Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection.
Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection.
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DOI：
10.1084/jem.20220679
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发表时间：
2023-01-02
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影响因子：
--
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通过scRNA-seq和scTCR-seq， Kasmani、Zander等人发现了慢性病毒感染过程中调节CD8 T细胞分化的多个分支通路。中间亚群由祖细胞产生，并分为末端效应器亚群和耗尽亚群。尽管最近的证据表明CD8+ T细胞在慢性感染期间存在异质性，但其命运决定的发育关系和机制仍不完全清楚。利用单细胞RNA和TCR测序，我们追踪了慢性LCMV感染期间CD8+ T细胞的克隆扩增和分化。我们发现了巨大的克隆和表型多样性，包括一个被称为中间细胞的子集。轨迹分析和感染模型显示，中间细胞起源于祖细胞，然后分化为末端效应器和耗尽亚群。基因消融实验发现，I型IFN通过irf7依赖机制驱动耗竭，可能是通过IFN刺激的亚群桥接祖细胞和耗竭细胞。相反，Zeb2对于产生效应细胞至关重要。有趣的是，一些T细胞克隆表现出谱系偏见。在机制上，我们发现TCR贪婪度与衰竭命运相关，而SHP-1选择性地限制低贪婪效应细胞的积累。因此，我们的工作阐明了持续感染期间CD8+ T细胞命运决定的新机制，并提出了两种导致衰竭的潜在途径。
Using scRNA-seq and scTCR-seq, Kasmani, Zander, and colleagues identify multiple branching pathways regulating CD8 T cell differentiation during chronic viral infection. An intermediate subset is shown to arise from progenitor cells and bifurcate into both terminal effector and exhausted subsets. 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.
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DOI：
10.4049/jimmunol.1001362
发表时间：
2010-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fowler CC;Pao LI;Blattman JN;Greenberg PD
通讯作者：
Greenberg PD
DOI：
10.1084/jem.20150186
发表时间：
2015-11-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Kaech SM
影响因子：
64.8
作者：
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通讯作者：
Walker, Bruce D.
影响因子：
5.5
作者：
Alford, Rebecca F.;Leaver-Fay, Andrew;Gray, Jeffrey J.
通讯作者：
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DOI：
10.1073/pnas.0801497105
发表时间：
2008-09-30
影响因子：
11.1
作者：
Blackburn, Shawn D.;Shin, Haina;Wherry, E. John
通讯作者：
Wherry, E. John