Allergic asthma and obesity are major public 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 unfolded protein response factor XBP1s in an mTOR- and MAPK-dependent manner in pro-allergic TH2 cells; 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 XBP1s expression in splenic CD4+ T cells. XBP1s is required for leptin-mediated pro-allergic TH2 cell survival and cytokine production. Our results reveal a previously unappreciated insight that obesity-associated hyperleptinemia contributes to enhanced pro-allergic lymphocyte responses through induction of XBP1s, leading to exacerbation of allergic asthma.

Autophagy is a homeostatic and inducible process affecting multiple aspects of the immune system. This intrinsic cellular process is involved in MHC-antigen (Ag) presentation, inflammatory signaling, cytokine regulation, and cellular metabolism. In the context of T cell responses, autophagy has an influential hand in dictating responses to self and non-self by controlling extrinsic factors (e.g., MHC-Ag, cytokine production) in antigen-presenting cells (APC) and intrinsic factors (e.g., cell signaling, survival, cytokine production, and metabolism) in T cells. These attributes make autophagy an attractive therapeutic target to modulate T cell responses. In this review, we examine the impact autophagy has on T cell responses by modulating multiple aspects of APC function; the importance of autophagy in the activation, differentiation and homeostasis of T cells; and discuss how the modulation of autophagy could influence T cell responses.

Maintenance of regulatory T (Treg) cells is crucial for the regulatory function of Treg cells in immune homeostasis and self-tolerance; however, the detailed underlying mechanisms remain elusive. In the current study, we found that the cytokine suppressor CIS is required for maintenance of Treg cell identity. Mice with Treg specific Cis-deficiency displayed aggravated

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.