Impaired CD4 T cell activation due to reliance upon B cell-mediated costimulation in nonobese diabetic (NOD) mice

Diabetes in nonobese diabetic (NOD) mice results from the activation of I-A (g7)-restricted, islet-reactive T cells. This study delineates several char acteristics of NOD CD4 T cell activation, which, independent of I-A(g7), ar e likely to promote a dysregulated state of peripheral T cell tolerance. NO D CD4 T cell activation was found to be resistant to antigenic stimulation via the TCR complex, using the progression of cell division as a measure. T he extent of NOD CD4 T cell division was highly sensitive to changes in Ag ligand density. Moreover, even upon maximal TCR complex-mediated stimulatio n, NOD CD4 T cell division prematurely terminated. Maximally stimulated NOD CD4 T cells failed to achieve the threshold number of division cycles requ ired for optimal susceptibility to activation-induced death, a critical mec hanism for the regulation of peripheral T cell tolerance, Importantly, thes e aberrant activation characteristics were not T cell-intrinsic but resulte d from reliance on B cell costimulatory function in NOD mice. Costimulation delivered by nonautoimmune strain APCs normalized NOD CD4 T cell division and the extent of activation-induced death. Thus, by disrupting the progres sion of CD4 T cell division, polarization of APC costimulatory function to the B cell compartment could allow the persistence and activation of diabet ogenic cells in NOD mice.