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IL-12 Administration Reveals Diabetogenic T Cells in Genetically Resistant I-E-Transgenic Nonobese Diabetic Mice: Resistance to Autoimmune Diabetes Is Associated with Binding of E-Derived Peptides to the I-A^g7 Molecule¹

Sylvie Trembleau^*, Silvia Gregori^*, Giuseppe Penna^*, Irmina Gorny and Luciano Adorini^2,*

^* Roche Milan Ricerche, Milan, Italy; and Research Institute of Molecular Pathology, Vienna, Austria

Nonobese diabetic (NOD) and NOD-DR transgenic (tg) mice, expressing A^d:A^g7 and A^d:A^g7 plus DR:E^g7 class II molecules, respectively, both develop insulin-dependent diabetes mellitus (IDDM), whereas NOD-E tg mice expressing A^d:A^g7 plus E:E^g7 are protected. We show that IL-12 administration induces rapid IDDM onset in NOD-DR but fails to provoke insulitis and diabetes in NOD-E tg mice. Nevertheless, T cells from IL-12-treated NOD-E tg mice secrete IFN- and transfer IDDM to NOD-SCID and NOD-E-SCID recipients, demonstrating the presence of peripheral diabetogenic Th1 cells in the protected mice. Surprisingly, regulatory cells were undetectable. Moreover, E:E^g7 could substitute for DR:E^g7 in Ag presentation, arguing against mechanisms of protection involving capture of diabetogenic I-A^g7-restricted epitopes by E:E^g7molecules. Interestingly, the expression of naturally processed epitopes derived from DR- and E-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 and NOD-E tg mice present the conserved DR/E 52-68 sequence, at high and low levels, respectively. In addition, only IDDM-resistant NOD-E tg mice possess APCs bearing E65-77/I-A^g7 complexes, which tolerize the specific T cells. This is associated with the selective inhibition of the response to insulinoma-associated protein 2 (IA-2), an autoantigen in IDDM. Our results support protective mechanisms based on I-A^g7 blockade by peptides unique to the E-chain, such as E65-77 and/or tolerance of diabetogenic T cells cross-reactive with E-peptide/I-A^g7 complexes.

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