Reduced function of the adaptor SH2B3 promotes T1D via altered gc cytokine-regulated, T cell intrinsic immune tolerance

Genome-wide assocation studie have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single haplotype strongly associated with risk for human T1D that includes the sinlge nucleotide variant rs3184505*T in SH2B3. To better characterize the role of SH2B3 in T1D, we used moouse modeling and found a T cell-intrisic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or. proliferation across antigen doses, yet enhance cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling. SH2B3 deficient CD8+T cells showed augmented STAT5-Myc and effector function gene expression partially reversed when blocking autocrine IL-2 in culture. Using the RIP-mOVA model, we found T cells lacking SH2B3 promoted early islet destruction and diasbetes without requiring CD4+ T cell help. SH2B3-deficient cells demontrated increased survival post-transfer compared to control cells despite a similar proliferation profile in the same host. Next we created a spontatneous NOD.Sh2b3-/- mouse model and found markedly increased incidence and accelerated T1D across genders. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T cell tolerance lmiting the T cell response to self-antigens.