H. Noorchashm et al., Impaired CD4 T cell activation due to reliance upon B cell-mediated costimulation in nonobese diabetic (NOD) mice, J IMMUNOL, 165(8), 2000, pp. 4685-4696
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.