IL-12 administration reveals diabetogenic T cells in genetically resistant I-Ealpha-transgenic nonobese diabetic mice: resistance to autoimmune diabetes is associated with binding of Ealpha-derived peptides to the I-A(g7) molecule.
Nonobese diabetic (NOD) and NOD-DRalpha transgenic (tg) mice, expressing Aalpha(d):Abeta(g7) and Aalpha(d):Abeta(g7) plus DRalpha:Ebeta(g7) class II molecules, respectively, both develop insulin-dependent diabetes mellitus (IDDM), whereas NOD-Ealpha tg mice expressing Aalpha(d):Abeta(g7) plus Ealpha:Ebeta(g7) are protected. We show that IL-12 administration induces rapid IDDM onset in NOD-DRalpha but fails to provoke insulitis and diabetes in NOD-Ealpha tg mice. Nevertheless, T cells from IL-12-treated NOD-Ealpha tg mice secrete IFN-gamma and transfer IDDM to NOD-SCID and NOD-Ealpha-SCID recipients, demonstrating the presence of peripheral diabetogenic Th1 cells in the protected mice. Surprisingly, regulatory cells were undetectable. Moreover, Ealpha:Ebeta(g7) could substitute for DRalpha:Ebeta(g7) in Ag presentation, arguing against mechanisms of protection involving capture of diabetogenic I-A(g7)-restricted epitopes by Ealpha:Ebeta(g7)molecules. Interestingly, the expression of naturally processed epitopes derived from DRalpha- and Ealpha-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-DRalpha and NOD-Ealpha tg mice present the conserved DRalpha/Ealpha 52-68 sequence, at high and low levels, respectively. In addition, only IDDM-resistant NOD-Ealpha tg mice possess APCs bearing Ealpha65-77/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 Ealpha-chain, such as Ealpha65-77 and/or tolerance of diabetogenic T cells cross-reactive with Ealpha-peptide/I-A(g7) complexes.
Trembleau
S
S
Roche Milan Ricerche, Via Olgettina 58, I-20132 Milan, Italy.
Gregori
S
S
Penna
G
G
Gorny
I
I
Adorini
L
L
D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism*; D001324:Autoantigens; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D018664:Interleukin-12 / Q000494:pharmacology*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology; D010446:Peptide Fragments; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D011948:Receptors, Antigen, T-Cell; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology
D000954:Antigens, Surface; D001324:Autoantigens; D016207:Cytokines; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; C024138:I-E-antigen; D008565:Membrane Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C117647:antigenic peptide Ealpha52-68; D018664:Interleukin-12; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8