ArticleDiabetes2025
Reduced Function of the Adaptor SH2B3 Promotes T1D via Altered Cytokine-Regulated, T-Cell-Intrinsic Immune Tolerance.
Article in Diabetes, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Lnk Governs chemokine-directed trafficking of CD8Molecular therapy. Oncology · 2026Article
- Lnk/Sh2b3 regulates initiation and severity of autoimmune insulitis and contributes to diabetes risk.Life science alliance · 2025Article
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14 authors.
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Abstract
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.
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