To investigate diabetes resistance to T cell-mediated disease transfer, we administered islet-specific T cell clones to the F1( )progeny of nonobese diabetic (NOD) mice that were crossed with various nondiabetes-prone inbred mouse strains. We investigated four diabetogenic CD4(+) T cell clones and all induced insulitis and full development of diabetes in (SWR x NOD)F-1, (SJL x NOD)F-1, and (C57BL/6 x NOD)F-1 mice. in contrast, (BALB/c x NOD)F-1 and (CBA x NOD)F-1 mice were susceptible to disease transfer by some T cell clones but not others, and (C57/L x NOD)F-1 mice seemed to be resistant to both insulitis and disease transfer by all of the clones tested. Disease induced by the T cell clones in susceptible F-1 strains was age dependent and could only be observed in recipients younger than 13 days old. Full or partial disease resistance did not correlate with the presence or absence of I-E, different levels of Ag expression in islet cells, or differences in APC function. The results from this study suggest that there may be multiple factors contributing to susceptibility of F-1 mice to T cell clone-mediated induction of diabetes, including non-MHC-related genetic background, the immunologic maturity of the recipient, and individual characteristics of the T cell clones.