Smad2 positively regulates the generation of Th17 cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Martinez GJ
PROVIDER: S-EPMC2937933 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:TGFβ is the quintessential cytokine of T cell homeostasis. TGFβ signaling is required for the efficient differentiation and maintenance of CD4(+)FOXP3(+) T cells that inhibit immune responses. Conversely, in conjunction with the inflammatory cytokine IL-6, TGFβ promotes Th17 cell differentiation. The mechanism by which TGFβ signals synergize with IL-6 to generate inflammatory versus immunosuppressive T cell subsets is unclear. TGFβ signaling activates receptor SMADs, SMAD2 and SMAD3, which associate with a variety of nuclear factors to regulate gene transcription. Defining relative contributions of distinct SMAD molecules for CD4 T cell differentiation is critical for mapping the versatile intracellular TGFβ-signaling pathways that tailor TGFβ activities to the state of host interaction with pathogens. We show here that SMAD2 is essential for Th17 cell differentiation and that it acts in part by modulating the expression of IL-6R on T cells. Although mice lacking SMAD2 specifically in T cells do not develop spontaneous lymphoproliferative autoimmunity, Smad2-deficient T cells are impaired in their response to TGFβ in vitro and in vivo, and they are more pathogenic than controls when transferred into lymphopenic mice. These results demonstrate that SMAD2 is uniquely essential for TGFβ signaling in CD4(+) T effector cell differentiation.
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Project description:STAT3 is a transcription factor that plays central roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. The mechanisms related to how STAT3 activity is regulated remain enigmatic. Here we show that overexpression of FAM64A potentiates IL-6-induced activation of STAT3 and expression of downstream target genes, whereas deficiency of FAM64A has the opposite effects. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Deficiency of Fam64a significantly impairs differentiation of Th17 but not Th1 or induced regulatory T cells (iTreg). In addition, Fam64a deficiency attenuates experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, which is correlated with decreased differentiation of Th17 cells and production of proinflammatory cytokines. Furthermore, Fam64a deficiency suppresses azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice. These findings suggest that FAM64A regulates Th17 differentiation and colitis and inflammation-associated cancer by modulating transcriptional activity of STAT3.
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Project description:Th17 cells, a recently discovered inflammatory T cell subtype, have been implicated with autoimmune disorders. However, mechanism of generation or functions of intratumoral Th17 cells are still unclear. We have been investigating the mechanism of induction and role of Th17 cells in malignant gliomas using primary tumor as well as cell lines. We report here that: (1) a higher frequency of Th17 cells in gliomas were associated with higher number of myeloid (CD11b) cells as well as the expression of TGF-?1 or IL-6; (2) conditioned medium from glioma cells (Gl CM) induced Th17 cell differentiation, which was inhibited by anti-TGF-?1 and anti-IL-6; (3) glioma-associated monocytes secreted Th17-promoting cytokines IL-1? and IL-23; (4) CM from glioma and monocyte co-culture (Gl+Mo CM) induced high frequency of Th17 cells in naïve T cell culture, which was abrogated by anti-IL-1? and anti-IL-23 antibodies; (5) In vitro Gl+Mo CM-mediated Th17 generation was associated with a decrease in IFN-? and a concomitant increase in IL-10 secretion. Anti-TGF-?1, but not anti-IL-6, significantly reversed this cytokine profile. These results demonstrate prevalence of Th17 cells in gliomas and implicate the cytokines derived from the tumor as well as infiltrating myeloid cells in the induction of Th17 cells in glioma microenvironment. Moreover, the data also suggest that glioma-associated Th17 cells may contribute to immune-suppression via TGF-?1-induced IL-10 secretion. Further studies on the mechanism of tumor-infiltration, developmental pathways, and pro-/anti-tumor functions of Th17 cells will provide rationale for developing novel adjuvant immunotherapeutic strategies for malignant gliomas.
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Project description:Aucuboside is an iridoid glycoside extracted from traditional Chinese medicine such as Rehmannia glutinosa, possessing a wide range of biological activities, including antioxidant, anti-aging, anti-inflammatory, and anti-fibrotic effects. The effects of aucuboside on inflammatory bowel disease (IBD) have not been studied. Therefore, the effects of aucuboside on the generation of Foxp3+ regulatory T (Treg) cells and IL-17-producing T helper (Th17) cells in colitis were studied. A mouse colitis model was established by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to mimic human IBD. The generation of Treg and Th17 cells was evaluated by flow cytometry. Aucuboside significantly alleviated colitis symptoms, including weight loss, high disease activity index, and inflammatory responses. The generation of Th17 cells in colitis was significantly inhibited by aucuboside and accompanied by the suppression of IL-17 expression. In Raw264.7 cells, the LPS-induced increase in IL-17 expression was also suppressed by aucuboside, which was significantly blocked by the RORγt inhibitor sr2211. In addition, the decrease in the proportion of Treg cells was also partially reversed by aucuboside, which may reflect the aucuboside-induced inhibition of Th17 cells. This previously unrecognized immunoregulatory function of aucuboside may have clinical applications in IBD.
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Project description:Mucosal barriers are densely colonized by pathobiont microbes such as Candida albicans, capable of invasive disseminated infection. However, systemic infections occur infrequently in healthy individuals, suggesting that pathobiont commensalism may elicit host benefits. We show that intestinal colonization with C. albicans drives systemic expansion of fungal-specific Th17 CD4+ T cells and IL-17 responsiveness by circulating neutrophils, which synergistically protect against C. albicans invasive infection. Protection conferred by commensal C. albicans requires persistent fungal colonization and extends to other extracellular invasive pathogens such as Staphylococcus aureus. However, commensal C. albicans does not protect against intracellular influenza virus infection and exacerbates allergic airway inflammation susceptibility, indicating that positively calibrating systemic Th17 responses is not uniformly beneficial. Thus, systemic Th17 inflammation driven by CD4+ T cells responsive to tonic stimulation by commensal C. albicans improves host defense against extracellular pathogens, but with potentially harmful immunological consequences.
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Project description:T cell activation and effector function is characterized by changes in metabolism. Altered metabolism is common to almost all types of activated T cells, but fatty acid synthesis seems to especially drive the formation of Th17 cells. Indeed, research has demonstrated that inhibition of early fatty acid synthesis through targeting of acetyl-CoA carboxylase (ACC1) can inhibit Th17 cell formation and instead promote the generation of regulatory T cells. Fatty acid synthase (FASN) is downstream of ACC, and previous studies have shown that FASN activity influences both cancer and inflammation. However, it remains to be determined whether FASN is a viable target for inhibiting Th17 cell function. Here, we demonstrate that FASN is a critical metabolic control for the generation of inflammatory subsets of Th17 cells. Conversely, inhibiting FASN function promotes IFN-? production by Th1 and Th1-like Th17 cells. In vivo, inhibition of FASN, specifically in Th17 cells, leads to reduction of experimental autoimmune encephalomyelitis disease. These studies demonstrate the necessity of FASN in the autoimmune inflammatory function of Th17 cells.
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Project description:Glutaminolysis is a well-known source of energy for effector T cells but its contribution to each T cell subset and the mechanisms which are responsible for the control of involved metabolic enzymes are not fully understood. We report that Th17 but not Th1, Th2, or Treg cell induction in vitro depends on glutaminolysis and the up-regulation of glutaminase 1 (Gls1), the first enzyme in the glutaminolysis pathway. Both pharmacological and siRNA-based selective inhibition of Gls1 reduced in vitro Th17 differentiation and reduced the CD3/TCR-mediated increase of the mammalian target of rapamycin complex 1 activity. Treatment of mice with a Gls1 inhibitor ameliorated experimental autoimmune encephalomyelitis. Furthermore, RAG1-deficient mice that received Gls1-shRNA-transfected 2D2 T cells had reduced experimental autoimmune encephalomyelitis scores compared with those that received control-shRNA-treated cells. Next we found that T cells deficient in inducible cAMP early repressor (ICER), a transcriptional factor known to promote Th17 differentiation, display reduced activity of oxidative phosphorylation rates in the presence of glutamine and reduced Gls1 expression, both of which could be restored by ICER overexpression. Finally, we demonstrate that ICER binds to the gls1 promoter directly and increases its activity. These findings demonstrate the importance of glutaminolysis in the generation of Th17 and the direct control of Gls1 activity by the IL-17-promoting transcription factor ICER. Pharmaceutical modulation of the glutaminolysis pathway should be considered to control Th17-mediated pathology.
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Project description:ObjectiveThe T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti-IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study.Research design and methods and resultsAlthough treatment with either anti-IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti-IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti-IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti-IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell-mediated dominant protective effect against autoimmunity.ConclusionsThese studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease.
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