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T cell specic SOCS1 decient histone deacetylase inhibitor mice developed autoimmune inammatory diseases with age and were extremely sensitive to dextran sulfate sodium induced colitis and ConA induced hepatitis, but were resistant to EAE, a common Th17 sort illness. Th17 suppression by SOCS1 deciency is most likely due to the hyperproduction and signal transduction of IFN?. Indeed, STAT1 histone deacetylase inhibitor activation in SOCS1 T cells was upregulated and strong Th1 skewing was corrected under STAT1 conditions. Interestingly, STAT3 activation was reduced in SOCS1decient T cells, mostly due to the upregulation of SOCS3 gene expression, which can account for reduced IL 6 responses and Th17 dierentiation. Indeed, SOCS3 tg mice were resistant to EAE, and Th17 dierentiation of SOCS3 tg T cells was suppressed.

The reciprocal regulation of Th1 and Th17 by SOCS1 and SOCS3 is illustrated in Figure 3. In addition, SOCS1 T cells were less responsive to TGF B, although the mechanism has not yet been claried. Reduced STAT3 activation and TGF B signaling may explain the suppression of Th17 dierentiation in SOCS1 decient T cells. Our microarray IEM 1754 analysis revealed that T bet, Eomesodermin, and G 1 were upregulated in SOCS1deceint T cells under Th17 skewing conditions, all of which have been reported to suppress Th17 dierentiation. Role of SOCS1 and SOCS3 in Th dierentiation is summarized in Figures 3 and 4A. Suppressor of cytokine signaling 1 also plays an important role in the regulation of regulatory T cells. Higher numbers of Tregs are observed in the thymus and spleen of T cell specic SOCS1decient mice.

This is probably due to higher IL 2 responses, because IL 2 enhances the proliferation of Tregs. Importantly, SOCS1 PARP has been shown to be a target of miRNA 155 in Tregs. During thymic dierentiation, the upregulation of Foxp3 drives the high expression of miR155, which in turn promotes the expansion of Treg cells by targeting SOCS1. However, SOCS1 has recently been found to play more important functional roles in Tregs. Various studies have suggested that Tregs may become harmful eector T cells in inammatory conditions. Lu et al. observed that SOCS1 deletion specically in Tregs induced the development of spontaneous dermatitis, splenomegaly, and lymphadenopathy, suggesting a defective Treg function in these mice. The defective suppression activity of SOCS1 decient Tregs was conrmed through the failure to suppress colitis in Rag2 mice by the co transfer of nave T cells and Tregs.

In the absence of SOCS1, Tregs easily lost Foxp3 expression, and became pathogenic T cells that induced severe colitis. In addition, SOCS1 plays an important role IEM 1754 in preventing inammatory cytokine production from Tregs. Normally, Tregs do not secrete inammatory cytokines even in inammatory conditions. In the absence of SOCS1, Tregs secrete IFN? and IL 17 by hyperactivation of STAT1 and STAT3, respectively. Thus, SOCS1 is a guardian of Tregs, since SOCS1 inhibits loss of Foxp3 and conversion of Tregs to Th1 or Th17 like cells. The degree to which SOCS3 expression in T cells is increased is correlated to the severity of human allergic diseases such as asthma and atopic dermatitis.

The enhanced action of SOCS3 may promote allergic responses, since transgenic SOCS3 expression in T cells inhibits Th1 development and promotes Th2 development. Enhanced Th2 development may be due to the suppression of Th1 because IL 12 mediated Th1 dierentiation by SOCS3 overexpression. Therefore, SOCS3 tg mice were sensitive to L. Major infection, where Th1 is necessary for eradication histone deacetylase inhibitor of this microbe. As described before, SOCS3 expressing T cells dierentiated into Th17 cells less efciently than WT T cells. In contrast, mice lacking SOCS3 in T cells result in reduced allergen induced eosinophilia in the airways. SOCS3 silencing with small interfering RNA in primary CD4 T cells attenuated the Th2 response in vitro and in vivo. SOCS3 deciency promoted Th17 dierentiation in T cells. Using VavCre SOCS3 cKO mice, Wong et al.

reported that the IL 1 induced inammatory joint disease model was severely deteriorated in the absence of SOCS3 accompanying the enhanced IL 17 production from CD4 T cells. SOCS3 deciency in T cells reduced atherosclerotic lesion development and vascular inammation, which was dependent on IL 17, IEM 1754 whereas the overexpression of SOCS3 in T cells reduced IL 17 and accelerated atherosclerosis. The absence of SOCS3 in helper T cells therefore generally inhibits Th1 and Th2 by producing IL 10 and TGF B, but had dramatic pro inammatory eects under Th17 conditions. Recently, leukemia inhibitory factor has been shown to inhibit Th17 dierentiation by inducing SOCS3. The paradoxical eect of SOCS3 on T cell regulation is mostly due to the dual function of STAT3, it promotes the production of both inammatory IL 17 and anti inammatory IL 10 and TGF B.