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

作者：Taylor K. Watson, Aaron B.I. Rosen, Travis Drow, Jacob A. Medjo, Matthew A. MacQuivey, Yan Ge, Denny Liggitt, Dane A. Grosvenor, Kimberly A. Dill‐McFarland, Matthew C. Altman, Patrick Concannon, Jane H. Buckner, David J. Rawlings, Eric J. Allenspach · 发表于：Diabetes · 年份：2025 · DOI：10.2337/db24-0655 · 被引用次数：2 · 研究领域：Diabetes and associated disorders、T-cell and B-cell Immunology、Immune Cell Function and Interaction

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 rs31...