I-A^g7 β56/57 polymorphisms regulate non-cognate negative selection to CD4⁺ T cell orchestrators of type 1 diabetes

Genetic susceptibility to type 1 diabetes is associated with homozygous expression of major histocompatibility complex class II alleles that carry specific beta chain polymorphisms. Why heterozygous expression of these major histocompatibility complex class II alleles does not confer a similar predisposition is unresolved. Using a nonobese diabetic mouse model, here we show that heterozygous expression of the type 1 diabetes-protective allele I-A^g7 β56P/57D induces negative selection to the I-A^g7-restricted T cell repertoire, including beta-islet-specific CD4⁺ T cells. Surprisingly, negative selection occurs despite I-A^g7 β56P/57D having a reduced ability to present beta-islet antigens to CD4⁺ T cells. Peripheral manifestations of non-cognate negative selection include a near complete loss of beta-islet-specific CXCR6⁺ CD4⁺ T cells, an inability to cross-prime islet-specific glucose-6-phosphatase catalytic subunit-related protein and insulin-specific CD8⁺ T cells and disease arrest at the insulitis stage. These data reveal that negative selection on non-cognate self-antigens in the thymus can promote T cell tolerance and protection from autoimmunity.