Several mechanisms have been proposed to explain how certain MHC class II molecules afford dominant resistance to autoimmune diseases like type 1 diabetes (T1D). However, it remains unclear how protective MHC types can blunt autoreactive T cell responses directed against a diverse repertoire of autoantigenic epitopes presented by disease-promoting MHCs. In this study, we show that expression of I-E on dendritic cells (DCs) of NOD mice promotes the differentiation of MHC promiscuous autoreactive CD4+ clonotypes into antidiabetogenic autoregulatory T cells. We expressed an I-EαkloxP transgene in NOD mice and used cell type–specific I-E ablation to show that I-E–expressing DCs, but not B cells, promote the generation of autoreactive CD4+Foxp3+ regulatory T cells (Tregs) and their accumulation in the pancreas-draining lymph nodes. There, these Tregs suppress the presentation of β cell Ags to naive autoreactive CD4+ and CD8+ T cells restricted by diabetogenic MHC molecules in an I-E–independent manner. Whereas selective removal of I-E on DCs abrogated autoregulatory Treg formation and T1D protection, selective removal of I-E on B cells was inconsequential. These results explain how certain MHC class II molecules can completely suppress antigenically complex autoimmune responses in an Ag-nonspecific manner.

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We investigated whether a prevalent epitope of the β-cell–specific autoantigen islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP206–214) reaches regional Ag-presentation pathways via unprocessed polypeptide chains, as free IGRP206–214 peptide or via preformed IGRP206–214/Kd complexes. This was accomplished by expressing bacterial artificial chromosome transgenes encoding wild-type (stable) or ubiquitinated (unstable) forms of IGRP in IGRP-deficient NOD mice carrying MHC class I–deficient β-cells, dendritic cells, or B cells. We investigated the ability of the pancreatic lymph nodes of these mice to prime naive IGRP206–214-reactive CD8+ T cells in vivo, either in response to spontaneous Ag shedding, or to synchronized forms of β-cell necrosis or apoptosis. When IGRP was made unstable by targeting it for proteasomal degradation within β-cells, the cross-priming, autoimmune-initiating potential of this autoantigen (designated autoantigenicity) was impaired. Yet at the same time, the direct presentation, CTL-targeting potential of IGRP (designated pathogenicity) was enhanced. The appearance of IGRP206–214 in regional Ag-presentation pathways was dissociated from transfer of IGRP206–214 or IGRP206–214/Kd from β cells to dendritic cells. These results indicate that autoantigenicity and pathogenicity are separable and inversely related properties and suggest that pathogenic autoantigens, capable of efficiently priming CTLs while marking target cells for CTL-induced killing, may have a critical balance of these two properties.