{"doi":"10.1101/2021.10.08.463715","title":"Single-cell RNA transcriptome analysis reveals CXCL16/CXCR6 as maintenance factors for CNS tissue resident T cells that drive synapse elimination during viral recovery","abstract":"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 (T R M) 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 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, 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 at 25 days post-infection 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 T R M cell biology, was identified as critically regulating CXCR6 expressing CD8 + T R M 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 is required not only for the maintenance of WNV-specific, CD8 T R M cells in the post-infectious CNS, but also contributes to their expression of T R M cell markers. Moreover, CXCR6 + CD8 + 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 T R M cells, microglial and astrocyte activation, and ongoing synapse elimination in virally recovered animals. We also show that therapeutic targeting of CXCL16 during recovery may reduce CNS CD8 + T R M cells.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":227012,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.958,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":552253,"name":"Allison Soung","orcid":"0000-0002-1590-6038","position":1,"is_corresponding":false},{"id":362435,"name":"Wei Yang","orcid":"0000-0001-8162-033X","position":2,"is_corresponding":false},{"id":821553,"name":"Shenjian Ai","orcid":"0000-0002-9433-8939","position":3,"is_corresponding":false},{"id":465206,"name":"Marlene Kanmogne","orcid":"0000-0001-7428-5270","position":4,"is_corresponding":false},{"id":712647,"name":"Veronica Davé","orcid":"0000-0002-3791-192X","position":5,"is_corresponding":false},{"id":380023,"name":"Sairam Prabhakar","orcid":null,"position":6,"is_corresponding":false},{"id":246482,"name":"Amanda Swain","orcid":"0000-0003-0683-368X","position":7,"is_corresponding":false},{"id":52958,"name":"Maxim N. Artyomov","orcid":"0000-0002-1133-4212","position":8,"is_corresponding":false},{"id":571161,"name":"Jeffrey A. Magee","orcid":"0000-0002-0766-4200","position":9,"is_corresponding":false},{"id":230439,"name":"Robyn S. Klein","orcid":"0000-0003-0281-1352","position":10,"is_corresponding":false},{"id":230437,"name":"Sarah F. Rosen","orcid":"0000-0001-8844-1203","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-18T23:54:38.004707Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}