3(+) cells. In addition to natural (n)Treg and induced (i)Treg cells that develop from naive precursors, suppressive IL-17A(+)Foxp3(+) and ex-Th17 Foxp3(+) cells are converted from IL-17A(+)Foxp3(neg) cells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A(+), ex-Th17 and iTreg cells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing Treg cell subsets. Although all Foxp3-expressing subsets are immunosuppressive, glycolysis is a prominent metabolic pathway exerted only by IL-17A(+)Foxp3(+) cells. Transcriptome analysis and flow cytometry of IL-17A(+)Foxp3(+) cells indicate that Folr4, GARP, Itgb8, Pglyrp1, Il1rl1, Itgae, TIGIT and ICOS are Th17-to-Treg cell transdifferentiation-associated markers. Tumour-associated Th17-to-Treg cell conversion identified here provides insights for targeting the dynamism of Th17-Treg cells in cancer immunotherapy.

  15. TLR-4 Cooperates with Dectin-1 and Mannose Receptor to Expand Th17 and Tc17 Cells Induced by Paracoccidioides brasiliensis Stimulated Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Vera Lucia Garcia Calich

    2015-03-01

    Full Text Available The concomitant use of diverse Pattern Recognition Receptors (PRRs by innate immune cells can result in synergistic or inhibitory activities that profoundly influence anti-microbial immunity. Dectin-1 and the Mannose Receptor (MR are C-type Lectin Receptors (CLRs previously reported to cooperate with Toll Like Receptors (TLRs signaling in the initial inflammatory response and in the induction of adaptive Th17 and Tc17 immunity mediated by CD4+ and CD8+ T cells, respectively. The protective immunity against paracoccidioidomycosis, the most prevalent fungal infection of Latin America, was previously shown to be influenced by these T cell subsets motivating us to study the contribution of TLRs, Dectin-1 and MR to the development of Th17/Tc17 immunity. First, curdlan a specific Dectin-1 agonist was used to characterize the influence of this receptor in the proliferative response and Th17/Tc17 differentiation of naïve lymphocytes induced by Paracoccidioides brasiliensis activated dendritic cells (DCs from C57BL/6 mice. Then, WT, Dectin-1-/-, TLR-2-/- and TLR-4-/- DCs treated or untreated with anti-Dectin-1 and anti-MR antibodies were used to investigate the contribution of these receptors in lymphocyte activation and differentiation. We verified that curdlan induces an enhanced lymphocyte proliferation and development of IL-17 producing CD4+ and CD8+ T cells. In addition, treatment of WT, TLR-2-/- and TLR-4-/- DCs by anti-Dectin-1 antibodies or antigen presentation by Dectin-1-/- DCs led to decreased lymphoproliferation and impaired Th17 and Tc17 expansion. These responses were also inhibited by anti-MR treatment of DCs, but a synergistic action on Th17/Tc17 differentiation was mediated by TLR-4 and MR. Taken together, our results indicate that diverse TLRs and CLRs are involved in the induction of lymphocyte proliferation and Th17/Tc17 differentiation mediated by P. brasiliensis activated DCs, but a synergist action was restricted to Dectin-1, TLR

  16. Significance of the balance between regulatory T (Treg and T helper 17 (Th17 cells during hepatitis B virus related liver fibrosis.

    Directory of Open Access Journals (Sweden)

    Jing Li

    Full Text Available BACKGROUND: Hepatitis B virus-related liver fibrosis (HBV-LF always progresses from inflammation to fibrosis. However, the relationship between these two pathological conditions is not fully understood. Here, it is postulated that the balance between regulatory T (Treg cells and T helper 17 (Th17 cells as an indicator of inflammation may predict fibrosis progression of HBV-LF. METHODOLOGY/PRINCIPAL FINDINGS: The frequencies and phenotypes of peripheral Treg and Th17 cells of seventy-seven HBeAg-positive chronic hepatitis B (CHB patients who underwent liver biopsies and thirty healthy controls were determined by flow cytometry. In the periphery of CHB patients, both Treg and Th17 frequencies were significantly increased and correlated, and a lower Treg/Th17 ratio always indicated more liver injury and fibrosis progression. To investigate exact effects of Treg and Th17 cells during HBV-LF, a series of in vitro experiments were performed using purified CD4(+, CD4(+CD25(+, or CD4(+CD25(- cells from the periphery, primary human hepatic stellate cells (HSCs isolated from healthy liver specimens, human recombinant interleukin (IL-17 cytokine, anti-IL-17 antibody and HBcAg. In response to HBcAg, CD4(+CD25(+ cells significantly inhibited cell proliferation and cytokine production (especially IL-17 and IL-22 by CD4(+CD25(- cells in cell-contact and dose-dependent manners. In addition, CD4(+ cells from CHB patients, compared to those from HC subjects, dramatically promoted proliferation and activation of human HSCs. Moreover, in a dramatically dose-dependent manner, CD4(+CD25(+ cells from CHB patients inhibited, whereas recombinant IL-17 response promoted the proliferation and activation of HSCs. Finally, in vivo evidence about effects of Treg/Th17 balance during liver fibrosis was obtained in concanavalin A-induced mouse fibrosis models via depletion of CD25(+ or IL-17(+ cells, and it's observed that CD25 depletion promoted, whereas IL-17 depletion

  17. Reduced TCR‐dependent activation through citrullination of a T‐cell epitope enhances Th17 development by disruption of the STAT3/5 balance

    Science.gov (United States)

    Tibbitt, Christopher; Falconer, Jane; Stoop, Jeroen; van Eden, Willem; Robinson, John H.

    2016-01-01

    Citrullination is a post‐translational modification of arginine that commonly occurs in inflammatory tissues. Because T‐cell receptor (TCR) signal quantity and quality can regulate T‐cell differentiation, citrullination within a T‐cell epitope has potential implications for T‐cell effector function. Here, we investigated how citrullination of an immunedominant T‐cell epitope affected Th17 development. Murine naïve CD4+ T cells with a transgenic TCR recognising p89‐103 of the G1 domain of aggrecan (agg) were co‐cultured with syngeneic bone marrow‐derived dendritic cells (BMDC) presenting the native or citrullinated peptides. In the presence of pro‐Th17 cytokines, the peptide citrullinated on residue 93 (R93Cit) significantly enhanced Th17 development whilst impairing the Th2 response, compared to the native peptide. T cells responding to R93Cit produced less IL‐2, expressed lower levels of the IL‐2 receptor subunit CD25, and showed reduced STAT5 phosphorylation, whilst STAT3 activation was unaltered. IL‐2 blockade in native p89‐103‐primed T cells enhanced the phosphorylated STAT3/STAT5 ratio, and concomitantly enhanced Th17 development. Our data illustrate how a post‐translational modification of a TCR contact point may promote Th17 development by altering the balance between STAT5 and STAT3 activation in responding T cells, and provide new insight into how protein citrullination may influence effector Th‐cell development in inflammatory disorders. PMID:27173727

  18. Dendritic cell are able to differentially recognize Sporothrix schenckii antigens and promote Th1/Th17 response in vitro.

    Science.gov (United States)

    Verdan, F F; Faleiros, J C; Ferreira, L S; Monnazzi, L G S; Maia, D C G; Tansine, A; Placeres, M C P; Carlos, I Z; Santos-Junior, R R

    2012-08-01

    Sporotrichosis is a disease caused by the dimorphic fungus Sporothrix schenckii. The main clinical manifestations occur in the skin, however the number of systemic and visceral cases has increased, especially in immunocompromised patients. Dendritic cells (DCs) are highly capable to recognize the fungus associated data and translate it into differential T cells responses both in vivo and in vitro. Although, the mechanisms involved in the interaction between DCs and S. schenckii are not fully elucidated. The present study investigated the phenotypic and functional changes in bone marrow dendritic cells (BMDCs) stimulated in vitro with the yeast form of S. schenckii or exoantigen (ExoAg) and its ability to trigger a cellular immune response in vitro. Our results demonstrated that the live yeast of S. schenckii and its exoantigen, at a higher dose, were able to activate BMDCs and made them capable of triggering T cell responses in vitro. Whereas the yeast group promoted more pronounced IFN-γ production rather than IL-17, the Exo100 group generated similar production of both cytokines. The exoantigen stimulus suggests a capability to deviate the immune response from an effector Th1 to an inflammatory Th17 response. Interestingly, only the Exo100 group promoted the production of IL-6 and a significant increase of TGF-β, in addition to IL-23 production. Interestingly, only Exo100 group was capable to promote the production of IL-6 and a significant increase on TGF-β, in addition with IL-23 detection. Our results demonstrated the plasticity of DCs in translating the data associated with the fungus S. schenckii and ExoAg into differential T cell responses in vitro. The possibility of using ex vivo-generated DCs as vaccinal and therapeutic tools for sporotrichosis is a challenge for the future.

  19. The levels of IL-17A and of the cytokines involved in Th17 cell commitment are increased in patients with chronic immune thrombocytopenia

    Science.gov (United States)

    Rocha, Andreia Maria Camargos; Souza, Cláudia; Rocha, Gifone Aguiar; de Melo, Fabrício Freire; Clementino, Nelma Cristina Diogo; Marino, Marília Campos Abreu; Bozzi, Adriana; Silva, Maria Luiza; Martins Filho, Olindo Assis; Queiroz, Dulciene Maria Magalhães

    2011-01-01

    Th17 cells have been associated with immune-mediated diseases in humans but it has still not been determined whether they play a role in immune thrombocytopenia. We evaluated representative cytokines of the Th17, Th1, Th2 and Treg cell commitment in the serum of patients with chronic immune thrombocytopenia, as well as the cell source of IL-17A. Higher levels of IL-17A and Th17-related cytokines, and an increased percentage of IL-17A producing CD4+ and neutrophils were observed in patients. The levels of cytokines involved in Th1 cell commitment IFN-γ, IL-2, IL12-p70 and the percentages of Th1 cells were also increased, but IL-4 was not detected. Although the concentrations of IL-10 were higher, the levels of TGF-β were similar in both groups. In conclusion, our results point to a putative role for Th-17 cells/IL-17A cytokine in the pathogenesis of chronic immune thrombocytopenia. PMID:21972211

  20. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

    Science.gov (United States)

    Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

    2015-08-15

    Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway.

  1. Imbalance of Treg/Th17 cells in patients with aplastic anemia and regulative role of umbilical cord-derived mesenchymal stem cells%再生障碍性贫血患者Treg/Th17细胞失衡及脐带MSCs对其的调节作用

    Institute of Scientific and Technical Information of China (English)

    陈莹; 陈柯材; 刘林

    2013-01-01

    目的 研究Treg/Th17细胞的平衡状态在再生障碍性贫血(aplastic anemia,AA)发病机制中的作用及意义,探讨脐带间充质干细胞(umbilical cord-derived mesenchymal stem cells,UC-MSCs)对AA患者外周血Treg/Th17比率的调节作用.方法 体外分离、培养和鉴定UC-MSCs.流式细胞术(flow cytometry,FCM)检测10例健康对照者、15例AA患者外周血Treg细胞和Th17细胞分别占外周血单个核细胞(peripheral blood mononuclear cells,PBMCs)的百分比,比较Treg/Th17细胞的比率.将AA患者的PBMCs与UC-MSCs共培养72 h,检测AA患者单独培养组和与MSCs共培养组Treg细胞、Th17细胞分别占PBMCs的百分比,比较Treg/Th17比率的变化.结果 经FCM鉴定MSCs表面标记CD90、CD105阳性率≥98%,CD34、CD45阳性率≤1%.AA患者组外周血Treg细胞百分率明显低于健康对照组(P<0.05),Th17细胞百分率明显高于健康对照组(P<0.05),Treg/Th17细胞比率明显低于健康对照组(P<0.05).AA患者的PBMC与UC-MSCs共培养后,Treg细胞百分率明显高于单独培养组(P<0.05),Th17细胞百分率明显低于单独培养组(P<0.05),Treg/Th17细胞比率较单独培养组明显升高(P<0.05).结论 AA患者外周血存在Treg/Th17分化失衡;UC-MSCs可能通过抑制Th17细胞分化,诱导Treg细胞生成/聚集,使得其Treg/Th17的失衡在一定程度上得到恢复.%Objective To determine the role and significance of the balance of Treg/Th17 cells in pathogenesis of aplastic anemia (AA),and to investigate the regulatory effect of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on the ratio of Treg/Th17 cells in patients with AA.Methods UC-MSCs were isolated,cultured and identified in vitro.Flow cytometry (FCM) was used to detect the percentage of Treg cells and Th17 cells in the peripheral blood mononuclear cells (PBMCs) from 10 healthy volunteers and 15 AA patients,respectively by FCM,and the ratio of Treg/Th17 cells was compared.After PBMCs of the

  2. Significance of the change of Th17 cells in patients with chronic heart failure%慢性心力衰竭患者Th17细胞的检测及意义

    Institute of Scientific and Technical Information of China (English)

    周军; 贺立群; 罗兵; 昌薇; 戴榕; 张帆

    2009-01-01

    目的:探讨慢性心力衰竭(CHF)患者外周血Th17细胞水平及意义.方法:采用流式细胞分析法检测66例CHF患者(CHF组)和23例正常对照者(对照组)外周血Th17细胞比例.结果:CHF患者外周血Th17/cD4+T细胞比例[(2.4±1.6)%]显著高于对照组[(0.4±0.3)%].Th17/CD4+T比例在缺血性心脏病者与非缺血性心脏病者间差异无统计学意义,但心功能NYHA分级Ⅲ~Ⅳ级者[(3.3±1.1)%]比例明显高于Ⅰ~Ⅱ级者[(1.7±0.9)%].结论:CHF患者外周血外周血Th17细胞比例增加,且与心功能有一定关系.Th17细胞可能参与了心力衰竭的发生发展.

  3. Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients.

    Directory of Open Access Journals (Sweden)

    Masaru Takeuchi

    Full Text Available Macrophages are involved in low-grade inflammation in diabetes, and play pathogenic roles in proliferative diabetic retinopathy (PDR by producing proinflammatory cytokines. T cells as well as other cells are also activated by proinflammatory cytokines, and infiltration into the vitreous of patients with PDR has been shown. In this study, we measured helper T (Th cell-related cytokines in the vitreous of PDR patients to define the characteristics of Th-mediated immune responses associated with PDR. The study group consisted of 25 type 2 diabetic patients (25 eyes with PDR. The control group consisted of 27 patients with epiretinal membrane (ERM, 26 patients with idiopathic macular hole (MH, and 26 patients with uveitis associated with sarcoidosis. Vitreous fluid was obtained at the beginning of vitrectomy, and centrifuging for cellular removals was not performed. Serum was also collected from PDR patients. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble sCD40L, and TNFα in the vitreous and serum samples were measured. Both percent detectable and levels of IL-4, IL-6, IL-17A, IL-21, IL-22, and TNFα in the vitreous were significantly higher than those in the serum in PDR patients. Vitreous levels of these cytokines and IL-31 were significantly higher in PDR than in ERM or MH patients. Vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα in PDR patients were also significantly higher than those of sarcoidosis patients. In PDR patients, vitreous IL-17A level correlated significantly with vitreous levels of IL-22 and IL-31, and especially with IL-4 and TNFα. Although it is unclear whether these cytokines play facilitative roles or inhibitory roles for the progression of PDR, the present study indicated that Th2- and Th17-related immune responses are involved in the pathogenesis of PDR.

  4. Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients.

    Science.gov (United States)

    Takeuchi, Masaru; Sato, Tomohito; Tanaka, Atsushi; Muraoka, Tadashi; Taguchi, Manzo; Sakurai, Yutaka; Karasawa, Yoko; Ito, Masataka

    2015-01-01

    Macrophages are involved in low-grade inflammation in diabetes, and play pathogenic roles in proliferative diabetic retinopathy (PDR) by producing proinflammatory cytokines. T cells as well as other cells are also activated by proinflammatory cytokines, and infiltration into the vitreous of patients with PDR has been shown. In this study, we measured helper T (Th) cell-related cytokines in the vitreous of PDR patients to define the characteristics of Th-mediated immune responses associated with PDR. The study group consisted of 25 type 2 diabetic patients (25 eyes) with PDR. The control group consisted of 27 patients with epiretinal membrane (ERM), 26 patients with idiopathic macular hole (MH), and 26 patients with uveitis associated with sarcoidosis. Vitreous fluid was obtained at the beginning of vitrectomy, and centrifuging for cellular removals was not performed. Serum was also collected from PDR patients. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble sCD40L, and TNFα in the vitreous and serum samples were measured. Both percent detectable and levels of IL-4, IL-6, IL-17A, IL-21, IL-22, and TNFα in the vitreous were significantly higher than those in the serum in PDR patients. Vitreous levels of these cytokines and IL-31 were significantly higher in PDR than in ERM or MH patients. Vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα in PDR patients were also significantly higher than those of sarcoidosis patients. In PDR patients, vitreous IL-17A level correlated significantly with vitreous levels of IL-22 and IL-31, and especially with IL-4 and TNFα. Although it is unclear whether these cytokines play facilitative roles or inhibitory roles for the progression of PDR, the present study indicated that Th2- and Th17-related immune responses are involved in the pathogenesis of PDR.

  5. Significance of Th17 cells detection in peripheral blood of patients with sepsis%脓毒血症患者外周血中Th17细胞检测及意义

    Institute of Scientific and Technical Information of China (English)

    亢翠翠; 吴铁军; 张保军

    2011-01-01

    目的 探讨脓毒症患者外周血Th17细胞和细胞因子IL-17、IL-6的表达水平及其对免疫功能的影响.方法 选取2010-04~2010-11住我院ICU病房的脓毒症患者62例,采用流式细胞术检测外周血Th17%(Th17/CD4+T),应用酶联免疫吸附方法(ELISA)检测血浆IL-17和IL-6的表达水平.同时选取来自我院查体中心的健康查体者30例作为对照组.结果 脓毒症患者外周血Th17%明显高于健康对照组(P<0.01);血浆IL-17、IL-6的表达亦显著高于对照组.患者血浆IL-17与IL-6表达水平呈正相关(r=0.886,P<0.01).Th17的表达与IL-17、IL-6的表达亦呈正相关(r1=0.846,r2=0.891,P均<0.01).结论 脓毒血症患者外周血中Th17%增加,血浆IL-17及IL-6表达水平亦升高,提示Th17参与脓毒血症的发病.%Objective To investigate the Th17 and its associated cytokines IL - 17 and IL -6 in patients with sepsis, and their impact on immune function. Methods Sixty - two patients admitted to ICU of our hospital in April 2010 to November 2010. The frequencies of Th17 in peripheral blood were detected by flow cytometric analysis. Th17 related plasma cytokines ( including IL - 17 and IL - 6 ) concentrations were measured by enzyme linked immuno - sorbent assay. Thirty healthy individuals came from the examination center of our hospital were served as controls. Results The frequencies of Th17 in peripheral blood was significant higher in septic patients than in normal controls ( P < 0. 01 ). Th17 related cytokines IL - 17and IL - 6 markedly increased in patients with sepsis compared with normal controls. Plasma concentration of IL - 17 was positively correlated with concentration of IL - 6 ( r = 0. 886,P < 0.01 ). Significant correlation was found between Th17 and IL - 17, IL - 6 ( r1 = 0. 846,r2 = 0. 891,both P < 0.01). Conclusion The frequencies of Th17 increase in patients with sepsis, and its related cytokines IL - 17 and IL - 6 also increase, which suggest Th17 may play a potential

  6. Distinctive Treg associated CCR4-CCL22 expression profile with altered frequency of Th17/Treg cell in the immunopathogenesis of Pemphigus Vulgaris.

    Science.gov (United States)

    Asothai, R; Anand, Vivek; Das, Dayasagar; Antil, Parul Singh; Khandpur, Sujay; Sharma, V K; Sharma, Alpana

    2015-10-01

    Pemphigus Vulgaris (PV), a relatively common autoimmune blistering disease in India, primarily mediated by anti-Desmoglein 3 (anti-Dsg3) autoantibodies. T-helper 17 (Th17) and T-regulatory (Treg) cells play significant role in regulating immune homeostasis in autoimmune disorders. To understand immunopathogenesis of PV, it is crucial to unfold the phenotypic expression and functional characteristics of these cells along with their specific homing chemokine receptor-ligand. This proposed study aims to unravel the functional expression of Th17 and Treg cells along with their specific homing chemokine receptor-ligand, transcription factors and cytokine levels to better understand the immunopathogenesis of PV. The Flow cytometry results showed decreased frequency of Treg cells and high number of Th17 cells (p<0.001) indicating immune dysregulation in PV. A significant increase (p<0.001) in the serum levels of Th17 associated molecules (IL-17A, CCL-20) and relative expression of RORγt, CCR6 and CCL20 was found in patients. For Treg cells, transcription factor FOXp3 was significantly lowered along with defective CCR4-CCL22 (p<0.05) that might be playing an ambiguous role in Treg generated immune regulation, leading to homing defect at lesional sites. This maiden study revealed the role of defective receptor-ligand interface that might have failed to suppress inflammatory milieu produced by Th17 cells thus promoting inflammation and contributing to immunopathogenesis of PV. This chemokine receptor-ligand can further be explored as potential target for development of novel therapies in PV.

  7. Changes of Th17 cytokine in human bronchial epithelial cells induced by coke oven emission%焦炉逸散物致支气管上皮细胞 Th17细胞因子改变

    Institute of Scientific and Technical Information of China (English)

    李红丽; 解秋艳; 刘秀玲; 牛勇; 戴宇飞; 郑玉新; 姚林; 段化伟

    2014-01-01

    OBJECTIVE To find the infla mmation bio markers induced by coke oven e missions (COE),we investigated the changes of T helper 17 (Th17 )cytokines in hu man bronchial epithelial (16HBE)cells.METHODS 16HBE cells were exposed to organic extracts of COE collected fro m co-king plant at the concentrations of 5,10 and 20 mg·L -1 for 24 h or 5 d to establish short-term and long-term cell models,respectively.Cell viability was measured by MTT assay and infla mmatory da mage was assessed by lactate dehydrogenase assay (LDH).The cytokines in culture supernatant sa mples was detected by co mmercial hu man Th17 cytokine panel kit.RESULTS COE Can induce infla mmation in COE 20 mg·L -1 group and no expression on IL-17 F and IL-1 β.The concentration of IL-10 was 1 .25 ± 0.54,1 .39 ±0.13 and (1 .90 ±0.73)pg·mL -1 in COE 5,10 and 20 mg·L -1 group showing good con-centration-effect relationship (r=0.98,P <0.05 ).IL-23 expression was found only higher at 10 and 20 mg·L -1 and the concentrations were 3.38 ±3.90 and (1 .74 ±2.00 )pg·mL -1 ,respectively.In 16HBE cells treated by COE for 5 d,elevated expression of IL-17A was found in COE 5 and 10 mg·L -1 group,and there was statistically sigificant difference between COE 10 mg·L -1 and DMSO group (P<0.05).Elevated concentration of IL-17F of 10.2 ±1 1 .78 and (6.79 ±7.84)pg·mL -1 was found in COE 5 and 10 mg·L -1 group.The concentration of IL-10 was 1 .71 ±0.02,1 .49 ±0.25 and (2.82 ± 0.33)pg·mL -1 in COE 5,10 and 20 mg·L -1 group,respectively.We found increased IL-1 βexpression with concentration of 2.72 ±0.62,2.25 ±0.33 and (0.93 ±0.21 )pg·mL -1 in COE 5,10 and 20 mg·L -1 group with negative dose-response relationship.We also found more elevated TNF-αlevels in the 5 d than in the 24 h model with no COE specific relationship.CONCLUSION COE induces expression changes of Th17 cytokines profile in 16HBE cells,including IL-23 and IL-1 βfor early and long-term infla mmation,respectively.IL-10 may be a candidate

  8. A New Recombinant BCG Vaccine Induces Specific Th17 and Th1 Effector Cells with Higher Protective Efficacy against Tuberculosis

    Science.gov (United States)

    da Costa, Adeliane Castro; Costa-Júnior, Abadio de Oliveira; de Oliveira, Fábio Muniz; Nogueira, Sarah Veloso; Rosa, Joseane Damaceno; Resende, Danilo Pires; Kipnis, André; Junqueira-Kipnis, Ana Paula

    2014-01-01

    Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that is a major public health problem. The vaccine used for TB prevention is Mycobacterium bovis bacillus Calmette-Guérin (BCG), which provides variable efficacy in protecting against pulmonary TB among adults. Consequently, several groups have pursued the development of a new vaccine with a superior protective capacity to that of BCG. Here we constructed a new recombinant BCG (rBCG) vaccine expressing a fusion protein (CMX) composed of immune dominant epitopes from Ag85C, MPT51, and HspX and evaluated its immunogenicity and protection in a murine model of infection. The stability of the vaccine in vivo was maintained for up to 20 days post-vaccination. rBCG-CMX was efficiently phagocytized by peritoneal macrophages and induced nitric oxide (NO) production. Following mouse immunization, this vaccine induced a specific immune response in cells from lungs and spleen to the fusion protein and to each of the component recombinant proteins by themselves. Vaccinated mice presented higher amounts of Th1, Th17, and polyfunctional specific T cells. rBCG-CMX vaccination reduced the extension of lung lesions caused by challenge with Mtb as well as the lung bacterial load. In addition, when this vaccine was used in a prime-boost strategy together with rCMX, the lung bacterial load was lower than the result observed by BCG vaccination. This study describes the creation of a new promising vaccine for TB that we hope will be used in further studies to address its safety before proceeding to clinical trials. PMID:25398087

  9. Distribution and significance of Th17/Th1 cells in the peripheral blood and tumor tissue from patients with cervical caner%宫颈癌患者外周血及肿瘤组织中Th17/Th1细胞分布及意义

    Institute of Scientific and Technical Information of China (English)

    付婷; 杨佩芳; 焦志军

    2011-01-01

    Objective : To explore the clistribution and significance of Th 17 and Th1 cells in peripheral blood mononuclear cells and tumor tissue from patients with cervical caner . Methods: The frequency of Th17 and Th1 cells in peripheral blood mononuclear and tumor tissue from patients with cervical cancer and health people was determined by intracelluar staining with flow cytometry . The correlation between Th17 and Th1 was assessed by using bivariate correlation analysis . Results : The expression levels of Th17 and in patients was higher than control groups ( P < 0. 01 ) , while Th1 levels was lower than controls ( P <0. 01 ) . There was a negative correlation between Th 17 and Th1 cells in tumor tissue from patients with cervical caner. Conclusion : There was an unbalance of Th17/Th1 cells in tumor tissue from cervical caner , which may be involved in the development of cervical cancer .%目的:探讨宫颈癌患者外周血、肿瘤局部组织中Th17、Th1细胞的分布特征及其在宫颈癌发病机制中的意义.方法:采用流式细胞术细胞内染色技术检测宫颈癌患者外周血、肿瘤组织标本和健康对照组外周血及子宫组织中Th17、Th1细胞;采用直线相关检验方法对Th17、Th1细胞进行相关性分析.结果:宫颈癌患者外周血、肿瘤组织中Th17细胞显著高于健康对照组(P<0.01),外周血中Th1细胞显著低于健康对照组(P<0.01),肿瘤组织中Th17、Th1细胞比例呈负相关.结论:宫颈癌患者局部肿瘤组织中存在Th17/ Th1细胞失衡现象,这种失衡可能是宫颈癌发生发展的机制之一.

  10. The Th17/Treg ratio, IL-1RA and sCD14 levels in primary HIV infection predict the T-cell activation set point in the absence of systemic microbial translocation.

    Directory of Open Access Journals (Sweden)

    Mathieu F Chevalier

    Full Text Available Impairment of the intestinal barrier and subsequent microbial translocation (MT may be involved in chronic immune activation, which plays a central role in HIV pathogenesis. Th17 cells are critical to prevent MT. The aim of the study was to investigate, in patients with primary HIV infection (PHI, the early relationship between the Th17/Treg ratio, monocyte activation and MT and their impact on the T-cell activation set point, which is known to predict disease progression. 27 patients with early PHI were included in a prospective longitudinal study and followed-up for 6 months. At baseline, the Th17/Treg ratio strongly negatively correlated with the proportion of activated CD8 T cells expressing CD38/HLA-DR or Ki-67. Also, the Th17/Treg ratio was negatively related to viral load and plasma levels of sCD14 and IL-1RA, two markers of monocyte activation. In untreated patients, the Th17/Treg ratio at baseline negatively correlated with CD8 T-cell activation at month 6 defining the T-cell activation set point (% HLA-DR(+CD38(+ and %Ki-67(+. Soluble CD14 and IL-1RA plasma levels also predicted the T-cell activation set point. Levels of I-FABP, a marker of mucosal damages, were similar to healthy controls at baseline but increased at month 6. No decrease in anti-endotoxin core antibody (EndoCAb and no peptidoglycan were detected during PHI. In addition, 16S rDNA was only detected at low levels in 2 out 27 patients at baseline and in one additional patient at M6. Altogether, data support the hypothesis that T-cell and monocyte activation in PHI are not primarily driven by systemic MT but rather by viral replication. Moreover, the "innate immune set point" defined by the early levels of sCD14 and IL-1RA might be powerful early surrogate markers for disease progression and should be considered for use in clinical practice.

  11. Prostaglandin E2 and IL-23 plus IL-1β differentially regulate the Th1/Th17 immune response of human CD161(+) CD4(+) memory T cells.

    Science.gov (United States)

    Barrie, Arthur; Khare, Anupriya; Henkel, Matthew; Zhang, Yingze; Barmada, M Michael; Duerr, Richard; Ray, Anuradha

    2011-08-01

    Prostaglandin E2 (PGE2), interleukin (IL)-23, and IL-1beta (β) propagate inflammatory bowel disease (IBD) by enhancing the development and function of IL-17 producing CD4(+) T helper (Th17) cells. CD4(+) T cells that express the C-type lectin-like receptor CD161 have been proposed to be the physiologic pool of circulating Th17 cells implicated in IBD. We sought to understand how PGE2, alone and in combination with IL-23 and IL-1β, modulate human peripheral CD161(+) CD4(+) memory T cells. We found that CD161(+) cells comprise a significant proportion of human peripheral CD4(+) memory T cells. PGE2 and IL-23 plus IL-1β synergistically induced early IL-17A secretion from CD161(+) CD4(+) memory T cells and the selective enrichment of IL-17A(+) CD161(+) CD4(+) memory T cells in culture. Conversely, IL-23 plus IL-1β partially opposed the PGE2-mediated repression of early interferon gamma (IFN-γ) secretion from CD161(+) cells, as well as the PGE2-mediated depletion of IFN-γ(+) CD161(+) cells. Our results suggest that PGE2 and IL-23 plus IL-1β induce the Th17 immune response preferentially in CD161(+) CD4(+) memory T cells, while divergently regulating their ability to express IFN-γ. We hypothesize that Th17-mediated chronic inflammation in IBD depends on the net response of CD161(+) CD4(+) memory T cells to both PGE2 and IL-23 plus IL-1β. © 2011 Wiley Periodicals, Inc.

  12. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of aβ1-42-induced Alzheimer's disease model rats.

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    Full Text Available Neuroinflammation, especially innate immunocyte-mediated neuroinflammation, has been reported to participate in pathogenesis of Alzheimer's disease (AD. However, the involvement of adaptive immune cells, such as CD4(+ T lymphocytes, in pathogenesis of AD is not well clarified. Herein, we focus on T helper 17 (Th17 cells, a subpopulation of CD4(+ T cells with high proinflammation, and show the implication of the cells in neurodegeneration of AD. Amyloid β1-42 (Aβ1-42 was bilaterally injected into hippocampus of rats to induce AD. On days 7 and 14 following the Aβ1-42 administration, escape latency of the rats in Morris water maze was increased, expression of amyloid precursor protein was upregulated, but expression of protein phosphatase 2A was downregulated in the hippocampus, and Nissl stain showed neuronal loss and gliosis in CA1 region. Infusion of FITC-linked albumin in blood circulation and combination with immunostaining of hippocampal sections for RORγ, a specific transcriptional factor of Th17 cells, demonstrated blood-brain barrier (BBB disruption and Th17 cells' infiltration into brain parenchyma of AD rats. Expression of Th17 proinflammatory cytokines, interleukin (IL-17 and IL-22, was increased in the hippocampus, and concentrations of the two cytokines were elevated in both the cerebrospinal fluid and the serum in AD occurrence and development. Compared with intact or saline-treated control rats, AD animals indicated an upregulated expression of Fas and FasL in the hippocampus. Further, the immunofluorescent histochemistry on AD hippocampal sections with NeuN, RORγ, Fas and FasL displayed that Fas was principally expressed by neurons and FasL was predominantly expressed by Th17 cells, and that neuronal apoptosis shown by TUNEL and NeuN double-labeled cells increased. These results suggest that Th17 cells, which were infiltrated into AD brain parenchyma, participate in neuroinflammation and neurodegeneration of AD by release of

  13. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of aβ1-42-induced Alzheimer's disease model rats.

    Science.gov (United States)

    Zhang, Jun; Ke, Kai-Fu; Liu, Zhan; Qiu, Yi-Hua; Peng, Yu-Ping

    2013-01-01

    Neuroinflammation, especially innate immunocyte-mediated neuroinflammation, has been reported to participate in pathogenesis of Alzheimer's disease (AD). However, the involvement of adaptive immune cells, such as CD4(+) T lymphocytes, in pathogenesis of AD is not well clarified. Herein, we focus on T helper 17 (Th17) cells, a subpopulation of CD4(+) T cells with high proinflammation, and show the implication of the cells in neurodegeneration of AD. Amyloid β1-42 (Aβ1-42) was bilaterally injected into hippocampus of rats to induce AD. On days 7 and 14 following the Aβ1-42 administration, escape latency of the rats in Morris water maze was increased, expression of amyloid precursor protein was upregulated, but expression of protein phosphatase 2A was downregulated in the hippocampus, and Nissl stain showed neuronal loss and gliosis in CA1 region. Infusion of FITC-linked albumin in blood circulation and combination with immunostaining of hippocampal sections for RORγ, a specific transcriptional factor of Th17 cells, demonstrated blood-brain barrier (BBB) disruption and Th17 cells' infiltration into brain parenchyma of AD rats. Expression of Th17 proinflammatory cytokines, interleukin (IL)-17 and IL-22, was increased in the hippocampus, and concentrations of the two cytokines were elevated in both the cerebrospinal fluid and the serum in AD occurrence and development. Compared with intact or saline-treated control rats, AD animals indicated an upregulated expression of Fas and FasL in the hippocampus. Further, the immunofluorescent histochemistry on AD hippocampal sections with NeuN, RORγ, Fas and FasL displayed that Fas was principally expressed by neurons and FasL was predominantly expressed by Th17 cells, and that neuronal apoptosis shown by TUNEL and NeuN double-labeled cells increased. These results suggest that Th17 cells, which were infiltrated into AD brain parenchyma, participate in neuroinflammation and neurodegeneration of AD by release of

  14. Bee Venom Acupuncture Alleviates Experimental Autoimmune Encephalomyelitis by Upregulating Regulatory T Cells and Suppressing Th1 and Th17 Responses.

    Science.gov (United States)

    Lee, Min Jung; Jang, Minhee; Choi, Jonghee; Lee, Gihyun; Min, Hyun Jung; Chung, Won-Seok; Kim, Jong-In; Jee, Youngheun; Chae, Younbyoung; Kim, Sung-Hoon; Lee, Sung Joong; Cho, Ik-Hyun

    2016-04-01

    suppressing T-helper (Th) 17 and Th1 responses. These results warrant further investigation of BVA as a treatment for autoimmune disorders of the central nervous system.

  15. Th17 cells and its role in bronchial asthma%Th17细胞及其在支气管哮喘发病中的作用

    Institute of Scientific and Technical Information of China (English)

    杨志明; 成俊芬

    2012-01-01

    Th17细胞是一类新型的CD4+T细胞,STAT3、RORγt和RORα等参与了其分化调控.最近,大量研究表明,Th17及其相关的细胞因子在支气管哮喘中起着重要的作用,参与了气道炎症、气道重塑以及气道高反应性.

  16. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells.

    Science.gov (United States)

    Niedbala, Wanda; Wei, Xiao-Qing; Cai, Beilei; Hueber, Axel J; Leung, Bernard P; McInnes, Iain B; Liew, Foo Y

    2007-11-01

    Epstein-Barr virus-induced gene 3 (EBI3) and the p35 subunit of IL-12 have been reported to form a heterodimeric hematopoietin in human and mouse. We have constructed a heterodimeric protein covalently linking EBI3 and p35, to form a novel cytokine which we now call IL-35. The Fc fusion protein of IL-35 induced proliferation of murine CD4(+)CD25(+) and CD4(+)CD25(-) T cells when stimulated with immobilized anti-CD3 and anti-CD28 antibodies in vitro. The IL-35-expanded CD4(+)CD25(+) T cell population expressed Foxp3 and produced elevated levels of IL-10, whereas the IL-35-induced CD4(+)CD25(-) T cells produced IFN-gamma but not IL-4. The in vitro expanded CD4(+)CD25(+) T cells retained their suppressive functions against CD4(+)CD25(-) effector cells. Furthermore, when cultured with soluble anti-CD3 antibody and antigen-presenting cells, IL-35 suppressed the proliferation of CD4(+)CD25(-) effector cells. Moreover, IL-35 inhibited the differentiation of Th17 cells in vitro. In vivo, IL-35 effectively attenuated established collagen-induced arthritis in mice, with concomitant suppression of IL-17 production but enhanced IFN-gamma synthesis. Thus, IL-35 is a novel anti-inflammatory cytokine suppressing the immune response through the expansion of regulatory T cells and suppression of Th17 cell development.

  17. Increased Expression and Clinical Significance of Th22 Cells and Th17 Cells in the Peripheral Blood of Patients with Ankylosing Spondylitis and Rheumatoid Arthritis%强直性脊椎炎和类风湿性关节炎患者外周血中Th22和Th17细胞含量上升及临床意义

    Institute of Scientific and Technical Information of China (English)

    郭勇; 朱海波

    2014-01-01

    目的:研究强直性脊椎炎(AS)和类风湿性关节炎(RA)患者外周血中Th1细胞、Th17细胞和Th22细胞的表达,为进一步探讨AS和RA的发病机制提供新的理论依据。方法采用流式细胞术测定38例AS患者、40例RA患者及30名健康体检者外周血中Th1细胞、Th17细胞及Th22细胞的含量。结果AS患者Th17和Th22细胞的含量分别为(3.78±1.93)%、(1.63±0.53)%,RA患者Th17和Th22的含量分别为(3.66±1.84)%、(1.58±0.65)%。结果显示,与健康对照相比, AS和RA患者的Th17和Th22细胞的含量差异都有统计学意义(P<0.05)。结论AS和RA患者外周血中Th22细胞和Th17细胞含量上升,提示Th22细胞和Th17细胞与AS和RA的发病机制有关。%Objective To investigate the expression of Th1 cells, Th17 cells and Th22 cells in peripheral blood from patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA), and provide the reference for the further research of AS and RA pathological mechanism. Methods A total of 38 AS, 40 RA and 30 healthy subjects were enrolled in the research. The expression percentages of Th1, Th22 and Th17 cells were determined by flow cytometry. Results The expression of Th17 and Th22 cells in AS patients were (3.78±1.93)%, (1.63±0.53)%respectively, while in RA patients, they were (3.66±1.84)%and (1.58±0.65)%, respectively. The results showed that the expressions of Th17 and Th22 cells in AS patients were significantly higher than those of healthy controls (P<0.05), as well as RA patients. Conclusion The expression of Th17 and Th22 cells were increased in peripheral blood from patients with AS and patients with RA. These findings suggest that Th17 cells and Th22 cells may be implicated in the pathogenesis of AS and RA.

  18. Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes TH17 cell differentiation.

    Science.gov (United States)

    Keles, Sevgi; Charbonnier, Louis Marie; Kabaleeswaran, Venkataraman; Reisli, Ismail; Genel, Ferah; Gulez, Nesrin; Al-Herz, Waleed; Ramesh, Narayanaswamy; Perez-Atayde, Antonio; Karaca, Neslihan E; Kutukculer, Necil; Wu, Hao; Geha, Raif S; Chatila, Talal A

    2016-11-01

    The autosomal recessive hyper-IgE syndrome (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency shares clinical features with autosomal dominant HIES because of signal transducer and activator of transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, which are suggestive of TH17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear. We sought to elucidate common mechanisms operating in the different forms of HIES. We analyzed the differentiation of CD4(+) TH cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. TH cell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and TH cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by using flow cytometry, immunofluorescence, coimmunoprecipitation, and gene expression analysis. There was a profound block in the differentiation of DOCK8-deficient naive CD4(+) T cells into TH17 cells. A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired TH17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity-dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression. DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  19. Roles of Treg/Th17 Cell Imbalance and Neuronal Damage in the Visual Dysfunction Observed in Experimental Autoimmune Optic Neuritis Chronologically.

    Science.gov (United States)

    Liu, Yuanyuan; You, Caiyun; Zhang, Zhuhong; Zhang, Jingkai; Yan, Hua

    2015-12-01

    Optic neuritis associated with multiple sclerosis and its animal model, experimental autoimmune optic neuritis (EAON), is characterized by inflammation, T cell activation, demyelination, and neuronal damage, which might induce permanent vision loss. Elucidating the chronological relationship among the features is critical for treatment of demyelinating optic neuritis. EAON was induced in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein subcutaneously, and visual function was assessed by flash-visual evoked potential (F-VEP) at days 7, 11, 14, 19, 23, 28 post-immunization. Retinal ganglion cell (RGC) apoptosis was measured by terminal-deoxynucleotidyl transferase-mediated nick-end labeling. Demyelination and axonal damage were verified with myelin basic protein (MBP) and β-amyloid precursor protein staining, respectively. Real-time polymerase chain reaction quantified IL-17, IL-1β, TGF-β, FoxP3, IL-6, and IL-10 mRNA expression in the optic nerve, as well as FoxP3 and IL-17 staining. Systemic changes of Th17 and Treg cells were tested by flow cytometry in spleen. F-VEP latency was prolonged at 11 days and peaked at 23 days commensurate with demyelination. However, F-VEP amplitude was reduced at 11 days, preceding axon damage, and was exacerbated at 23 days when a peak in RGC apoptosis was detected. Th17 cells up-regulated as early as 7 days and peaked at 11 days, while Treg cells down-regulated inversely compared to Th17 cells change as verified by IL-17 and FoxP3 expression; spleen cell samples were slightly different, demonstrating marked changed at 14 days. Treg/Th17 cell imbalance in the optic nerve precedes and may initiate neuronal damage of axons and RGCs. These changes are commensurate with the appearances of visual dysfunction reflected in F-VEP and hence may offer a novel therapeutic avenue for vision preservation.

  20. Expressions of the Th17 cells related cytokines in psoriasis vulgaris%寻常性银屑病患者外周血Th17细胞相关因子的表达

    Institute of Scientific and Technical Information of China (English)

    刘栋; 廖非; 李雅琳; 乔树芳; 徐丽敏; 焦振山

    2012-01-01

    目的:探讨Th17细胞相关因子白介素(IL)-23、IL-17A、IL-17F、IL-22与银屑病的关系与意义.方法:30例寻常性银屑病患者分为进行期15例,稳定期15例;30例正常人作为对照,取外周血,采用双抗体夹心ELISA法检测血浆IL-23的含量,实时荧光定量逆转录聚合酶链反应(FQ-RT-PCR)技术检测外周血中外周血单个核细胞(PBMC)IL-17A mRNA、IL-17FmRNA、IL-22 mRNA的相对表达量.结果:进行期银屑病患者血浆IL-23浓度、PBMC IL-17A mRNA、IL-17F mRNA、IL-22mRNA的表达均明显高于正常对照组,进行期患者PBMC IL-17A mRNA、IL-22 mRNA的表达高于静止期患者,而稳定期患者上述指标的表达与正常对照无统计学差异.结论:Th17细胞可能参与进行期寻常性银屑病病理过程.%Objectives: To detect the expressions of Thl7 cells related cytokines including IL-17A, IL-17F, IL-22 and IL-23 in peripheral blood of patients with psoriasis vulgaris, and further illustrate the pathogenesis of psoriasis vulgaris. Methods: Peripheral blood was obtained from 15 patients with stable psoriasis vulgaris, 15 patients with progressive psoriasis vulgaris and 30 healthy controls. The level of IL-23 in plasma was determined by ELISA, and the mRNA expression of IL-17A, IL-17F and IL-22 in peripheral blood mononuclear cell (PBMC) detected by FQ-RT-PCR (real time fluorescent quantitative-reverse transcriptase-polymerase chain reaction). Results: The level of IL-23 in progressive psoriasis was significantly higher than that of healthy control (P = 0.002), but this different was not found between the stable psoriasis patients and healthy control (P = 0.169). The levels of IL-17A mRNA, IL-17F mRNA and IL-22 mRNA in progressive psoriasis were significantly higher than those of healthy control (P= 0.007; P= 0.015; P= 0.002). The levels of IL-17A mRNA and IL-22 mRNA in progressive psoriasis were significantly higher than that in stable psoriasis other than IL-17FmRNA. Conclusions: Thl7