The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation

Abstract

Transcription factors of the STAT (signal transducer and activator of transcription) family are critical in the cytokine-mediated functional differentiation of CD4 + helper T cells. Members of the SOCS (suppressor of cytokine signaling) family negatively regulate the activation of STAT proteins; however, their roles in the differentiation and function of helper T cells are not well understood. Here we found that the SOCS protein CIS, which was substantially induced by interleukin 4 (IL-4), negatively regulated the activation of STAT3, STAT5 and STAT6 in T cells. CIS-deficient mice spontaneously developed airway inflammation, and CIS deficiency in T cells led to greater susceptibility to experimental allergic asthma. CIS-deficient T cells showed enhanced differentiation into the T H 2 and T H 9 subsets of helper T cells. STAT5 and STAT6 regulated IL-9 expression by direct binding to its gene. Our data thus demonstrate a critical role for CIS in controlling proallergic generation of helper T cells.

Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination

“…Therefore, the level of pSTAT3 in monocytes likely reflects the sum of diverse inflammatory stimuli targeting STAT3. Consistent with these observations, the phosphorylation levels of STAT3 and other STAT proteins have been found to be increased in asthma (30) and in other inflammatory conditions (31). With respect to the influenza vaccine response, our results indicate that the natural variation in circulating free testosterone could drive many of the differences observed in the response to vaccines.…”

Prerequisites for Functional Interleukin 31 Signaling and Its Feedback Regulation by Suppressor of Cytokine Signaling 3 (SOCS3)

“…In particular, skin inflammation is strongly regulated by SOCS1 and SOCS3, as SOCS3 deficiency in keratinocytes causes severe skin inflammation, whereas keratinocyte-specific SOCS1 overexpression down-regulates the expression of specific pro-inflammatory mediators in the skin (30). In the context of type 2 inflammation, the SOCS family member cytokine-inducible SH2-containing protein (CIS) has recently been shown to regulate pro-allergic T helper cell development and to control allergic inflammation (31). In this study, we demonstrated that IL-31 is able to enhance the expression of SOCS1, SOCS2, SOCS3, and CISH in a time-dependent manner.…”

Cell Regulation by Phosphotyrosine-Targeted Ubiquitin Ligases

“…SOCS proteins then provide feedback inhibition by binding to cytokine receptors and JAK kinases. Accordingly, mutations of SOCS1 (100-102) and SOCS3 (103-105) have major effects on erythropoiesis, the immune system, and the placenta, while CISH deletion also affects immunity but in a more subtle way (106).…”