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SOCS1 profoundly influences the development and peripheral homeostasis of CD8+ T cells but has less impact on CD4+ T cells. Despite the moderate influence of SOCS1 in the development of the total CD4 T-cell lineage, we show here that SOCS1 deficiency resulted in a 10-fold increase in Foxp3+ CD4+ T cells in the thymus. Increased numbers of Foxp3+ thymocytes occurred in mice with T-cell-specific ablation of SOCS1, suggesting that the effect is T-cell intrinsic. This increase in Foxp3+ CD4+cells in SOCS1-deficient mice also occurred in the absence of IFN-γ or/and IL-7 signaling. Increase in CD25+CD4+ T cells in the absence of SOCS1 could be partly due to enhanced survival by CD25+CD4+cells, to a lesser degree CD25−CD4+ T cells, from SOCS1-deficient mice with or without T-cell growth factors.Immunology and Cell Biology (2009) 87, 473–480; doi:10.1038/icb.2009.23; published online 21 April 2009 [ABSTRACT FROM AUTHOR]

CD4+ T cells can actively kill β-cells in type I diabetes as well as help CD8+ T cells become cytolytic. Cytokines have the potential to kill β-cells, or upregulate Fas on β-cells, and increase their susceptibility to FasL. We investigated the direct effects of cytokines on β-cells in perforin-deficient non-obese diabetic (NOD) mice and NOD4.1 TCR transgenic mice, two models in which CD8+ T cells play a less dominant role. Inhibiting the effects of cytokines by the overexpression of suppressor of cytokine signalling-1 (SOCS1) in β-cells did not reduce diabetes or insulitis in perforin-deficient NOD, NOD4.1 or interleukin (IL)-1 receptor-deficient NOD4.1 mice. SOCS1 overexpression prevented Fas upregulation on NOD4.1 β-cells, but did not prevent islet destruction because SOCS1 transgenic islets were killed when grafted into NOD4.1.scid mice. Likewise, Fas-deficient NOD.lpr islets were destroyed in NOD4.1 mice. Although blocking the effects of interferon (IFN)γ on β-cells did not affect diabetes in NOD4.1 mice, global deficiency of IFNγR2 reduced diabetes and insulitis, suggesting that IFNγ is involved in CD4+ T-cell activation or migration. Our data show that β-cells under attack by CD4+ T cells are not destroyed by the effects of cytokines including IFNγ and IL-1 or Fas-dependent cytotoxicity.Immunology and Cell Biology (2009) 87, 178–185; doi:10.1038/icb.2008.81; published online 18 November 2008 [ABSTRACT FROM AUTHOR]

Pro-inflammatory cytokines have been implicated in the death of pancreatic beta cells leading to type 1 diabetes. NIT-1 cells are an insulinoma cell line derived from mice expressing the SV40 large T antigen. These cells are a useful tool in analysis of beta cell death. NIT-1 cells are highly susceptible to caspase-dependent apoptosis induced by TNF-α alone. Primary islets are not susceptible to cell death induced by TNF-α alone; however, they are killed by TNF-α and IFN-γ in a nitric oxide-dependent manner. We examined signal transduction in NIT-1 cells in response to cytokines to determine the mechanism for TNF-α-induced apoptosis. We found that NIT-1 cells are defective in the activation of nuclear factor-κB (NFκB) as a result of functionally deficient RelA activity, because overexpression of RelA protected NIT-1 cells from apoptosis. TNF-α also did not induce phosphorylation of c-Jun N-terminal kinase in NIT-1 cells. Together, these defects prevent expression of anti-apoptotic genes in NIT-1 cells and make them susceptible to TNF-α. To determine whether similar defects in primary beta cells would induce the same effect, we examined TNF-α-induced apoptosis in islets isolated from mice deficient in NFκB p50. These islets were as susceptible as wild-type islets to TNF-α and IFN-γ-induced cell death. In contrast to wild-type islets, cell death was not prevented by inhibition of nitric oxide in p50-deficient islets. Blocking NFκB has been proposed as a mechanism for protection of beta cells from cytokine-induced cell death in vivo. Our results suggest that this would make beta cells equally or more sensitive to cytokines. [ABSTRACT FROM AUTHOR]