1. CXCL16-dependent scavenging of oxidized lipids by islet macrophages promotes differentiation of pathogenic CD8 + T cells in diabetic autoimmunity.
- Author
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Srivastava N, Hu H, Peterson OJ, Vomund AN, Stremska M, Zaman M, Giri S, Li T, Lichti CF, Zakharov PN, Zhang B, Abumrad NA, Chen YG, Ravichandran KS, Unanue ER, and Wan X
- Subjects
- Animals, Mice, Mice, Inbred C57BL, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Lipoproteins, LDL metabolism, Lipoproteins, LDL immunology, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 metabolism, Chemokine CXCL16 metabolism, Macrophages immunology, Macrophages metabolism, Mice, Inbred NOD, Islets of Langerhans immunology, Islets of Langerhans metabolism, Autoimmunity, Cell Differentiation, Mice, Knockout
- Abstract
The pancreatic islet microenvironment is highly oxidative, rendering β cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Tex
int ) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16-/- mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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