Reduced Function of the Adaptor SH2B3 Promotes T1D via Altered Cytokine-Regulated, T-Cell–Intrinsic Immune Tolerance

Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D. Fine mapping has demonstrated the most credible causative variant is the single nucleotide rs3184504*T polymorphism in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T-cell–intrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on T-cell receptor (TCR) signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common γ-chain–dependent and interferon-γ receptor signaling. SH2B3-deficient naive CD8+ T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the rat insulin promoter–membrane-bound ovalbumin (RIP-mOVA) model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival and reduced activation-induced cell death. Lastly, we created a spontaneous NOD.Sh2b3−/− mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T-cell tolerance limiting the T-cell response to self-antigens. Article Highlights The rs3184504*T polymorphism, encoding a hypomorphic variant of the negative regulator SH2B3, strongly associates with type 1 diabetes. SH2B3 deficiency results in hypersensitivity to cytokines, including IL-2 and IFN-γ, in murine CD4+ and CD8+ T cells, particularly postactivation. SH2B3-deficient CD8+ T cells exhibit a transcriptome comparable to wild-type CD8+ T cells at baseline, but, upon antigen stimulation, SH2B3-deficient cells upregulate genes characteristic of enhanced JAK-STAT signaling and effector functions. T-cell–intrinsic SH2B3 deficiency results in severe islet destruction in an adoptive transfer murine type 1 diabetes model, whereas global SH2B3 deficiency accelerates spontaneous NOD diabetes across sexes.