Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection.

Autor:	Kasmani MY; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI.; Blood Research Institute, Versiti Wisconsin, Milwaukee, WI., Zander R; Blood Research Institute, Versiti Wisconsin, Milwaukee, WI., Chung HK; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA., Chen Y; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI.; Blood Research Institute, Versiti Wisconsin, Milwaukee, WI., Khatun A; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI.; Blood Research Institute, Versiti Wisconsin, Milwaukee, WI., Damo M; Department of Immunobiology, Yale University School of Medicine, New Haven, CT., Topchyan P; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI.; Blood Research Institute, Versiti Wisconsin, Milwaukee, WI., Johnson KE; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI., Levashova D; Department of Microbiology, Immunology, and Cancer Biology, and Carter Immunology Center, University of Virginia, Charlottesville, VA., Burns R; Blood Research Institute, Versiti Wisconsin, Milwaukee, WI., Lorenz UM; Department of Microbiology, Immunology, and Cancer Biology, and Carter Immunology Center, University of Virginia, Charlottesville, VA., Tarakanova VL; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI., Joshi NS; Department of Immunobiology, Yale University School of Medicine, New Haven, CT., Kaech SM; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA., Cui W; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI.; Blood Research Institute, Versiti Wisconsin, Milwaukee, WI.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2023 Jan 02; Vol. 220 (1). Date of Electronic Publication: 2022 Oct 31.
DOI:	10.1084/jem.20220679
Abstrakt:	Although recent evidence demonstrates heterogeneity among CD8+ T cells during chronic infection, developmental relationships and mechanisms underlying their fate decisions remain incompletely understood. Using single-cell RNA and TCR sequencing, we traced the clonal expansion and differentiation of CD8+ T cells during chronic LCMV infection. We identified immense clonal and phenotypic diversity, including a subset termed intermediate cells. Trajectory analyses and infection models showed intermediate cells arise from progenitor cells before bifurcating into terminal effector and exhausted subsets. Genetic ablation experiments identified that type I IFN drives exhaustion through an IRF7-dependent mechanism, possibly through an IFN-stimulated subset bridging progenitor and exhausted cells. Conversely, Zeb2 was critical for generating effector cells. Intriguingly, some T cell clones exhibited lineage bias. Mechanistically, we identified that TCR avidity correlates with an exhausted fate, whereas SHP-1 selectively restricts low-avidity effector cell accumulation. Thus, our work elucidates novel mechanisms underlying CD8+ T cell fate determination during persistent infection and suggests two potential pathways leading to exhaustion. (© 2022 Kasmani et al.)
Databáze:	MEDLINE
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