APOPTOSIS RESISTANCE OF NONOBESE DIABETIC PERIPHERAL LYMPHOCYTES LINKED TO THE IDD5 DIABETES SUSCEPTIBILITY REGION

Defects in lymphocyte apoptosis may lead to autoimmune disorders and c ontribute to the pathogenesis of type 1 diabetes. Lymphocytes of nonob ese diabetic (NOD) mice, an animal model of autoimmune diabetes, hare been found resistant to various apoptosis signals, including the alkyl ating drug cyclophosphamide. Using an F-2 intercross between the apopt osis-resistant NOD mouse and the apoptosis-susceptible C57BL/6 mouse, we define a major locus controlling the apoptosis-resistance phenotype and demonstrate its linkage (logarithm of odds score = 3.9) to a grou p of medial markers on chromosome 1, The newly defined gene cannot be dissociated from Ctla4 and Cd28 and in fact marks a 20-centimorgan reg ion encompassing Idd5, a previously postulated diabetes susceptibility locus, Interestingly, we find that the CTLA-4 (cytotoxic T lymphocyte -associated antigen 4) and the CD28 costimulatory molecules are defect ively expressed in NOD mice, suggesting that one or both of these mole cules may be involved in (he control of apoptosis resistance and, in t urn, in diabetes susceptibility.