Reduced Function of the Adaptor SH2B3 Promotes T1D via Altered Cytokine-Regulated, T-Cell–Intrinsic Immune Tolerance
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.
Authors
- Kimberly A. Dill‐McFarland (ORCID: https://orcid.org/0000-0003-1481-7065)
- Jane H. Buckner (ORCID: https://orcid.org/0000-0002-9005-1885)
- David J. Rawlings (ORCID: https://orcid.org/0000-0002-0810-1776)
- Eric J. Allenspach (ORCID: https://orcid.org/0000-0001-7346-5835)
- Aaron B.I. Rosen (ORCID: https://orcid.org/0000-0003-4416-1837)
- Matthew C. Altman (ORCID: https://orcid.org/0000-0002-1784-8505)
- Matthew A. MacQuivey
- Patrick Concannon (ORCID: https://orcid.org/0000-0002-5801-1859)
- Denny Liggitt (ORCID: https://orcid.org/0000-0003-4511-1700)
- Travis Drow (ORCID: https://orcid.org/0000-0002-1302-3872)
- Yan Ge (ORCID: https://orcid.org/0009-0001-4374-9404)
- Jacob A. Medjo
- Taylor K. Watson (ORCID: https://orcid.org/0000-0001-7346-340X)
- Dane A. Grosvenor
Institutions
- Center for Infectious Disease Research (US)
- Seattle Children's Hospital (US)
- University of Pittsburgh (US)
- University of Washington (US)
- University of Florida (US)
- Genetic Resources Center (JP)
- Carnegie Mellon University (US)
Publication Details
- Journal
- Diabetes
- Published
- 2025-03-06
- DOI
- https://doi.org/10.2337/db24-0655
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80