Analysis of the role of variation of major histocompatibility complex class II expression on nonobese diabetic (NOD) peripheral T cell response

The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-asso ciated MHC molecules leads to a T cell-mediated immune response and resulta nt autoimmune sequelae. The data presented below offer a different model fo r this association of MHC with autoimmune diabetes. We used several mouse l ines expressing different levels of I-A(g7) and I-A(k) on the nonobese diab etic (NOD) background to evaluate the role of MHC class II in the previousl y described NOD T cell autoproliferation. The ratio of I-A(g7) to I-A(k) ex pression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD x NOD.I-A(null) ]F1, and NO D I-A(k) transgenic mice demonstrated autoproliferative responses (after pr iming with self-peptides), whereas the NOD.H2(h4) (containing I-A(k)) conge nic and [NOD x NOD.H2(h4) congenic]F1 mice did not. Analysis of CD4(+) T ce lls in the NOD I-A(k) transgenic primed lymph node cells showed that autore active CD4(+) T cells in the NOD I-A(k) transgenic mice were restricted and exclusively by I-A(g7). Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacit y of NOD I-A(g7) suggested a new hypothesis to explain the effects of MHC c lass II expression on the peripheral autoimmune repertoire in NOD mice. Thi s new explanation suggests that the association of MHC with diabetes result s from "altered" thymic selection in which high affinity self-reactive (pot entially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression i n NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.