Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection. J Exp Med 2023 Jan 02;220(1)
Date
11/01/2022Pubmed ID
36315049Pubmed Central ID
PMC9623343DOI
10.1084/jem.20220679Scopus ID
2-s2.0-85140941501 (requires institutional sign-in at Scopus site) 22 CitationsAbstract
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.
Author List
Kasmani MY, Zander R, Chung HK, Chen Y, Khatun A, Damo M, Topchyan P, Johnson KE, Levashova D, Burns R, Lorenz UM, Tarakanova VL, Joshi NS, Kaech SM, Cui WAuthor
Vera Tarakanova PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
CD8-Positive T-LymphocytesCell Differentiation
Cells, Cultured
Humans
Receptors, Antigen, T-Cell
