CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer’s disease pathology

Wei Su, Jordy Saravia, Isabel Risch, Sherri Rankin, Cliff Guy, Nicole M. Chapman, Hao Shi, Yu Sun, Anil Kc, Wei Li, Hongling Huang, Seon Ah Lim, Haoran Hu, Yan Wang, Danting Liu, Yun Jiao, Ping Chung Chen, Hadeer Soliman, Koon Kiu Yan, Jonathan ZhangPeter Vogel, Xueyan Liu, Geidy E. Serrano, Thomas G. Beach, Jiyang Yu, Junmin Peng, Hongbo Chi

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Neurodegenerative diseases, including Alzheimer’s disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8+ T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8+ T cells restrict AD pathologies, including β-amyloid deposition and cognitive decline. Ligand–receptor interaction analysis identifies CXCL16–CXCR6 intercellular communication between microglia and CD8+ T cells. Further, Cxcr6 deficiency impairs accumulation, tissue residency programming and clonal expansion of brain PD-1+CD8+ T cells. Ablation of Cxcr6 or CD8+ T cells ultimately increases proinflammatory cytokine production from microglia, with CXCR6 orchestrating brain CD8+ T cell–microglia colocalization. Collectively, our study reveals protective roles for brain CD8+ T cells and CXCR6 in mouse AD pathogenesis and highlights that microenvironment-specific, intercellular communication orchestrates tissue homeostasis and protection from neuroinflammation.

Original languageEnglish
Pages (from-to)1735-1747
Number of pages13
JournalNature Immunology
Volume24
Issue number10
DOIs
StatePublished - Oct 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

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