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

Hao Hu, Anthony N. Vomund, Orion J. Peterson, Neetu Srivastava, Tiandao Li, Lisa Kain, Wandy L. Beatty, Bo Zhang, Chyi-Song Hsieh, Luc Teyton, Cheryl F. Lichti, Emil R. Unanue and Xiaoxiao Wan ()
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Hao Hu: Washington University School of Medicine
Anthony N. Vomund: Washington University School of Medicine
Orion J. Peterson: Washington University School of Medicine
Neetu Srivastava: Washington University School of Medicine
Tiandao Li: Washington University School of Medicine
Lisa Kain: Scripps Research Institute
Wandy L. Beatty: Washington University School of Medicine
Bo Zhang: Washington University School of Medicine
Chyi-Song Hsieh: Washington University School of Medicine
Luc Teyton: Scripps Research Institute
Cheryl F. Lichti: Washington University School of Medicine
Emil R. Unanue: Washington University School of Medicine
Xiaoxiao Wan: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52619-5

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