HIGH-FREQUENCY APOPTOSIS OF RECENT THYMIC EMIGRANTS IN THE LIVER OF LYMPHOPENIC DIABETES-PRONE BIOBREEDING RATS

Diabetes-prone (DP) BioBreeding (BB) rats develop spontaneous autoimmu ne diabetes. DP-BB thymocyte export is reduced, and most thymic emigra nts disappear rapidly from peripheral lymphoid tissues, DP-BB rats are consequently lymphopenic and circulate severely reduced numbers of T cells. Peripheral T cells present are phenotypically immature (Thy1(+) ) and appear activated. We hypothesized that DP-BB recent thymic emigr ants have a shortened life span and disappear by apoptosis, The percen tage of T cells with an alpha beta TCR(low)B220(+)CD4(-)CD8(-) phenoty pe was increased in DP peripheral lymphoid tissues when compared with normal, nonlymphopenic diabetes-resistant (DR) BB rat tissues. There w as no evidence of DNA fragmentation in freshly isolated DP- or DR-BB r at cells, but, after 24 h of culture, a higher proportion of DP- than DR-BB splenic T cells underwent apoptosis. We then tested the hypothes is that BB rat T cells with the alpha beta TCR(low)B220(+)CD4(-)CD8(-) phenotype accumulate and undergo apoptosis in the liver. Such cells w ere observed undergoing apoptosis in both DP- and DR-BB rats, but comp rised similar to 80% of intrahepatic T cells in DP vs similar to 20% i n DR-BB rats. Most alpha beta TCR(low)B220(+)CD4(-)CD8(-) cells in the liver were also Thy1(+). The data suggest that T cell apoptosis in th e DP-BB rat is underway in peripheral lymphoid tissues and is complete d in the liver. Increased intrahepatic apoptosis of recent thymic emig rants appears in part responsible for lymphopenia in DP-BB rats and th e concomitant predisposition of these animals to autoimmunity.