IL-12 administration reveals diabetogenic T cells in genetically resistantI-E alpha-transgenic nonobese diabetic mice: Resistance to autoimmune diabetes is associated with binding of E alpha-derived peptides to the I-A(g7) molecule

Nonobese diabetic (NOD) and NOD-DR alpha transgenic (tg) mice, expressing A alpha (d):A beta (g7) and A alpha (d):A beta (g7) plus DR alpha :E beta (g 7) class II molecules, respectively, both develop insulin-dependent diabete s mellitus (IDDM), whereas NOD-E alphaa tg mice expressing A alpha (d):A be ta (g7) plus E alpha :E beta (g7) are protected. We show that IL-12 adminis tration induces rapid IDDM onset in NOD-DR alpha but fails to provoke insul itis and diabetes in NOD-E alpha tg mice. Nevertheless, T cells from IL-12- treated NOD-E alpha tg mice secrete IFN-gamma and transfer IDDM to NOD-SCID and NOD-E alpha -SCID recipients, demonstrating the presence of peripheral diabetogenic Th1 cells in the protected mice. Surprisingly, regulatory cel ls were undetectable. Moreover, E alpha :E beta (g7) could substitute for D R alpha :E beta (g7) in Ag presentation, arguing against mechanisms of prot ection involving capture of diabetogenic I-A(g7)-restricted epitopes by E a lpha: E beta (g7) molecules. Interestingly, the expression of naturally pro cessed epitopes derived from DR alpha- and E alpha -chains bound to I-A(g7) is different in the two strains of tg mice, and the difference is enhanced by IL-12 administration. I-A(g7) molecules from both NOD-DR alpha and NOD- E alpha tg mice present the conserved DR alpha /E alpha 52-68 sequence, at high and low levels, respectively. In addition, only IDDM-resistant NOD-E a lpha tg mice possess APCs bearing E alpha 65-77/I-A(g7) complexes, which to lerize the specific T cells. This is associated with the selective inhibiti on of the response to insulinoma-associated protein 2 (IA-2), an autoantige n in IDDM. Our results support protective mechanisms based on I-A(g7) block ade by peptides unique to the E alpha -chain, such as E alpha 65-77 and/or tolerance of diabetogenic T cells cross-reactive with E alpha -peptide/I-A( g7) complexes.