Using immunopeptidome analysis in T1D patients, Srivastava et al. discovered a cys-to-ser mutation at position 19 (C19S) of insulin, within an MHC-II binding region. C19S could be contextually elicited via oxidative stress in islets, representing a dominant transformation among single AA variants (SAVs) and post-translational modifications. The conversion was also potentiated in APCs by cytokine exposure. In NOD mice and humans, InsB12-20(C19S) elicited a unique corresponding T cell population that was present in the non-diabetic state, yet expanded with diabetes progression to a greater extent than native InsB12-20-specific T cells, and was enriched in activated, Th1-like memory cells.
Contributed by Morgan Janes
ABSTRACT: 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(+) T cells that expand at diabetes onset. These neoepitope-specific CD4(+) 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.
Author Info: (1) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Hum
Author Info: (1) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (2) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (3) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (4) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (5) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (6) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (7) Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA. (8) Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA. (9) Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA. (10) Department of Pediatrics, Division of Endocrinology, Diabetes, and Metabolism, Washington University School of Medicine, St. Louis, MO, USA. (11) Department of Pediatrics, Division of Endocrinology, Diabetes, and Metabolism, Washington University School of Medicine, St. Louis, MO, USA. (12) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (13) Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA. (14) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. (15) Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA. (16) Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA. (17) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (18) Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. (19) Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA. (20) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. (21) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (22) Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA. (23) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. (24) Department of Pediatrics, Division of Endocrinology, Diabetes, and Metabolism, Washington University School of Medicine, St. Louis, MO, USA. (25) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. clichti@wustl.edu. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. clichti@wustl.edu. (26) Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA. wanx@wustl.edu. The Andrew M. and Jane M. Bursky Center for Human Immunology, Washington University School of Medicine, St. Louis, MO, USA. wanx@wustl.edu.
