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IL-23 plays an essential role in TH17 cell-mediated cellular immunity and inflammation. However, the detailed mechanism remains elusive. In the current study, we found IL-23 activated the unfolded protein response (UPR) and promoted TH17 cell function. IL-23 induced UPR factor XBP1s and promotes its downstream genes in TH17 cells, leading to increased expression of TH17 cell cytokines. Induction of XBP1s required IRE1 activation by IL-23; pharmaceutical blockade of IRE1 largely diminished the effects of IL-23 on induction of TH17 cell effector cytokines. Taken together, our results suggest that IL-23 promotes TH17 cell function through activation of the UPR pathway. Targeting the IL-23-UPR axis may provide therapeutic benefit for TH17 cell-driven inflammatory and autoimmune diseases.

Maintenance of regulatory T (Treg) cells is crucial for the regulatory function of Treg cells in immune homeostasis and self-tolerance; however, the detailed mechanisms remain elusive. In this study, we found that the cytokine suppressor CIS is required for maintenance of Treg identity. Mice with Treg specific Cis-deficiency displayed aggravated experimental allergic asthma and in adulthood, developed splenomegaly, lymphadenopathy and spontaneous eosinophilic airway inflammation, accompanied by accumulation of memory T helper (TH) cells. Cis-deficiency led to decreased expression of Foxp3 and suppressive function of Treg cells. Cis-deficient Treg cells expressed TH2 signature genes, Gata3, Irf4 and Il4, and excessive IL-4-STAT6 signals resulted in repressive chromatin modification in the Foxp3 locus and permissive modification in the Il4 loci. In vitro, blockade of IL-4 restored expression of Foxp3 and suppressive function of iTreg cells. Thus, we identified a novel feedback loop in stabilization of Treg cells and inhibition of TH2 type inflammation.

Allergic asthma and obesity are both leading health problems in the world. Recent Meta-analysis studies implicated a positive relationship between serum leptin, which is elevated in obese individuals, and the risk of asthma. However, it is not well understood how obesity-associated elevation of leptin increases the risk of asthma. In the current study, we have found that leptin induces the stress response factor XBP1s in pro-allergic TH2 cells, which is required for leptin-mediated pro-allergic TH2 cell survival and cytokine production. In vivo, mice fed with high fat diet had increased serum leptin as observed in human obese population and exacerbated asthmatic symptoms, associated with increased stress responses in CD4+ T cells. Our results reveal a previously unappreciated insight that obesity-associated hyperleptinemia contributes to enhanced pro-allergic lymphocyte responses through targeting the stress response pathway, leading to exacerbation of allergic asthma.

TH17 cells play an essential role in the development of both human multiple sclerosis and animal experimental autoimmune encephalomyelitis (EAE). Nevertheless, it is not well understood how the pathogenicity of TH17 cells is controlled in the autoimmune neuro-inflammation. In vitro, we found Lumican (Lum), an extracellular matrix (ECM) protein, is selectively expressed by TH17 cells among tested murine TH subsets. Lum-deficiency leads to earlier onset and enhanced severity of experimental autoimmune encephalomyelitis. This enhanced disease in Lum-deficient mice is associated with increased production of IL-17 and IL-21 and decreased TH17 cell apoptosis. Dysregulation in cytokine production appears to be specific to TH17 cells as TH1 and TH2 cell polarization and/or cytokine production were unaltered. Furthermore, adoptive transfer of MOG-specific TH17 cells derived from Lum-deficient mice led to earlier onset and increased severity of disease compared to controls highlighting a TH17 cell-intrinsic effect of Lum. Taken together, our results suggest that Lum negatively regulates encephalitic TH17 cells, implicating a potential therapeutic pathway in TH17 cell-mediated autoimmune and inflammatory diseases.