Crinophagic granules in pancreatic β cells contribute to mouse autoimmune diabetes by diversifying pathogenic epitope repertoire.

Autor: Hu H; Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO, USA., Vomund AN; 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 and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA., Peterson OJ; 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 and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA., Srivastava N; 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 and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA., Li T; Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA., Kain L; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA., Beatty WL; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA., Zhang B; Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA., Hsieh CS; Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA., Teyton L; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA., Lichti CF; 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 and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA., Unanue ER; 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 and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA., Wan X; 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 and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA. wanx@wustl.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 27; Vol. 15 (1), pp. 8318. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1038/s41467-024-52619-5
Abstrakt: Autoimmune attack toward pancreatic β cells causes permanent loss of glucose homeostasis in type 1 diabetes (T1D). Insulin secretory granules store and secrete insulin but are also thought to be tissue messengers for T1D. Here, we show that the crinophagic granules (crinosome), a minor set of vesicles formed by fusing lysosomes with the conventional insulin dense-core granules (DCG), are pathogenic in T1D development in mouse models. Pharmacological inhibition of crinosome formation in β cells delays T1D progression without affecting the dominant DCGs. Mechanistically, crinophagy inhibition diminishes the epitope repertoire in pancreatic islets, including cryptic, modified and disease-relevant epitopes derived from insulin. These unconventional insulin epitopes are largely undetectable in the MHC-II epitope repertoire of the thymus, where only canonical insulin epitopes are presented. CD4 + T cells targeting unconventional insulin epitopes display autoreactive phenotypes, unlike tolerized T cells recognizing epitopes presented in the thymus. Thus, the crinophagic pathway emerges as a tissue-intrinsic mechanism that transforms insulin from a signature thymic self-protein to a critical autoantigen by creating a peripheral-thymic mismatch in the epitope repertoire.
(© 2024. The Author(s).)
Databáze: MEDLINE
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