PD-1 deficiency reveals various tissue-specific autoimmunity by H-2b and dose-dependent requirement of H-2g7 for diabetes in NOD mice.

Although many autoimmune diseases are associated with particular HLA/H-2 haplotypes, the mechanisms through which specific HLA/H-2 haplotypes afford autoimmune susceptibility remain enigmatic. Here, we analyzed the effects of the diabetes-associated (H-2(g7)) and an antidiabetogenic (H-2(b)) H-2 haplotypes in NOD mice deficient for programmed cell death-1 (PD-1, Pdcd1), a unique model of type 1 diabetes that confers complete penetrance and rapid onset of the disease. NOD-H2(b/b)Pdcd1(-/-) mice were completely protected from diabetes, confirming that H-2(g7) is indispensable for diabetes even in the absence of PD-1. However, NOD-H2(b/b)Pdcd1(-/-) mice developed autoimmune inflammation in multiple tissues including peripheral nerves, stomachs, and exocrine tissues, demonstrating that autoreactive T cells are generated in the context of H-2(b). These autoreactive T cells damaged target tissues only in the absence of PD-1, confirming that PD-1 deficiency unravels the hidden autoimmune susceptibility of the strain by reducing the threshold of T cell activation. Transfer experiments revealed that CD4 T cells are the effector cells of neuritis, and nerve-infiltrating CD4 T cells are strongly deviated toward Th1. Interestingly, neuritogenic T cells were also generated in the context of H-2(g7), in sharp contrast to the strict requirement of H-2(g7) for diabetes. In addition, 60% of the NOD-H2(b/g7)Pdcd1(-/-) mice developed diabetes, suggesting that H-2(b) does not dominantly suppress diabetes and that H-2(g7) induces diabetes in a dose-dependent fashion.