A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes
The antigenic landscape of autoimmune diabetes reflects a failure to preserve self-tolerance, yet how novel neoantigens emerge in humans remains incompletely understood. Here we designed an immunopeptidomics-based approach to probe HLA-II-bound, islet-derived neoepitopes in patients with type 1 diabetes. We uncovered a Cys→Ser transformation, conserved between mice and humans, that reshapes autoreactivity to insulin at the single-residue level. This transformation, which we call C19S, arises from oxidative remodeling of insulin in stressed pancreatic islets and also occurs in cytokine-activated antigen-presenting cells, contributing to a feed-forward loop of neoepitope formation and presentation. Despite involving just one amino acid, C19S is recognized by HLA-DQ8-restricted, register-specific CD4<sup>+</sup> T cells that expand at diabetes onset. These neoepitope-specific CD4<sup>+</sup> T cells lack regulatory potential but acquire a poised central memory phenotype that persists throughout disease progression. These findings reveal a distinct, microenvironment-driven route of neoantigen formation that fuels sustained autoreactivity in diabetes.
Authors
- Rongzhen Yu (ORCID: https://orcid.org/0000-0002-0270-2730)
- Luc Teyton (ORCID: https://orcid.org/0000-0002-4049-1583)
- Yuqing Yang (ORCID: https://orcid.org/0000-0003-0409-2590)
- Alok V. Joglekar (ORCID: https://orcid.org/0000-0001-7554-7447)
- Orion J. Peterson (ORCID: https://orcid.org/0000-0003-2978-1501)
- Ana María Arbeláez (ORCID: https://orcid.org/0000-0001-6977-9786)
- Siddhartha Sharma (ORCID: https://orcid.org/0000-0001-8597-7547)
- Tiandao Li (ORCID: https://orcid.org/0000-0003-1650-0555)
- Laura Campisi (ORCID: https://orcid.org/0000-0003-4173-4521)
- Laura Santambrogio (ORCID: https://orcid.org/0000-0002-4674-7041)
- Lisa Kain (ORCID: https://orcid.org/0000-0001-5873-8647)
- Chyi‐Song Hsieh (ORCID: https://orcid.org/0000-0001-5976-9250)
- Anthony N. Vomund (ORCID: https://orcid.org/0000-0001-8513-7118)
- Omar Abousaway (ORCID: https://orcid.org/0000-0003-1336-6127)
- Cheryl F. Lichti (ORCID: https://orcid.org/0000-0003-4099-4954)
- Aisha Ansar (ORCID: https://orcid.org/0000-0002-8091-0658)
- Cristina C. Clement (ORCID: https://orcid.org/0000-0003-1464-407X)
- Emil R. Unanue (ORCID: https://orcid.org/0000-0001-8629-0018)
- Neetu Srivastava (ORCID: https://orcid.org/0000-0001-7315-6258)
- Xiaoxiao Wan (ORCID: https://orcid.org/0000-0001-7439-9374)
- David P Turicek (ORCID: https://orcid.org/0000-0003-0837-2688)
- Chang Liu (ORCID: https://orcid.org/0000-0001-6624-1454)
- Bo Zhang (ORCID: https://orcid.org/0000-0003-2962-5314)
- Hao Hu (ORCID: https://orcid.org/0000-0003-3622-9897)
- R. Abi Melhem
- Pamela Stone
Institutions
- Scripps Research Institute (US)
- University of St Andrews (GB)
- University of Pittsburgh (US)
- University of Washington (US)
- Washington University in St. Louis (US)
- Cornell University (US)
- Lander Institute (IL)
- Hope Center for Neurological Disorders (US)
- UPMC Hillman Cancer Center (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41590-025-02343-z
- Citations
- 3
- Primary Topic
- Diabetes and associated disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.45