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

• Published in: Nature communications Vol. 15; no. 1; pp. 8318 - 22
• Main Authors: Hu, Hao, Vomund, Anthony N., Peterson, Orion J., Srivastava, Neetu, Li, Tiandao, Kain, Lisa, Beatty, Wandy L., Zhang, Bo, Hsieh, Chyi-Song, Teyton, Luc, Lichti, Cheryl F., Unanue, Emil R., Wan, Xiaoxiao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/31; 14/28; 38/39; 631/250/1619/554/1898; 631/250/21/569; 631/250/2152/1566/1618; 692/699/249/1313/1418; 82/58; Animal models; Animals; Autoantigens - immunology; Autoantigens - metabolism; Autoimmune diseases; Beta cells; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell culture; Cell death; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Disease Models, Animal; Epitopes; Epitopes - immunology; Female; Granular materials; Granule cells; Homeostasis; Humanities and Social Sciences; Humans; Insulin; Insulin - immunology; Insulin - metabolism; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - metabolism; Lymphocytes; Lymphocytes T; Lysosomes; Lysosomes - immunology; Lysosomes - metabolism; Major histocompatibility complex; Mice; Mice, Inbred NOD; multidisciplinary; Pancreas; Phenotypes; Science; Science (multidisciplinary); Secretory vesicles; Secretory Vesicles - immunology; Secretory Vesicles - metabolism; Thymus; Thymus gland; Thymus Gland - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52619-5

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. Dense-core granules (DCG) store insulin in pancreatic β cells. Here the authors show that crinosome, formed by fusing lysosome and DCGs, are pathogenic in mouse models of type 1 diabetes by diversifying local insulin epitopes beyond those tolerizing ones expressed in the thymus, thereby inducing autoreactive CD4 T cells for β cell death and insulin deficiency.