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

Nat Immunol. 2023 Oct;24(10):1735-1747. doi: 10.1038/s41590-023-01604-z. Epub 2023 Sep 7.

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.

MeSH terms

  • Alzheimer Disease* / pathology
  • Animals
  • Brain / metabolism
  • CD8-Positive T-Lymphocytes*
  • Humans
  • Mice
  • Microglia / metabolism
  • Programmed Cell Death 1 Receptor
  • Receptors, CXCR6* / metabolism

Substances

  • CXCR6 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, CXCR6
  • Cxcr6 protein, mouse