Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, NY.
Weill Cornell Medical College, New York, NY.
J Exp Med. 2022 Jun 6;219(6). doi: 10.1084/jem.20212169. Epub 2022 May 23.
Transcription factors ThPOK and Runx3 regulate the differentiation of "helper" CD4+ and "cytotoxic" CD8+ T cell lineages respectively, inducing single positive (SP) T cells that enter the periphery with the expression of either the CD4 or CD8 co-receptor. Despite the expectation that these cell fates are mutually exclusive and that mature CD4+CD8+ double positive (DP) T cells are present in healthy individuals and augmented in the context of disease, yet their molecular features and pathophysiologic role are disputed. Here, we show DP T cells in murine and human tumors as a heterogenous population originating from SP T cells which re-express the opposite co-receptor and acquire features of the opposite cell type's phenotype and function following TCR stimulation. We identified distinct clonally expanded DP T cells in human melanoma and lung cancer by scRNA sequencing and demonstrated their tumor reactivity in cytotoxicity assays. Our findings indicate that antigen stimulation induces SP T cells to differentiate into DP T cell subsets gaining in polyfunctional characteristics.
转录因子 ThPOK 和 Runx3 分别调节“辅助”CD4+和“细胞毒性”CD8+T 细胞谱系的分化，诱导表达 CD4 或 CD8 共受体的单阳性 (SP)T 细胞进入外周。尽管预期这些细胞命运是相互排斥的，并且成熟的 CD4+CD8+双阳性 (DP)T 细胞在健康个体中存在并且在疾病情况下增加，但它们的分子特征和病理生理作用存在争议。在这里，我们在鼠类和人类肿瘤中显示 DP T 细胞是一种异质性群体，源自重新表达相反共受体的 SP T 细胞，并在 TCR 刺激后获得相反细胞类型表型和功能的特征。我们通过单细胞 RNA 测序在人类黑色素瘤和肺癌中鉴定了不同克隆扩增的 DP T 细胞，并在细胞毒性测定中证明了它们的肿瘤反应性。我们的研究结果表明，抗原刺激诱导 SP T 细胞分化为 DP T 细胞亚群，获得多功能特征。
