CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice

The genes conferring susceptibility to autoimmune (insulin-dependent) diabe tes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd 1 has been assessed. Here we show that thymocytes and peripheral lymphocyte s of the non-obese diabetic (NOD) mouse are relatively resistant to apoptos is induced by gamma -irradiation. By linkage analysis of F2 progeny mice, w e map this trait to a locus on chromosome 1 containing the Idd5 diabetes su sceptibility region. By the use of congenic mice, we confirm the linkage da ta and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, bei ng localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility regi on. In line with this, we demonstrate that T cells from Ctla4(-/-) deficien t mice show a similar resistance to gamma -irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contribut es to the pathogenesis of autoimmune diabetes. (C) 2001 Academic Press.