Purpose : To investigate whether crude house-dust-mite antigen exacerbates eosinophilic inflammation in the conjunctival tissues of an atopic keratoconjunctivitis mouse model in a dose-dependent manner. Materials and Methods : An atopic keratoconjunctivitis mouse model was established by percutaneous sensitization and crude house-dust-mite antigen application in NC/Nga mice. To assess the dose-dependent response, conjunctival specimens from groups that were administered high- (High-HDM) or low-dose house-dust-mite antigen (Low-HDM) following percutaneous sensitization and the control without house-dust-mite antigen administration (control group) were evaluated. Histological examination and immunofluorescence staining were performed to determine eosinophil density and the number of IL-13-positive cells. Polymerase chain reaction array was used to obtain adaptive and innate immunity-related factor profile, and quantitative polymerase chain reaction was used to determine Il13, Il17a, Ccl11, and Ccl24 expression. Atopic keratoconjunctivitis model mice injected with anti-IL-1α antibody (IL-1α group) or vehicle (vehicle group) to the upper and lower eyelids before atopic keratoconjunctivitis development were evaluated. Results : Eosinophil density in the conjunctiva increased with house-dust-mite antigen application in a dose-dependent manner. CD4, CXCL10, CCR6, C3, and IL-13 mRNA levels increased more than 5-fold in the conjunctiva of the High-HDM group animals compared to those in control animals. mRNA expression of Il13 and Ccl11 in the conjunctiva of the High-HDM group animals significantly increased compared with that in the Low-HDM and control group animals. Conversely, the eosinophil density and Il13 mRNA expression significantly decreased in the IL-1α group compared with those in the vehicle group. Conclusions : The house-dust-mite antigen increased eosinophilic infiltration and Il13 mRNA expression in the conjunctiva of an atopic keratoconjunctivitis mouse model in a dose-dependent manner. These inflammatory alterations were partially alleviated by eyelid injection of anti-IL-1α antibody. These findings indicate that IL-1α-induced IL-13 production constitutes a major exacerbating factor for house-dust-mite antigen-induced atopic keratoconjunctivitis.

Keywords: Atopic keratoconjunctivitis; IL-13; eosinophil; house-dust-mite; mouse model.

Increasing evidence has supported the crucial role of CARD14 in the pathogenesis of psoriasis, whereas the precise cellular signaling involved in skin physiopathology remains poorly understood. In this article, we show that neither genetic ablation of Il17a nor elimination of T cells was sufficient to restrain the skin inflammation in a CARD14-E138A-mutation-induced psoriasis-like mouse model, whereas depletion of Il23, which extremely blocked the IL-23/T17 axis, was more effective. Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14 ^E138A/+ mice. Selective inactivation of keratinocyte-specific MALT1 proteolytic activity strongly ameliorated the Card14 ^E138A/+- and Card14 ^ΔQ136/+-induced skin disease, which was reproduced by using the imiquimod-induced mouse model. Together, our results suggest a sequence of events under CARD14-mutation-induced psoriasis condition that keratinocyte-intrinsic activation of CBM complex initiates the skin inflammation depending on the IL-23/T17 axis. Targeting keratinocytes by inactivation of MALT1 paracaspase activity might be a promising therapeutic target for early psoriasis treatment.

Previous studies have shown the participation of the cytokines interleukin (IL) 17A and IL22 in the development of vitiligo. The aryl hydrocarbon receptor (AhR) functions in the pathogenesis of vitiligo and can modulate cytokine production. The aim of the present study was to determine the relationship between AhR activation and the secretion of IL17A and IL22 in CD4⁺ T cells in vitiligo. A total of 20 newly diagnosed patients with progressive, unstable vitiligo and 20 healthy controls were recruited. CD4⁺ T cells and skin samples were collected. Immunohistochemistry, ELISA, reverse transcription-quantitative PCR, western blotting and RNA interference experiments were performed. The expression of AhR was significantly lower in the CD4⁺ T cells and skin, both lesional and nonlesional, of patients with vitiligo compared with healthy subjects. AhR expression was markedly lower in nonlesional compared with lesional skin of patients with vitiligo. The expression levels of IL17A and IL22 were significantly higher in patients with vitiligo compared with healthy subjects. Knockdown of AhR significantly increased the production of IL17A and markedly decreased IL22 levels in the CD4⁺ T cells of patients with vitiligo. Ginkgo biloba extract EGb 761 activated AhR, inhibited IL17A secretion and enhanced IL22 release in the CD4⁺ T cells of patients with vitiligo. In conclusion, reduced AhR expression is associated with progressive, unstable vitiligo. Activation of AhR with G. biloba extract EGb 761 may have therapeutic potential for decreasing IL17A levels and increasing IL22 levels in patients with vitiligo.

Keywords: Ginkgo biloba; aryl hydrocarbon receptor; interleukin 17A; interleukin 22; vitiligo.

Objective: ZAP-70^W163C BALB/c (SKG) mice develop reactive arthritis (ReA) after Chlamydia muridarum (Cmu) infection. Since intracellular pathogens enhance their replicative fitness in stressed host cells, we examined how myeloid cells taking up Cmu drive arthritis.

Methods: Female SKG, Il17a-deficient SKG and BALB/c mice were genitally infected with Cmu or Cmu Luciferase. Cmu dissemination was assessed by in vivo imaging or genomic DNA amplification. Macrophages were depleted using clodronate liposomes. Anti-TNF, anti-IL-23p19 were administered after infection or arthritis onset. Hspa5, Tgtp1, Il23a, Il17a, Il12b and Tnf expression was compared in SKG and BALB/c mice.

Results: One-week post infection, macrophages and neutrophils infiltrated the uterus; both carried Cmu DNA to the spleen. Cmu load was higher in SKG than BALB/c. Macrophage depletion reduced Cmu load and prevented arthritis. Compared with BALB/c, expression of Il23a and Il17a was increased in SKG uterine and splenic neutrophils. Anti-IL-23p19 during infection or Il17a deficiency suppressed arthritis. Tnf was over-expressed in SKG joints within one-week post infection and persisted. TNF inhibition during infection or at arthritis onset suppressed arthritis. Endoplasmic reticulum stress was constitutively increased in SKG joints but was induced, with immunity-related GTPase, by Cmu infection in uterus.

Conclusion: The load of Cmu is higher in SKG than BALB/c mice. While proinflammatory IL-23 produced by neutrophils contributes to the initiation of Cmu-mediated ReA, macrophage depletion reduces Cmu dissemination to other tissues, tissue burden, and arthritis. TNF inhibition suppresses arthritis. Our data suggest that enhanced bacterial dissemination in SKG macrophages drives TNF production required for persistent arthritis.

Since TH17 cells could play a role in the pathogenesis of allograft nephropathy, we investigated them in peripheral blood and kidney allograft infiltrates. We compared percentages of TH17 cells and IL17A in peripheral blood of 14 kidney allograft recipients and 8 healthy volunteers. Allograft recipients experiencing graft dysfunction and kidney biopsy specimens showing chronic allograft nephropathy (CAN) were distinguished from a "control group," both of which were tested for TH17 and CD15+ staining. Allograft recipients displayed a significantly lower percentage of TH17 cells and IL17A blood levels than healthy volunteers, suggesting effects of the immunosuppressive regimen. No difference in these values was observed between the CAN group and the control group. On kidney allograft biopsies, CD15+ infiltrate was significantly higher in the CAN group than in the control group. In CAN, IL17 secretion might play a chemoattractant role for neutrophils. However, these preliminary data have to be confirmed in larger studies.

Interleukin-17 receptor D (IL17RD or IL-17RD) also known as Sef (similar expression to fibroblast growth factor), is a single pass transmembrane protein that is reported to regulate several signaling pathways . IL17RD was initially described as a feedback inhibitor of fibroblast growth factor (FGF) signaling during zebrafish and frog development. It was subsequently determined to regulate other receptor tyrosine kinase signaling cascades as well as several proinflammatory signaling pathways including Interleukin-17A (IL17A), Toll-like receptors (TLR) and Interleukin-1α (IL1α) in several vertebrate species including humans. This review will provide an overview of IL17RD regulation of signaling pathways and functions with emphasis on regulation of development and pathobiological conditions. We will also discuss gaps in our knowledge about IL17RD function to provide insight into opportunities for future investigation. Video Abstract.

Keywords: Cellular signaling; Fibroblast growth factor (FGF); Fibroblast growth factor receptor (FGFR); Interleukin-17; Interleukin-17 receptor D (IL17RD); Sef.

OBJECTIVE

To investigate the effect of transfusion of necrotic cells on regulatory T (Treg) and Th17 cell balance in septic mice.

METHODS

Thirty-four C57BL/6 mice were randomized into PBS group (n=5), sham-operated group (n=5), sepsis group (n=12), and necrotic cell transfusion group (n=12) and subjected to intraperitoneal PBS injection, sham operation by separating the cecum only, cecal ligation and puncture (CLP), and injection of 2 × 10⁷ necrotic cells 5 days before CLP, respectively. All the mice were sacrificed 2 weeks after CLP for analyzing the proportion of CD4⁺Foxp3⁺Treg cells and CD4⁺IL17A⁺Th17 cells in the peripheral blood, spleen and thymus by flow cytometry.

RESULTS

The percentage of Th17 cells and Treg/Th17 ratio in the spleen was significantly higher in CLP group than in the sham-operated group and PBS group (P<0.01). The percentage of Treg cells in the thymus was significantly lower in CLP group than in the sham-operated group (P<0.01). Pre-infusion of necrotic cells redressed the abnormality of Treg and Th17 cell percentages and Treg/Th17 imbalance in mice following CLP (P<0.05).

CONCLUSIONS

Pre-infusion of necrotic cells can reverse Treg/Th17 imbalance in septic mice.

<AbstractText>Immune and inflammatory reactions contribute to the progression of atherosclerosis. The walls of the different arteries and segments of the arteries have heterogeneous haemodynamic and histological features. We aimed to explore the relationship between the circulating T-cell subsets and the abundance of carotid atherosclerosis in different segments of carotid arteries.</AbstractText><AbstractText>70 patients underwent ultrasound duplex scanning to determine the degree of stenosis of the common carotid artery (CCA), the CCA bifurcation or the internal carotid artery (ICA). The blood frequencies of T-, B-, NK-cells, regulatory T cells (Treg), activated T-helpers (Th), IL10-producing Th, Th1 and Th17, as well as blood levels of hsCRP, sCD25, IL10 and <em>IL17a</em> were assessed.</AbstractText><AbstractText>The frequencies of Th17 were increased in patients with ICA stenosis >35% and >50% vs. patients with ICA stenosis <35%. Th17 blood level ≥0.55 % of lymphocytes was associated with more severe stenosis of ICA (OR 4.3 (1.0-17.6), p < 0.05 for ICA stenosis of 35-50% and 6.8 (1.3-35.0), p < 0.05 for ICA stenosis >50%). BMI positively correlated with the CCA bifurcation stenosis degree (r = 0.33, p < 0.05).</AbstractText><AbstractText>The severity of ICA stenosis can be associated with the circulating Th17 level.</AbstractText>

Urinary tract infections (UTI) frequently progress to chronicity in infected individuals but the mechanisms of pathogenesis underlying chronic UTI are not well understood. We examined the role of interleukin (IL)-17A in UTI because this cytokine promotes innate defense against uropathogenic Escherichia coli (UPEC). Analysis of UPEC persistence and pyelonephritis in mice deficient in IL-17A revealed that UPEC CFT073 caused infection at a rate higher than the multidrug resistant strain EC958. Il17a^-/- mice exhibited pyelonephritis with kidney bacterial burdens higher than those of wild-type (WT) mice. Synthesis of IL-17A in the bladder reflected a combination of γδ-T and T_H 17 cell responses. Analysis of circulating inflammatory mediators at 24h postinoculation identified predictors of progression to chronicity, including IL-6 and monocyte chemoattractant protein-1 (MCP-1). Histological analysis identified infiltrating populations of neutrophils, NK cells, and γδ T cells in the bladder, whereas neutrophils predominated in the kidney. Analysis of the contribution of flagella to chronicity using hyper-flagellated and fliC-deficient UPEC in WT and Il17a^-/- mice revealed that, in a host that is deficient for the production of IL-17A, flagella contribute to bacterial persistence. These findings show a role for IL-17A in defense against chronic UTI and a contribution of flagella to the pathogenesis of infection.

Keywords: Escherichia coli; Gram-negative pathogens; bacterial pathogenesis; innate immunity; urinary tract infection.

OBJECTIVE

Innate lymphocytes play a key role in maintaining the immune bowel barrier, which provides resistance to infection. However, the effects of probiotics on changes in the function of innate lymphocytes in the postoperative intestine remain known.

METHODS

Ninety-six male SD rats were divided into the blank group and the preoperative Lactobacillus intervention group, and parts of the ileum were sampled on days 0, 3, 5 and 7 after partial small bowel resection. Distal ileum samples were evaluated using immunohistochemistry to detect IL-5, IL-13, IL-17a and IL-22.

RESULTS

(1) There were more immune cells in the experimental group than in the blank group on day. (2) After the first 3 days, the levels of IL-22 and IL-5 (p = 0.024) were higher in the experimental group than in the blank group. From the third to the fifth day, the IL-5 and IL-22 levels were higher and the IL-13 and IL-17A levels were lower in the experimental group than in the blank group. From the fifth to the seventh day, the IL-5 and IL-13 levels were lower and the IL-22 and IL17A levels were higher in the experimental group than in the blank group.

CONCLUSIONS

Probiotics stabilize the fluctuation of the intestinal immune system postoperatively.

Celiac disease (CD) is characterized by a spectrum of intestinal inflammatory lesions. Most patients have villous atrophy (overt-CD), whilst others have a morphologically normal mucosa, despite the presence of CD-specific autoantibodies (potential-CD). As the mechanism responsible for villous atrophy is not completely elucidated, we investigated biomarkers specific for the different celiac lesions. Phenotype and cytokine production of intestinal mucosa cells were analysed by flow-cytometry in gut biopsies of children with overt- or potential-CD, and in healthy controls. Density of TCRγδ⁺ T cells was found markedly enhanced in intestinal mucosa of children with overt-CD compared to potential-CD or controls. By contrast, very few IL4⁺ T cells infiltrated the mucosa with villous atrophy compared to morphologically normal mucosa. IL4⁺ T cells were classical CD4⁺ T-helper cells (CD161^- ), producing or not IFNγ, and negative for IL17A. Our study demonstrated that the transition to villous atrophy in CD patients is characterized by increased density of TCRγδ⁺ T cells, and concomitant disappearance of IL4⁺ cells. These findings suggest that immunomodulatory mechanisms are active in potential-CD to counteract the inflammatory cascade responsible of villous atrophy. Further studies are required to validate the use of IL4⁺ and TCRγδ⁺ T cells as biomarkers of the different CD forms. This article is protected by copyright. All rights reserved.

Background: Systemic sclerosis (SSc) T cells can induce apoptosis of autologous skin fibroblasts in vitro. Th17 cells have been reported to increase in SSc patients, and interleukin-17A (IL-17A) has a profibrotic function. We used a system based on T-cell-autologous fibroblast co-cultures to further investigate a possible role of IL-17A in SSc. Methods: T cells from diffuse SSc patients were co-cultured with autologous skin fibroblasts. IL17A mRNA was assessed by real-time PCR in co-cultured and control T cells, while IL17RA, CXCL1, CCL2, CCL3, COL1A1, COL3A1, CTGF, TGFBR2, and SMAD3 mRNAs were assessed in co-cultured and control fibroblasts. In subset experiments, co-cultures and control cells were treated with either IL-17A or IL-17A plus anti-IL17 receptor monoclonal antibody (α-IL-17RA mAb). Chemokine and procollagen type I (PCI) production was further investigated at the protein level in cell culture supernatants by multiple suspension immunoassay and sandwich ELISA, respectively. Co-cultured and control fibroblasts were also stained with Annexin V and analyzed by flow cytometry. Results: T cell-fibroblast co-cultures overexpressed IL17A and IL17RA. Furthermore, co-cultured fibroblasts upregulated IL-17A targets CXCL1, CCL2, and CCL3, while COL1A1, COL3A1, CTGF, and two key effectors of the TGF-β signaling, TGFBR2 and SMAD3, were found downregulated. Consistently, chemokine concentrations were increased in co-culture supernatants, while PCI levels were reduced, especially after stimulation with ectopic IL-17A. Finally, simultaneous α-IL-17RA mAb treatment restored PCI levels and reduced fibroblast apoptosis in IL-17A-stimulated co-cultures. Conclusion: These data suggest that IL-17A upregulation might play a role in modulating T cell-mediated antifibrotic and proapoptotic effects in co-cultured autologous skin fibroblasts.

Compelling evidence has demonstrated that Th17 cells play an essential role in the pathogenesis of multiple sclerosis (MS). Long noncoding RNAs (lncRNAs) have been confirmed as vital regulators of immune cell differentiation and other functions. However, whether and how lncRNAs influence Th17 cell differentiation and functional behaviors remain largely unclear. Here, we identified that a lncRNA, namely Gm15575, is specifically enriched in Th17 cells and spleen tissues of EAE mice. Functionally, knockdown of Gm15575 in Th17 cells suppressed the secretion of IL17A. Mechanistically, Gm15575 served as a competing endogenous RNA (ceRNA) to block the function of miR-686, positively regulating the expression of CCL7, a pro-inflammatory chemokine with high expression in Th17 cells, and Th17 differentiation. Taken together, our study revealed that Gm15575-miR-686 axis promoted the progression of EAE by regulating Th17 differentiation and expression of CCL7 which elucidated the pathogenesis of autoimmune diseases at genetic level. Gm15575 can be involved in the course of Th17-related autoimmune diseases.

Keywords: Experimental autoimmune encephalomyelitis; Long non-coding RNAs; Multiple sclerosis; Th17 cells; ceRNA.

Coronary artery disease (CAD) is a major global health problem. In China, the incidence of CAD and the rate of mortality arising from it have increased every year. Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by activated T cells, and it may be involved in the development of CAD. Genetic polymorphisms in functional regions of the IL17A gene have a plausible role in modulating the risk of CAD. To evaluate the role of IL17A polymorphisms as a risk factor for CAD, we performed a detailed analysis of possible functional single nucleotide polymorphisms (SNPs) in regulatory regions of IL17A. This study examined the potential association between CAD and five SNPs (rs8193037, rs8193036, rs3819024, rs2275913, and rs3748067) of the IL17A gene. The allelic or genotypic frequencies of the rs8193037 (promoter region) and rs8193036 (promoter region) polymorphisms in CAD were significantly different from those in healthy controls. The CAD subjects had a significantly lower frequency of the A allele of rs8193037 (P = 0.009, OR = 1.772, 95%CI = 1.146- 2.742) and the T allele of rs8193036 (P = 0.010, OR = 1.754, 95%CI = 1.139-2.701). Strong linkage disequilibrium was observed in one block (D'>> 0.9). Significantly fewer T-G-G-A haplotypes (P = 0.045) were found in CAD subjects in block 1. These data suggest that IL17A gene polymorphisms confer susceptibility to CAD, and support the notion that dysfunction of IL-17A is involved in the pathophysiological process of CAD.

Interleukin 17A (IL-17A) is a pro-inflammatory cytokine of the IL-17 family predominantly secreted by T helper 17 cells. IL-17A is involved with the pathogenesis of inflammatory diseases such as asthma but seems to decrease the disease severity of bronchiolitis. [1] In our previous studies, the IL17A rs2275913 single nucleotide polymorphism (SNP) was associated with asthma risk at 11-13 years of age, but not earlier at 5-7 years of age, in the cohort of originally 166 children hospitalised for bronchiolitis at younger than six months of age. [2] The IL17A rs4711998 and rs8193036 SNPs were also studied and they did not show any such associations at either age. [3].

Interleukin (IL-)17A, plays a role in pathogenic defence, but is implicated in chronic inflammatory diseases, and has recently been associated with variable pregnancy outcomes. We investigated the role of maternal IL-17-[G197A]-specific effects of third-trimester IL-17 mRNA expression, NOx exposure levels and other variables on gestational age, in the Mother and Child in the Environment (MACE) birth cohort in South Africa. A total of 327 participants were genotyped for IL-17-[G197A] by polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP). Quantitative real-time PCR was used to quantitate IL-17-mRNA expression in whole blood. Multivariate linear regression analysis, stratified by IL-17-[G197A] genotype, was used to test for effects of NOx , IL17A/GAPDH, haemoglobin, body mass index, HIV-1 positivity, maternal education and income level on gestational age. Lower expression was associated with the IL-17-GG versus GA in the cohort and HIV-1-negative group (p = .0007, p = .0058), while no difference was observed in the HIV-1 positives. Elevated IL-17A expression was observed in the high NOx exposure groups, within IL-17[G197G] (p = .0004). IL-17[G197G] was associated with PTB (p < .0001), and the PTB group had lower IL-17A expression compared to the full-term group (p = .0002). IL-17 expression was associated with an increase in gestational age (p = .038), and NOx was associated with a decrease in gestational age in the IL-17[G197G] model (p = .046).

BACKGROUND

The interleukin (IL)-17 family of cytokines has emerged as an important pro-inflammatory mediator of psoriasis and psoriatic arthritis (PsA). Ixekizumab is an IL17A inhibitor that has been approved for the treatment of chronic plaque psoriasis. Phase III studies of ixekizumab in treating of PsA demonstrated promise by minimizing disease severity and progression. Areas covered: This review focuses on the biologic properties, pharmacokinetics and key clinical trial results that demonstrated the safety and efficacy of ixekizumab in treating psoriatic disease. Expert commentary: Ixekizumab is a biologic that has been approved for the treatment of chronic plaque psoriasis. With respect to safety, ixekizumab is generally well tolerated with injection-site reactions, nasopharyngitis, and upper respiratory tract infections being the most common adverse events. Most patients with anti-drug antibodies have low antibody titer levels resulting in no meaningful interference in clinical response to ixekizumab.

IL-17A and IL-17F are both involved in the pathogenesis of neutrophilic inflammation observed in COPD and severe asthma. To explore this, mice deficient in both Il17a and Il17f and wild type (WT) mice were exposed to cigarette smoke or environmental air for 5 to 28 days and changes in inflammatory cells in bronchoalveolar lavage (BAL) fluid were determined. We also measured the mRNA expression of keratinocyte derived chemokine (Kc), macrophage inflammatory protein-2 (Mip2), granulocyte-macrophage colony stimulating factor (Gmcsf) and matrix metalloproteinase-9 (Mmp9 ) in lung tissue after 8 days, and lung morphometric changes after 24 weeks of exposure to cigarette smoke compared to air-exposed control animals. Macrophage counts in BAL fluid initially peaked at day 8 and again on day 28, while neutrophil counts peaked between day 8 and 12 in WT mice. Mice dual deficient with Il17a and 1l17f showed similar kinetics with macrophages and neutrophils, but cell numbers at day 8 and mRNA expression of Kc, Gmcsf and Mmp9 were significantly reduced. Furthermore, airspaces in WT mice became larger after cigarette smoke exposure for 24 weeks, whereas this was not seen dual Il17a and 1l17f deficient mice. Combined Il17a and Il17f deficiency resulted in significant attenuation of neutrophilic inflammatory response and protection against structural lung changes after long term cigarette smoke exposure compared with WT mice. Dual IL-17A/F signalling plays an important role in pro-inflammatory responses associated with histological changes induced by cigarette smoke exposure.

CD4⁺ T-helper 22 (Th22) cells are a phenotypically distinct lymphocyte subset that produces high levels of interleukin (IL)-22 without co-production of IL-17A. However, the developmental origin and lineage classification of Th22 cells, their interrelationship to Th17 cells, and potential for plasticity at sites of infection and inflammation remain largely undefined. An improved understanding of the mechanisms underpinning the outgrowth of Th22 cells will provide insights into their regulation during homeostasis, infection, and disease. To address this knowledge gap we generated 'IL-17A-fate-mapping IL-17A/IL-22 reporter transgenic mice' and show that Th22 cells develop in the gastrointestinal tract and lung during bacterial infection without transitioning via an Il17a-expressing intermediate, although in some compartments alternative transition pathways exist. Th22-cell development was not dependent on T-bet; however, this transcription factor functioned as a promiscuous T-cell-intrinsic regulator of IL-17A and IL-22 production, in addition to regulating the outgrowth, phenotypic stability, and plasticity of Th22 cells. Thus, we demonstrate that at sites of mucosal bacterial infection Th22 cells develop as a distinct lineage independently of Th17 cells; though both lineages exhibit bidirectional phenotypic flexibility within infected tissues and their draining lymph nodes, and that T-bet plays a critical regulatory role in Th22-cell function and identity.