Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
Nat Immunol. 2024 Jun;25(6):1046-1058. doi: 10.1038/s41590-024-01843-8. Epub 2024 May 30.
The durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8 T cells (Tpex). Tpex serve as a resource for replenishing effector T cells and preserve their quantity through self-renewal. However, it is unknown how T cell receptor (TCR) engagement affects the self-renewal capacity of Tpex in settings of continued antigen exposure. Here we use a Lewis lung carcinoma model that elicits either optimal or attenuated TCR signaling in CD8 T cells to show that formation of Tpex in tumor-draining lymph nodes and their intratumoral persistence is dependent on optimal TCR engagement. Notably, attenuated TCR stimulation accelerates the terminal differentiation of optimally primed Tpex. This TCR-reinforced Tpex development and self-renewal is coupled to proximal positioning to dendritic cells and epigenetic imprinting involving increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, this study highlights the critical function of TCR engagement in sustaining Tpex during tumor progression.
抗肿瘤免疫反应的持久性部分是由祖细胞耗竭的 CD8 T 细胞（Tpex）的持续存在介导的。Tpex 可作为补充效应 T 细胞的资源，并通过自我更新来维持其数量。然而，在持续抗原暴露的情况下，T 细胞受体（TCR）的结合如何影响 Tpex 的自我更新能力尚不清楚。在这里，我们使用一种引发 CD8 T 细胞中最佳或减弱 TCR 信号的 Lewis 肺癌模型，表明肿瘤引流淋巴结中 Tpex 的形成及其在肿瘤内的持续存在依赖于最佳 TCR 结合。值得注意的是，减弱的 TCR 刺激加速了最佳初始 Tpex 的终末分化。这种 TCR 增强的 Tpex 发育和自我更新与树突状细胞的近端定位以及涉及 Egr2 和 Tcf1 靶基因座染色质可及性增加的表观遗传印记有关。总的来说，这项研究强调了 TCR 结合在肿瘤进展过程中维持 Tpex 的关键作用。
