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Summary: T helper 17 (Th17) cells specifically transcribe the Il17 and Il17f genes, which are localized in the same chromosome region, but the underlying mechanism is unclear. Here, we report a cis element that we previously named conserved noncoding sequence 2 (CNS2) physically interacted with both Il17 and Il17f gene promoters and was sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 resulted in impaired retinoic acid-related orphan receptor gammat (RORγt)-driven IL-17 expression in vitro. CNS2-deficient T cells also produced substantially decreased amounts of IL-17F. These cytokine defects were associated with defective chromatin remodeling in the Il17-Il17f gene locus, possibly because of effects on CNS2-mediated recruitment of histone-modifying enzymes p300 and JmjC domain-containing protein 3 (JMJD3). CNS2-deficient animals were also shown to be resistant to experimental autoimmune encephalomyelitis (EAE). Our results thus suggest that CNS2 is sufficient and necessary for Il17 and optimal Il17f gene transcription in Th17 cells. [ABSTRACT FROM AUTHOR]

The CD70-CD27 interaction is known to positively regulate T cell expansion and effector function by providing costimulatory signals. In this issue of Immunity, Coquet et al. (2013) show an unexpected T-helper-17-cell-specific negative regulation mediated by CD70-CD27 interaction. [ABSTRACT FROM AUTHOR]

Fever, an evolutionarily conserved physiological response to infection, is also commonly associated with many autoimmune diseases, but its role in T cell differentiation and autoimmunity remains largely unclear. T helper 17 (Th17) cells are critical in host defense and autoinflammatory diseases, with distinct phenotypes and pathogenicity. Here, we show that febrile temperature selectively regulated Th17 cell differentiation in vitro in enhancing interleukin-17 (IL-17), IL-17F, and IL-22 expression. Th17 cells generated under febrile temperature (38.5°C–39.5°C), compared with those under 37°C, showed enhanced pathogenic gene expression with increased pro-inflammatory activities in vivo. Mechanistically, febrile temperature promoted SUMOylation of SMAD4 transcription factor to facilitate its nuclear localization; SMAD4 deficiency selectively abrogated the effects of febrile temperature on Th17 cell differentiation both in vitro and ameliorated an autoimmune disease model. Our results thus demonstrate a critical role of fever in shaping adaptive immune responses with implications in autoimmune diseases. • Treatment with anti-pyretic regents reduced Th17 cell differentiation in vivo • Febrile temperature promotes the differentiation and pathogenicity of Th17 cells • SMAD4 SUMOylation is indispensable for Th17 cell differentiation at febrile temperature • Smad4-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) Fever has been proposed to have an evolutionarily conserved protective role in infectious diseases. In this study, Wang et al. demonstrate a selective role of fever in boosting Th17 cell differentiation and associated pathogenic functions in autoimmune diseases via heat-shock-response-induced SMAD4 SUMOylation. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells play essential roles in regulating humoral immunity, especially germinal center reactions. However, how CD4+ T cells integrate the antigenic and costimulatory signals in Tfh cell development is still poorly understood. Here, we found that phorbol 12-myristate 13-acetate (PMA) + ionomycin (P+I) stimulation, together with interleukin-6 (IL-6), potently induce Tfh cell-like transcriptomic programs in vitro. The ERK kinase pathway was attenuated under P+I stimulation; ERK2 inhibition enhanced Tfh cell development in vitro and in vivo. We observed that inducible T cell costimulator (ICOS), but not CD28, lacked the ability to activate ERK, which was important in sustaining Tfh cell development. The transcription factor Zfp831, whose expression was repressed by ERK, promoted Tfh cell differentiation by directly upregulating the expression of the transcription factors Bcl6 and Tcf7. We have hence identified an ERK-Zfp831 axis, regulated by costimulation signaling, in critical regulation of Tfh cell development. [Display omitted] • PMA + ionomycin promote Tfh cell generation in vitro • ERK kinase pathway negatively regulates Tfh cell differentiation program • CD28 and ICOS signaling differentially regulate ERK during Tfh cell differentiation • Repressed by ERK, Zfp831 is a transcription factor that promotes Tfh cell development Tfh cell essentially regulates humoral immunity, but its differentiation process is not fully understood. Wan et al. reveal that ICOS and CD28 differentially regulate the ERK kinase pathway and ERK is Tfh-repressive. Repressed by ERK, the transcriptional factor Zfp831 promotes T follicular helper cell differentiation. [ABSTRACT FROM AUTHOR]

The interleukin (IL)-17 family, consisting of six members, promotes host defense but can in some context promote the development of autoimmune disease. Here, we examined the role of IL-17D, a poorly understood member in the IL-17 family. IL-17D was expressed primarily by colonic epithelial cells. Il17d −/− mice were more susceptible to acute colitis, bacterial infection and experimentally induced colon cancer than their wildtype counterparts. Il17d deficiency impaired IL-22 production by group 3 innate lymphoid cells (ILC3s) and reduced expression of IL-22-dependent antimicrobial peptides, RegIIIβ and RegIIIγ, in colon tissue at steady state and in colitis; this was associated with changes in microbial composition and dysbiosis. Protein purification studies revealed that IL-17D bound not canonical IL-17 receptors, but rather CD93, a glycoprotein expressed on mature ILC3s. Mice lacking Cd93 in ILC3s exhibited impaired IL-22 production and aggravated colonic inflammation in experimental colitis. Thus, an IL-17D-CD93 axis regulates ILC3 function to preserve intestinal homeostasis. [Display omitted] • IL-17D is required for intestinal hemostasis • IL-17D deficiency results in defective IL-22 production by ILC3s • CD93 is a functional receptor of IL-17D expressed on mature ILC3s • CD93 deficiency decreases ILC3 development and IL-22 production in ILC3s Among IL-17 cytokines, IL-17D is the least studied member. In this study, Dong et al. demonstrate that intestine epithelial cells-derived IL-17D serve as a critical factor in regulating ILC3s function and intestinal homeostasis by binding the receptor CD93. [ABSTRACT FROM AUTHOR]

RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells whose upregulation in developing Th17 cells is critically regulated by interleukin-6 (IL-6) and TGF-β, the molecular mechanisms of which remain largely unknown. Here we identified conserved non-coding sequences (CNSs) 6 and 9 at the Rorc gene, essential for its expression during Th17 cell differentiation but not required for RORγt expression in innate lymphocytes and γδ T cells. Mechanistically, the IL-6-signal transducer and activator of transcription 3 (STAT3) axis appeared to be largely dependent on CNS9 and only partially on CNS6 in controlling RORγt expression and epigenetic activation of the Rorc locus. TGF-β alone was sufficient to induce RORγt expression in a CNS6- but not CNS9-dependent manner through CNS6 binding by SMAD proteins. Our study reveals an important synergistic mechanism downstream of IL-6 and TGF-β in regulation of RORγt expression and Th17 cell commitment via distinct cis -regulatory elements. • CNS6 and CNS9 are not required for RORγt expression in innate immune cells • Deficiency in CNS6 or CNS9 decreases Th17 cell differentiation and EAE disease • CNS9 and, to a lesser extent, CNS6 are required for IL-6-induced RORγt expression • CNS6, but not CNS9, is indispensable for TGF-β-induced RORγt expression IL-6 and TGF-β induce Th17 cell differentiation. Chang et al. demonstrate that these two cytokines initiate Th17 cell differentiation by inducing de novo Rorc transcription via the distinct conserved non-coding sequences CNS6 and CNS9. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells provide essential help to B cells in germinal center (GC) reactions. Bcl6 is the obligatory lineage transcription factor in Tfh cells. Here, we examined the molecular pathways that induce Bcl6 gene expression and underscore Bcl6-dependent function during Tfh cell commitment. Integration of genome-wide Bcl6 occupancy in Tfh cells and differential gene expression analyses suggested an important role for the transcription factor Tox2 in Tfh cell differentiation. Ectopic expression of Tox2 was sufficient to drive Bcl6 expression and Tfh development. In genome-wide ChIP-seq analyses, Tox2-bound loci associated with Tfh cell differentiation and function, including Bcl6. Tox2 binding was associated with increased chromatin accessibility at these sites, as measured by ATAC-seq. Tox2 −/− mice exhibited defective Tfh differentiation, and inhibition of both Tox2 and the related transcription factor Tox abolished Tfh differentiation. Thus, a Tox2-Bcl6 axis establishes a transcriptional feed-forward loop that promotes the Tfh program. • Tox2 is highly expressed in Tfh cells and regulated by Bcl6 and STAT3 • Forced expression of Tox2 drives Tfh development • Tox2 directly binds to Tfh-associated genes, promoting chromatin accessibility • Combined deletion of Tox2 and Tox abrogates Tfh development T follicular helper (Tfh) cells provide help to B cells in germinal center reactions and are essential to humoral immunity. Xu et al. define a feed-forward loop mediated by the transcription factors Bcl6 and Tox2 that promotes and establishes the Tfh program. [ABSTRACT FROM AUTHOR]

Summary Psoriasis is a chronic autoinflammatory skin disease. Although interleukin-17, derived from lymphocytes, has been shown to be critical in psoriasis, the initiation and maintenance of chronic skin inflammation has not been well understood. IL-25 (also called IL-17E), another IL-17 family cytokine, is well known to regulate allergic responses and type 2 immunity. Here we have shown that IL-25, also highly expressed in the lesional skin of psoriasis patients, was regulated by IL-17 in murine skin of a imiquimod (IMQ)-induced psoriasis model. IL-25 injection induced skin inflammation, whereas germline or keratinocyte-specific deletion of IL-25 caused resistance to IMQ-induced psoriasis. Via IL-17RB expression in keratinocytes, IL-25 stimulated the proliferation of keratinocytes and induced the production of inflammatory cytokines and chemokines, via activation of the STAT3 transcription factor. Thus, our data demonstrate that an IL-17-induced autoregulatory circuit in keratinocytes is mediated by IL-25 and suggest that this circuit could be targeted in the treatment of psoriasis patients. [ABSTRACT FROM AUTHOR]