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

Moujtaba Y. Kasmani, Ryan Zander, H. Kay Chung, Yao Chen, Achia Khatun, Martina Damo, Paytsar Topchyan, Kaitlin E. Johnson, Darya Levashova, Robert Burns, Ulrike M. Lorenz, Vera L. Tarakanova, Nikhil S. Joshi, Susan M. Kaech, Weiguo Cui

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish
Article numbere20220679
JournalJournal of Experimental Medicine
Issue number1
StatePublished - Jan 2 2023


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