天天快播：T细胞衰竭的不同克隆分化轨迹

美国斯坦福大学Ansuman T. Satpathy团队近期取得重要工作进展，他们研究发现了T细胞衰竭的不同克隆分化轨迹。该项研究成果2022年10月26日在线发表于《自然—免疫学》杂志上。

研究人员生成了小鼠慢性病毒感染中T细胞衰竭的单细胞多组学图谱，它重新定义了Tex的表型多样性，包括两个晚期Tex亚群，具有终端衰竭（Texterm）或杀伤细胞凝集素样受体表达的细胞毒性（TexKLR）的表型。研究人员使用配对的单细胞RNA和T细胞受体测序来揭示获得两种表型的Texterm偏斜、TexKLR偏斜或发散的克隆分化轨迹。高T细胞受体信号通路亲和性与Texterm相关，而低亲和性与效应子样TexKLR命运相关。

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研究人员在人肿瘤浸润淋巴细胞中发现了类似的克隆分化轨迹。这些发现揭示T细胞对慢性抗原反应的克隆异质性，影响Tex的命运和持久性。

据了解，在病毒感染或癌症期间，慢性抗原暴露会促进T细胞（Tex）衰竭状态，并降低效应功能。然而，是否所有抗原特异性T细胞克隆遵循相同的Tex分化轨迹尚不清楚。

附：英文原文

Title: Divergent clonal differentiation trajectories of T cell exhaustion

Author: Daniel, Bence, Yost, Kathryn E., Hsiung, Sunnie, Sandor, Katalin, Xia, Yu, Qi, Yanyan, Hiam-Galvez, Kamir J., Black, Mollie, J. Raposo, Colin, Shi, Quanming, Meier, Stefanie L., Belk, Julia A., Giles, Josephine R., Wherry, E. John, Chang, Howard Y., Egawa, Takeshi, Satpathy, Ansuman T.

Issue&Volume: 2022-10-26

Abstract: Chronic antigen exposure during viral infection or cancer promotes an exhausted T cell (Tex) state with reduced effector function. However, whether all antigen-specific T cell clones follow the same Tex differentiation trajectory remains unclear. Here, we generate a single-cell multiomic atlas of T cell exhaustion in murine chronic viral infection that redefines Tex phenotypic diversity, including two late-stage Tex subsets with either a terminal exhaustion (Texterm) or a killer cell lectin-like receptor-expressing cytotoxic (TexKLR) phenotype. We use paired single-cell RNA and T cell receptor sequencing to uncover clonal differentiation trajectories of Texterm-biased, TexKLR-biased or divergent clones that acquire both phenotypes. We show that high T cell receptor signaling avidity correlates with Texterm, whereas low avidity correlates with effector-like TexKLR fate. Finally, we identify similar clonal differentiation trajectories in human tumor-infiltrating lymphocytes. These findings reveal clonal heterogeneity in the T cell response to chronic antigen that influences Tex fates and persistence.

DOI: 10.1038/s41590-022-01337-5

Source: https://www.nature.com/articles/s41590-022-01337-5

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