Defect in activation-induced cell death in non-obese diabetic (NOD) T lymphocytes

Activation-induced cell death (AICD) represents a major means of peripheral tolerance induction, eliminating effector cells. NOD mice. a widely used model for autoimmune diabetes, are characterized by high levels of circulating T lymphocytes and by resistance to several apoptosis-inducing signals. The aim of this study was to analyse AICD in peripheral NOD T lymphocytes. First, we demonstrated in an in vitro AICD model that NOD T lymphocytes are more resistant to AICD (64 +/- 2%) compared to non-autoimmune C57BL/6 T lymphocytes (73 +/- 2%), but also diabetes-resistant NOR T lymphocytes (76 +/- 3%, P < 0.05). Moreover, both CD4(+) and CD8(+) subsets were affected. Analysis of the cellular and molecular pathways revealed lower caspase 8 levels, a central caspase proximally involved in the AICD-pathway (fluorescence of 258 147 in NOD vs. 441 16 in NOR and 414 61 in C57BL/6 T lymphocytes, P < 0.05). Gene expression analysis using real-time RT-PCR additionally revealed low expression of Fas and FasL. the death receptor system activating caspase 8 and contributing to AICD. Additionally, low IL-2 levels, together with high TGFbeta and Bclx-L levels. confirm the presence of a NOD-specific AICD-resistance profile. In conclusion, we present cellular and molecular evidence for disturbed AICD mechanisms in NOD T lymphocytes. This resistance in AICD may contribute to defective tolerance induction to autoantigens in NOD mice. (C) 2003 Elsevier Science Ltd. All rights reserved.