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Single-cell RNA transcriptome analysis of CNS immune cells reveals CXCL16/CXCR6 as maintenance factors for tissue-resident T cells that drive synapse elimination. | LitMetric

AI Article Synopsis

  • Emerging RNA viruses like West Nile virus (WNV) can lead to cognitive impairments, particularly through microglial-mediated synapse elimination in the hippocampus, impacting learning and memory in infected individuals.
  • Researchers used single-cell RNA sequencing to analyze immune cells in the brains of WNV-recovered mice, uncovering interactions between T cells and microglia that may contribute to synaptic loss and impaired learning.
  • The study identified the CXCL16/CXCR6 signaling pathway as crucial for maintaining CD8 memory T cells in the brain, and these cells were found to drive persistent glial activation and synaptic changes following WNV infection.

Article Abstract

Background: Emerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS-resident memory T (TM) cells activate microglia, limiting synapse recovery and inducing spatial learning defects in WNV-recovered mice. The signals involved in T cell-microglia interactions are unknown.

Methods: Here, we examined immune cells within the murine WNV-recovered forebrain using single-cell RNA sequencing to identify putative ligand-receptor pairs involved in intercellular communication between T cells and microglia. Clustering and differential gene analyses were followed by protein validation and genetic and antibody-based approaches utilizing an established murine model of WNV recovery in which microglia and complement promote ongoing hippocampal synaptic loss.

Results: Profiling of host transcriptome immune cells at 25 days post-infection in mice revealed a shift in forebrain homeostatic microglia to activated subpopulations with transcriptional signatures that have previously been observed in studies of neurodegenerative diseases. Importantly, CXCL16/CXCR6, a chemokine signaling pathway involved in TM cell biology, was identified as critically regulating CXCR6 expressing CD8 TM cell numbers within the WNV-recovered forebrain. We demonstrate that CXCL16 is highly expressed by all myeloid cells, and its unique receptor, CXCR6, is highly expressed on all CD8 T cells. Using genetic and pharmacological approaches, we demonstrate that CXCL16/CXCR6 not only is required for the maintenance of WNV-specific CD8 TM cells in the post-infectious CNS, but also contributes to their expression of TM cell markers. Moreover, CXCR6CD8 T cells are required for glial activation and ongoing synapse elimination.

Conclusions: We provide a comprehensive assessment of the role of CXCL16/CXCR6 as an interaction link between microglia and CD8 T cells that maintains forebrain TM cells, microglial and astrocyte activation, and ongoing synapse elimination in virally recovered animals. We also show that therapeutic targeting of CXCL16 in mice during recovery may reduce CNS CD8 TM cells.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9509564PMC
http://dx.doi.org/10.1186/s13073-022-01111-0DOI Listing

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