Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3+ regulatory T cells

Polymorphisms in MHC class II molecules, in particular around ?-chain position-57 (?57), afford susceptibility/resistance to multiple autoimmune diseases, including type 1 diabetes, through obscure mechanisms. Here, we show that the antidiabetogenic MHC class II molecule I-Ab affords diabetes resistance by promoting the differentiation of MHC-promiscuous autoreactive CD4+ T cells into diseasesuppressing natural regulatory T cells, in a ?56-67-regulated manner. We compared the tolerogenic and antidiabetogenic properties of CD11c promoter-driven transgenes encoding I-Ab or a form of I-Ab carrying residues 56-67 of I-A?g7 (I-Ab-g7) in wild-type nonobese diabetic (NOD) mice, as well as NOD mice coexpressing a diabetogenic and I-Ag7-restricted, butMHC-promiscuous T-cell receptor (4.1). Both I-A transgenes protected NOD and 4.1-NOD mice from diabetes. However, whereas I-Ab induced 4.1-CD4+ thymocyte deletion and 4.1-CD4+Foxp3+ regulatory T-cell development, I-Ab-g7 promoted 4.1-CD4 +Foxp3+ Treg development without inducing clonal deletion. Furthermore, non-T-cell receptor transgenic NOD.CD11cP-I-Ab and NOD.CD11cP-IAb-g7 mice both exported regulatory T cells with superior antidiabetogenic properties than wild-type NOD mice. We propose that I-A b, and possibly other protective MHC class II molecules, afford disease resistance by engaging a naturally occurring constellation of MHC-promiscuous autoreactive T-cell clonotypes, promoting their deviation into autoregulatory T cells.