Deficient activation and resistance to activation-induced apoptosis of CD8+ T cells is associated with defective peripheral tolerance in nonobese diabetic mice |
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Authors: | Arreaza Guillermo Salojin Konstantin Yang Wen Zhang Jian Gill Bruce Mi Qing-Sheng Gao Jian-Xin Meagher Craig Cameron Mark Delovitch Terry L |
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Institution: | Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, NG6 2V4, London, ON, Canada. |
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Abstract: | Activation-induced cell death (AICD) is a mechanism of homeostasis that limits the clonal expansion of autoreactive T cells and regulates central and peripheral tolerance. In nonobese diabetic (NOD) mice, defects in central and peripheral tolerance are associated with a proliferative hyporesponsiveness of thymocytes and peripheral T cells elicited upon TCR activation. We investigated whether these defects in tolerance induction and hyporesponsiveness of NOD T cells manifest in an altered susceptibility to TCR-induced AICD. TCR-activated NOD splenic CD4+ and CD8+ T cells are more resistant to AICD than control strain C57BL/6, BALB/c, and NOR T cells. NOR CD4+ but not CD8+ T cells are resistant to TCR-induced AICD. Whereas c-FLIP expression is reduced in activated T cells from control strains, it persists in activated NOD CD8+ T cells and is accompanied by diminished activity of caspase-3 and -8. IL-4 reduces this c-FLIP expression and increases caspase-3 and -8 activity in activated NOD CD8+ T cells. Moreover, IL-4 and CD28 costimulation restores the susceptibility of NOD CD8+ T cells to AICD, and this is associated with increased expression of CD25, CD95, CD95L, and TNFR2. Thus, deficient activation of CD8+ T cells and their greater resistance to TCR-induced AICD may mediate defective peripheral tolerance and the development of T1D in NOD mice. |
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Keywords: | NOD mice Type 1 diabetes T cells Apoptosis Resistance |
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