Function Of Th17 Cells Research Articles

The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus.

We aimed at investigating whether the frequency and function of T helper 17 (Th17) and regulatory T cells (Treg) are affected by a restriction of dietary sodium intake in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We enrolled RA and SLE patients not receiving drugs known to increase urinary sodium excretion. Patients underwent a dietary regimen starting with a restricted daily sodium intake followed by a normal-sodium daily intake. The timepoints were identified at baseline (T0), after 3 weeks of low-sodium dietary regimen (T3), after 2 weeks of normal-sodium dietary regimen (T5). On these visits, we measured the 24-hour urinary sodium excretion, the frequency and function of Th17 and Treg cells in the peripheral blood, the serum levels of cytokines. Analysis of urinary sodium excretion confirmed adherence to the dietary regimen. In RA patients, a trend toward a reduction in the frequencies of Th17 cells over the low-sodium dietary regimen followed by an increase at T5 was observed, while Treg cells exhibited the opposite trend. SLE patients showed a progressive reduction in the percentage of Th17 cells that reached a significance at T5 compared to T0 (p = 0.01) and an increase in the percentage of Treg cells following the low-sodium dietary regimen at both T1 and T3 compared to T0 (p = 0.04 and p = 0.02, respectively). No significant apoptosis or proliferation modulation was found. In RA patients, we found a reduction at T5 compared to T0 in serum levels of both TGFβ (p = 0.0016) and IL-9 (p = 0.0007); serum IL-9 levels were also reduced in SLE patients at T5 with respect to T0 (p = 0.03). This is the first study investigating the effects of dietary sodium intake on adaptive immunity. Based on the results, we hypothesize that a restricted sodium dietary intake may dampen the inflammatory response in RA and SLE patients.

Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer

Interleukin-17 (IL-17), a pleiotropic proinflammatory cytokine, is reported to be significantly generated by a distinct subset of CD4+ T-cells, upgrading cancer-elicited inflammation and preventing cancer cells from immune surveillance. T-helper (Th)17 cells produced from naive CD4+ T cells have recently been renowned and generally accepted, gaining eminence in cancer studies and playing the effective role in context of cancer. Th17 cells are the main source of IL-17-secreting cells, It was found that other cell types produced this cytokine as well, including Group 3 innate lymphoid cells (ILC3), δγT cells, invariant natural killer T (iNKT) cells, lymphoid-tissue inducer (LTi)-like cells and Natural killer (NK) cells. Th17-associated cytokines give impetus to tumor progression, or inducing angiogenesis and metastasis. This review demonstrates an understanding on how the pro- or antitumor function of Th17 cells and IL-17 may change cancer progression, leading to the appearance of complex and pivotal biologic activities in tumor.

T helper type 17 cells in immune-mediated glomerular disease.

CD4+ T cells are important drivers of tissue damage in immune-mediated renal diseases, such as anti-glomerular basement membrane glomerulonephritis, anti-neutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis. The discovery of a distinct, IL-17-producing CD4+ T-cell lineage termed T helper type 17 (TH17) cells has markedly advanced current understanding of the pathogenic mechanisms of organ-specific immunity and the pathways that lead to target organ damage. TH17 cells are characterized by the expression of the transcription factor RORγt, the production of the pro-inflammatory cytokines IL-17A, IL-17F, IL-22, and high expression of the chemokine receptor C-C-motif chemokine receptor 6 (CCR6). An emerging body of evidence from experimental models and human studies supports a key role for these cells in the development of renal damage, and has led to the identification of targets to inhibit the production of TH17 cells in the intestine, their migration, or their actions within the kidney. Here, we describe the identification, regulation, and function of TH17 cells and their associated pathways in immune-mediated kidney diseases, with a particular focus on the mechanisms underlying renal tissue injury. We also discuss the rationale for the translation of these findings into new therapeutic approaches in patients with autoimmune kidney disease.

Ubiquitin specific peptidase 4 stabilizes interferon regulatory factor protein and promotes its function to facilitate interleukin-4 expression in T helper type 2 cells.

We speculated that ubiquitin specific peptidase 4 (USP4) may deubiquitinate interferon regulatory factor 4 (IRF4) and affect T helper type 2 (Th2) cell function. This study aimed to validate this hypothesis. Here, the interaction between USP4 and IRF4 were analyzed by co-immunoprecipitation assay. The deubiquitin effect of USP4 on IRF4 was analyzed by the Ni-NTA pull down assay. Luciferase reporter gene constructs were used to analyze the effects of USP4, IRF4 and nuclear factor of activated T cell-2 (NFATc2) on the activation of the interleukin-4 (IL-4) promoter. Then, the Th2 cells were infected with sh-USP4 to analyze the effects of USP4 on the expression levels of IRF4 and Th2-related cytokines. Western blotting and RT-qPCR were used to detect the protein and mRNA expression levels, respectively. To determine the levels of IL-4 and IRF4 in rheumatic heart disease (RHD) patients, peripheral blood mononuclear cells (PBMCs) were separated by density gradient centrifugation from RHD patients and healthy controls, and flow cytometric analysis was performed. Our results validated the interaction between USP4 and IRF4, and effects of USP4 on stabilization and deubiquitination of IRF4 were also found. Importantly, USP4 and IRF4 synergized with NFATc2 to specifically enhance NFAT-mediated activation of the IL-4 promoter. USP4 knockdown not only decreased the expression level of IRF4, but also affected the expression level of Th2-related cytokines. Finally, the increased level of IL-4 and IRF4 in PBMCs of RHD patients were observed. On the whole, our data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of RHD.

Activated hepatic stellate cells directly induce pathogenic Th17 cells in chronic hepatitis B virus infection

Th17 cells are involved in liver fibrosis by activating hepatic stellate cells (HSCs). We aimed to investigate whether HSCs are able to regulate the function of Th17 cells and to determine the relevant mechanism. Sixty-five patients diagnosed with chronic hepatitis B (CHB) were enrolled in this study. To determine the effect of HSCs on T cells, naïve CD4+T cells and Th17 cells were sorted from CHB patients and cultured with or without activated-HSCs, and cytokine expression and gene transcription were analyzed. In addition, the regulatory mechanism of HSCs was investigated. ELISA and qRT-PCR showed that Th17 cells from CHB patients were more pathogenic, on the basis of the expression of IL-17A, IL-23R, RORC, CCL20 and CCR6, and meanwhile, they could activate the primary HSCs. Co-culture experiments indicated that activated HSCs dramatically promoted proliferation of CD4+T cells in a time- and dose-dependent manner. In addition, they could induce naïve CD4+T cells to become Th17 cells which had a more pathogenic phenotype. Moreover, activated HSCs-mediated induction of Th17 cells might depend on the release of IL-1β and IL-6 as well as on the COX-PGE2 pathway. Th17 cells cooperated with HSCs in a proinflammatory feedback loop might provide a better understanding of the pathogenic role of Th17 cells in the chronicity of HBV infection.

TLR7 Signaling Regulates Th17 Cells and Autoimmunity: Novel Potential for Autoimmune Therapy.

Innate regulation through TLR signaling has been shown to be important for promoting T cell subset development and function. However, limited information is known about whether differential TLR signaling can selectively inhibit Th17 and/or Th1 cells, which are important for controlling excessive inflammation and autoimmune responses. In this article, we demonstrate that activation of TLR7 signaling in T cells can inhibit Th17 cell differentiation from naive T cells and IL-17 production in established Th17 cells. We further report that downregulation of STAT3 signaling is responsible for TLR7-mediated inhibition of Th17 cells due to induction of suppressor of cytokine signaling 3 and 5. TLR7-mediated suppression of Th17 cells does not require dendritic cell involvement. In addition, we show that TLR7 signaling can suppress Th1 cell development and function through a mechanism different from Th17 cell suppression. Importantly, our complementary in vivo studies demonstrate that treatment with the TLR7 ligand imiquimod can inhibit Th1 and Th17 cells, resulting in the prevention of, and an immunotherapeutic reduction in, experimental autoimmune encephalomyelitis. These studies identify a new strategy to manipulate Th17/Th1 cells through TLR7 signaling, with important implications for successful immunotherapy against autoimmune and inflammatory diseases.

Menin Controls the Memory Th2 Cell Function by Maintaining the Epigenetic Integrity of Th2 Cells

Posttranslational modifications of histones are well-established epigenetic modifications that play an important role in gene expression and regulation. These modifications are partly mediated by the Trithorax group (TrxG) complex, which regulates the induction or maintenance of gene transcription. We investigated the role of Menin, a component of the TrxG complex, in the acquisition and maintenance of Th2 cell identity using T cell-specific Menin-deficient mice. Our gene expression analysis revealed that Menin was involved in the maintenance of the high expression of the previously identified Th2-specific genes rather than the induction of these genes. This result suggests that Menin plays a role in the maintenance of Th2 cell identity. Menin directly bound to the Gata3 gene locus, and this Menin-Gata3 axis appeared to form a core unit of the Th2-specific gene regulatory network. Consistent with the phenotype of Menin-deficient Th2 cells observed in vitro, Menin deficiency resulted in the attenuation of effector Th2 cell-induced airway inflammation. In addition, in memory Th2 (mTh2) cells, Menin was found to play an important role in the maintenance of the expression of Th2-specific genes, including Gata3, Il4, and Il13 Consequently, Menin-deficient mTh2 cells showed an impaired ability to recruit eosinophils to the lung, resulting in the attenuation of mTh2 cell-induced airway inflammation. This study confirmed the critical role of Menin in Th2 cell-mediated immune responses.

ILC2s regulate adaptive Th2 cell functions via PD-L1 checkpoint control.

Group 2 innate lymphoid cells (ILC2s) are important effector cells driving the initiation of type 2 immune responses leading to adaptive T helper 2 (Th2) immunity. Here we show that ILC2s dynamically express the checkpoint inhibitor molecule PD-L1 during type 2 pulmonary responses. Surprisingly, PD-L1:PD-1 interaction between ILC2s and CD4+ T cells did not inhibit the T cell response, but PD-L1-expressing ILC2s stimulated increased expression of GATA3 and production of IL-13 by Th2 cells both in vitro and in vivo. Conditional deletion of PD-L1 on ILC2s impaired early Th2 polarization and cytokine production, leading to delayed worm expulsion during infection with the gastrointestinal helminth Nippostrongylus brasiliensis Our results identify a novel PD-L1-controlled mechanism for type 2 polarization, with ILC2s mediating an innate checkpoint to control adaptive T helper responses, which has important implications for the treatment of type 2 inflammation.

Impact of intensified antiretroviral therapy during early HIV infection on gut immunology and inflammatory blood biomarkers

Standard antiretroviral therapy (ART) is slow to reverse gut mucosal immune defects that cause persistent inflammation and immune activation. We examined whether intensifying early-administered ART through the addition of maraviroc and raltegravir would accelerate their resolution. ART-naïve men with early HIV infection were randomized in a double-blind manner to receive ART (emtricitabine/tenofovir disoproxil fumarate + lopinavir/ritonavir), together with either combined placebo or raltegravir + maraviroc, for 48 weeks. In a predefined substudy, paired blood and sigmoid biopsies were collected at baseline and week 48. Mucosal CD4 T-cell immune subsets (Th1, Th17, and Th22 cells), CD8 T-cell immune activation, and soluble blood markers of inflammation (IL-6, IL-17, macrophage inflammatory protein-1b, soluble CD14, and IL-10) and coagulation (D-dimer) were measured. A total of 22 participants were enrolled, a median of 4 months after HIV acquisition. At baseline, there was substantial systemic and mucosal immune activation, and gut CD4 T-cell numbers, Th22 cell numbers, and Th17 cell function were reduced compared with controls. Early ART restored gut Th22 numbers, improved but did not restore overall CD4 numbers, and had no impact on Th17 function. Plasma levels of soluble CD14 and D-dimer normalized, whereas other inflammatory cytokines were reduced but not normalized. ART intensification had no impact on any blood or gut immune parameters. Early HIV infection causes substantial mucosal and systemic immune activation, and gut CD4 T-cell dysfunction. One year of ART improved but did not normalize most parameters, regardless of intensification with raltegravir and maraviroc, and did not restore mucosal Th17 function.

Hox5 Paralogous Genes Modulate Th2 Cell Function during Chronic Allergic Inflammation via Regulation of Gata3.

Allergic asthma is a significant health burden in western countries, and continues to increase in prevalence. Th2 cells contribute to the development of disease through release of the cytokines IL-4, IL-5, and IL-13, resulting in increased airway eosinophils and mucus hypersecretion. The molecular mechanisms behind the disease pathology remain largely unknown. In this study we investigated a potential regulatory role for the Hox5 gene family, Hoxa5, Hoxb5, and Hoxc5, genes known to be important in lung development within mesenchymal cell populations. We found that Hox5-mutant mice show exacerbated pathology compared with wild-type controls in a chronic allergen model, with an increased Th2 response and exacerbated lung tissue pathology. Bone marrow chimera experiments indicated that the observed enhanced pathology was mediated by immune cell function independent of mesenchymal cell Hox5 family function. Examination of T cells grown in Th2 polarizing conditions showed increased proliferation, enhanced Gata3 expression, and elevated production of IL-4, IL-5, and IL-13 in Hox5-deficient T cells compared with wild-type controls. Overexpression of FLAG-tagged HOX5 proteins in Jurkat cells demonstrated HOX5 binding to the Gata3 locus and decreased Gata3 and IL-4 expression, supporting a role for HOX5 proteins in direct transcriptional control of Th2 development. These results reveal a novel role for Hox5 genes as developmental regulators of Th2 immune cell function that demonstrates a redeployment of mesenchyme-associated developmental genes.

Th2/1 Hybrid Cells Occurring in Murine and Human Strongyloidiasis Share Effector Functions of Th1 Cells

Infections by the soil-transmitted threadworm Strongyloides stercoralis affect 30–100 million people worldwide, predominantly in tropic and sub-tropic regions. Here we assessed the T helper cell phenotypes in threadworm-infected patients and experimental murine infections with focus on CD4+ T cells co-expressing markers of Th2 and Th1 differentiation. We show that mice infected with the close relative S. ratti generate strong Th2 responses characterized by the expansion of CD4+ GATA-3+ cells expressing IL-4/-5/-13 in blood, spleen, gut-draining lymph nodes, lung and gut tissue. In addition to conventional Th2 cells, significantly increased frequencies of GATA-3+T-bet+ Th2/1-hybrid cells were detected in all organs and co-expressed Th2- and Th1-cytokines at intermediate levels. Assessing the phenotype of blood-derived CD4+ T cells from South Indian patients infected with S. stercoralis and local uninfected control donors we found that GATA-3 expressing Th2 cells were significantly increased in the patient cohort, coinciding with elevated eosinophil and IgE/IgG4 levels. A fraction of IL-4+CD4+ T cells simultaneously expressed IFN-γ hence displaying a Th2/1 hybrid phenotype. In accordance with murine Th2/1 cells, human Th2/1 cells expressed intermediate levels of Th2 cytokines. Contrasting their murine counterparts, human Th2/1 hybrids were marked by high levels of IFN-γ and rather low GATA-3 expression. Assessing the effector function of murine Th2/1 cells in vitro we found that Th2/1 cells were qualified for driving the classical activation of macrophages. Furthermore, Th2/1 cells shared innate, cytokine-driven effector functions with Th1 cells. Hence, the key findings of our study are that T helper cells with combined characteristics of Th2 and Th1 cells are integral to immune responses of helminth-infected mice, but also occur in helminth-infected humans and we suggest that Th2/1 cells are poised for the instruction of balanced immune responses during nematode infections.

Neuro-immune interactions in allergic diseases: novel targets for therapeutics.

Recent studies have highlighted an emerging role for neuro-immune interactions in mediating allergic diseases. Allergies are caused by an overactive immune response to a foreign antigen. The peripheral sensory and autonomic nervous system densely innervates mucosal barrier tissues including the skin, respiratory tract and gastrointestinal (GI) tract that are exposed to allergens. It is increasingly clear that neurons actively communicate with and regulate the function of mast cells, dendritic cells, eosinophils, Th2 cells and type 2 innate lymphoid cells in allergic inflammation. Several mechanisms of cross-talk between the two systems have been uncovered, with potential anatomical specificity. Immune cells release inflammatory mediators including histamine, cytokines or neurotrophins that directly activate sensory neurons to mediate itch in the skin, cough/sneezing and bronchoconstriction in the respiratory tract and motility in the GI tract. Upon activation, these peripheral neurons release neurotransmitters and neuropeptides that directly act on immune cells to modulate their function. Somatosensory and visceral afferent neurons release neuropeptides including calcitonin gene-related peptide, substance P and vasoactive intestinal peptide, which can act on type 2 immune cells to drive allergic inflammation. Autonomic neurons release neurotransmitters including acetylcholine and noradrenaline that signal to both innate and adaptive immune cells. Neuro-immune signaling may play a central role in the physiopathology of allergic diseases including atopic dermatitis, asthma and food allergies. Therefore, getting a better understanding of these cellular and molecular neuro-immune interactions could lead to novel therapeutic approaches to treat allergic diseases.

Rapamycin Ameliorates Experimental Autoimmune Encephalomyelitis by Suppressing the mTOR-STAT3 Pathway.

Rapamycin is a new immunosuppressant that has a primarily anti-inflammatory effect and selectively inhibits the activation of T helper (Th)-cell subsets. It is widely used to treat autoimmune disease. We studied the mechanism of rapamycin action against experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a classic animal model of multiple sclerosis. Rapamycin significantly inhibited the development of EAE by decreasing both clinical scores and inflammatory cell infiltration into the spinal cord. Furthermore, rapamycin reversed EAE symptoms in mice showing the initial signs of paralysis. Rapamycin, is a mammalian target of rapamycin (mTOR) inhibitor. By measuring the downstream markers phospho-mTOR (p-mTOR)/mTOR and phospho-signal transducer and activator of transcription 3 (p-STAT3)/STAT3, we showed that rapamycin suppressed the mTOR-STAT3 pathway in EAE mice. The mTOR-STAT3 signaling pathway is important for Th1 and Th17 cell responses. We found that rapamycin-treated mice had reduced proportions of Th1 and Th17 cells, as well as lower mRNA expression for the transcription factors T-bet and RoRγt in EAE mouse splenocytes. To evaluate Th1 and Th17 cell function, we examined expression of their specific cytokines in the peripheral immune system and central nervous system. Rapamycin treatment reduced protein and mRNA levels of interferon (IFN)-γand interleukin (IL)-17 in splenocytes, and reduced IFN-γ and IL-17 mRNA levels in the spinal cords of EAE mice. These findings suggest that rapamycin treatment inhibits the mTOR-STAT3 pathway in EAE mice, thereby promoting immunosuppression. This study may provide new insight into the mechanism controlling rapamycin effects in multiple sclerosis.

T-cell activation RhoGTPase-activating protein plays an important role in TH17-cell differentiation.

T-cell activation RhoGTPase-activating protein (TAGAP) is a GTPase-activating protein specific for RhoA that is exclusively expressed in activated T cells. Genome-wide association studies and metagenome SNPs analyses have indicated that TAGAP is associated with the pathogenesis of multiple autoimmune diseases, including psoriasis, rheumatoid arthritis, Crohn's disease, celiac disease and multiple sclerosis. However, the precise function of TAGAP remains unclear. Because TH17 cells contribute to TAGAP-associated autoimmune diseases, we hypothesized that TAGAP plays key roles in the differentiation and/or function of TH17 cells. To evaluate this hypothesis, we analyzed the effect of TAGAP on TH17 differentiation in vitro and established a line of TAGAP-deficient mice. We found that TAGAP was required for TH17 differentiation in vitro and that the loss of TAGAP in mice ameliorated the clinical features of experimental autoimmune encephalomyelitis, indicating that TAGAP is critical for disease progression. We also demonstrated that TAGAP interacts with RhoH, an adapter protein that interacts with lck and ZAP70 in proximal TCR signaling. TAGAP competes with ZAP70 for RhoH binding, thereby inhibiting TCR-associated signal transduction. Consistent with these findings, TCR-induced ERK activation was increased in TAGAP-deficient T cells. Because the upregulation of TCR signaling inhibits Th17 differentiation, TAGAP may prevent TCR signaling activity from reaching the limit of the induction of TH17 cells. Collectively, our findings indicate that TAGAP is a novel factor required for TH17-cell differentiation and that TAGAP potentially represents a novel target of autoimmune disease therapies.

Negative regulation of Th17 cell development and function by the REV-ERBs

Abstract A significant amount of work has identified key factors that drive Th17 cell development, including the nuclear receptors (NRs) RORα and RORγ. However, cell-intrinsic mechanisms that negatively regulate Th17 cell development and inflammation have received less attention. Two other members of the NR superfamily, the REV-ERBs (REV-ERBα and REV-ERBβ), are often co-expressed in the same tissues as the RORs, bind the same DNA response elements, and co-regulate their shared target genes. The REV-ERBs have well described roles in the regulation of the circadian rhythm and metabolism, but their roles in immune cell function are poorly understood. Therefore, we hypothesize that the REV-ERBs are key negative regulators of Th17 cell development and function. We we aim to understand the role of the REV-ERBs in Th17 cell development as well as determine whether targeting these NRs is a viable therapeutic option for the treatment of Th17-mediated autoimmune diseases. Our results indicate that the REV-ERBs are differentially expressed during Th17 cell development. Overexpression and pharmacological modulation of REV-ERB activity suppresses Th17 cell development whereas genetic deletion of the REV-ERBs perturbs Th17 cell development in vitro and induces autoimmunity in vivo. Using REV-ERB-specific small molecules that we have developed, we have found that pharmacological modulation of REV-ERB activity suppresses Th17 cell development in vitro and development of autoimmunity in vivo. Collectively, our data suggest that the REV-ERBs are key negative regulators of Th17 cell development and function and represent a novel therapeutic target for the treatment of Th17-mediated autoimmune diseases. Funding support – NIH (R01AI116885-01A1)

S1P1 Agonist SEW2871 Inhibits human Th17 cell generation and functions

Abstract S1P1 is a G-protein coupled receptor expressed by lymphocytes and is required for their egress out of secondary lymphoid organs. Fingolimod, an agonist of four S1P receptors including S1P1, is used in multiple sclerosis (MS) treatment in humans; however, less is known regarding the impact of S1P1 agonists on the egress-independent biology and functions of human Th17 and Treg cells. In this study, we explored the effects of S1P1 agonists SEW2871 and FTY720 on the ex vivo generation and functions of human Th17 and Treg cells. We report that a selective S1P1 agonist SEW2871 inhibited human Th17 development ex vivo, from naïve T cells, associated with reduced IL-17 and IL-22 production, demonstrated by ELISA and intracellular cytokine staining. On the other hand, Treg generation was augmented in SEW2871+ cultures. Additionally, SEW2871-exposed monocytes and dendritic cells produced less IL-23, a cytokine required for Th17 cell-expansion and pathogenicity. Th17 differentiation in the presence or absence of antigen presenting cells revealed that SEW2871 could inhibit Th17 generation either by blocking APC-derived IL-23 or directly affecting T cells. Our data provide novel information as to egress-independent effects of S1P1 agonists on Th17 cells.

Short chain fatty acids differentially regulate differentiation and function of Th1 and Th17 cells in the intestines

Abstract The mechanisms by which gut microbiota regulate host immune responses are still not completely understood. Short chain fatty acids (SCFA), mainly acetate (C2), propionate (C3), and butyrate (C4), the metabolites produced solely by gut microbiota, have been shown to promote development of Treg cells, and possibly other T cell subsets, in the intestines. However, the mechanisms involved remain unclear. In this report, we investigated how SCFA regulate development and function of microbiota antigen-specific T cells. We treated CBir1 transgenic T cells, specific for an immunodominant microbiota antigen CBir1 flagellin, with SCFA under various T cell polarization conditions to determine how they regulate T cell differentiation, and transferred those T cells into RAG−/− mice to determine their function in induction of colitis. Our results demonstrated that C2, C3 and C4 all promoted T cell production of IFN-γ and IL-10 when cultured under neutral and Th1 conditions. Under Th17 conditions C2, C3 promoted, while C4 inhibited, T cell IL-17 production at early stage of cell divisions. However, all three SCFA promoted T cell IL-10 production. Mechanistically, SCFA activation of mTOR pathway but not inhibition of HDAC or binding GPR43 mediated their effects on Th1 and Th17 cells. Functionally, transfer of C2- and C4-treated Th1 and Th17 cells induced less severe colitis in RAG−/− mice compared to untreated T cells, probably through induction of IL-10 by those T cells. Collectively, our study indicated that SCFA differentially regulate T cells differentiation and function in the intestines, which could contribute the maintenance of intestinal homeostasis.

Th17 cells modulate the LN microenvironment through IL-17 dependent regulation of fibroblastic reticular cells

Abstract Integrins play a critical role in the function and migration of Th17 cells in CNS, and blockade of inflammatory T cell migration is used therapeutically in multiple sclerosis. Our previously published data demonstrated a critical role for αvβ3 in driving encephalitogenic Th17 cell migration in experimental autoimmune encephalomyelitis (EAE), in an IL-23R-dependent manner. Herein, we show that fibronectin, a ligand for integrin αvβ3, is significantly upregulated in the dLNs of EAE mice. Strikingly, the expression of fibronectin in dLN was significantly reduced in IL23R−/− mice following immunization. Fibronectin expression increased in dLNs during the progression of EAE with similar kinetics but delayed peak compared to IL-17. Since IL23R regulates IL-17 production, we analyzed LN from IL-17−/− and IL17Ra−/− mice immunized for EAE, and observed a similar defect in fibronectin expression in the absence of IL-17 signaling. CD45−gp38+CD31− fibroblastic reticular cells (FRCs) in the T cell zone are the major producers of fibronectin in the dLNs, and these stromal cells expand during EAE. Although IL-17RA−/− LN appeared similarly enlarged following immunization, indicating an inflammatory response, the number of FRCs was decreased in immunized IL17Ra−/− LN, corresponding to decreased fibronectin. Taken together, our data suggests that during priming of the immune response, and before migrating to their peripheral target tissue, Th17 cells modulate the local LN environment in which they are activated through production of IL-17 to promote FRCs expansion and induction of ECM. This could have long-term consequences in the host upon future infectious challenge, as well as influencing chronicity of Th17-mediated autoimmune disease.

Controlling T cell development and function via innate Toll-like receptor signaling for autoimmune therapy

Abstract Innate regulation through Toll-like receptor (TLR) signaling has been shown to be important for promoting T cell subset development and function. However, limited information is known about whether differential TLR signaling can selectively inhibit Th17 and/or Th1 cells, important for controlling excessive inflammation and autoimmune responses. Here we demonstrate that activation of TLR7 signaling in T cells can inhibit both Th17 cell differentiation from naïve T cells and IL-17 production in established Th17 cells. We further report that down-regulation of STAT3 signaling is responsible for TLR7-mediated inhibition of Th17 cells due to induction of SOCS3 and SOCS5. TLR7-mediated suppression of Th17 cells does not require DC involvement. In addition, we show that TLR7 signaling can suppress Th1 cell development and function due to a mechanism different from Th17 cell suppression. Importantly, our complementary in vivo studies demonstrate that treatment with the TLR7 ligand imiquimod can inhibit both Th1 and Th17 cells, resulting in prevention of and immunotherapeutic reduction in experimental autoimmune encephalomyelitis (EAE). These studies identify a new strategy to manipulate Th17/Th1 cells through TLR7 signaling, with important implications for successful immunotherapy against autoimmune and inflammatory diseases.

Bcl11b, a novel GATA3-interacting protein, regulates T-helper-2-cell differentiation and function

Abstract GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. Fine-tuning GATA3 transcription activity is critical for effectively expelling extracellular parasites and preventing allergic disorders. However, it is still elusive how GATA3 function is regulated in Th2 cells. Here, we report that the transcription factor B-cell Lymphoma 11b (Bcl11b) is a novel component of the GATA3 transcriptional complex executing GATA3-mediated gene expression. Bcl11b binds to GATA3 through protein-protein interaction; ChIP-Seq analysis showed co-localization of Bcl11b and GATA3 at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5 and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent indicating that Bcl11b inhibits GATA3-mediated cytokines production. Genome-wide analysis of Bcl11b- and GATA3-mediated gene regulation (RNA-Seq) and co-binding pattern (ChIP-Seq) suggests that GATA3/Bcl11b complex are involved in limiting Th2 gene expression as well as inhibiting non-Th2 gene expression. Thus, Bcl11b, a previously unknown GATA3 binding protein, fine-tunes GATA3-mediated gene expression in Th2 cells.