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CXCL16-dependent scavenging of oxidized lipids by islet macrophages promotes differentiation of pathogenic CD8+ T cells in diabetic autoimmunity. Immunity 2024 Jul 09;57(7):1629-1647.e8

Date

05/17/2024

Pubmed ID

38754432

Pubmed Central ID

PMC11236520

DOI

10.1016/j.immuni.2024.04.017

Scopus ID

2-s2.0-85194456425 (requires institutional sign-in at Scopus site)   2 Citations

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 (Texint) 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.

Author List

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, Wan X

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Autoimmunity
CD8-Positive T-Lymphocytes
Cell Differentiation
Chemokine CXCL16
Diabetes Mellitus, Type 1
Islets of Langerhans
Lipoproteins, LDL
Macrophages
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout