肿瘤抗原接触后的数小时内，CD8+ T细胞功能障碍的特征已经确立，而在细胞分裂之前。
Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division.
发表日期：2023 Aug 03
作者：
Michael W Rudloff, Paul Zumbo, Natalie R Favret, Jessica J Roetman, Carlos R Detrés Román, Megan M Erwin, Kristen A Murray, Sriya T Jonnakuti, Friederike Dündar, Doron Betel, Mary Philip
来源：
Epigenetics & Chromatin
摘要：
癌症患者中的肿瘤特异性CD8+T细胞（TST）功能失调，无法阻止癌症进展。TST功能失调，也被称为衰竭，被认为是由于慢性T细胞抗原受体（TCR）刺激持续几天到几周所致。然而，在激活几小时内，关于CD8+T细胞功能、细胞分裂和表观遗传重塑之间的相互作用我们了解甚少。本研究评估了肿瘤负荷小鼠和急性感染小鼠中早期CD8+T细胞分化、细胞分裂、染色质可及性和转录。令人惊讶的是，尽管经历了强烈的激活和增殖，TST在细胞分裂之前就几乎完全失去了效应器功能，并且获得了与较后期功能失调/衰竭相关的染色质可及性特征。此外，持续的肿瘤/抗原暴露会导致渐进性表观遗传重塑，形成了这种功能失调的“印记”。我们的研究揭示了在肿瘤与感染背景下，在细胞分裂之前T细胞命运选择的快速分歧。© 2023年，作者（们）在Springer Nature America, Inc.的独家许可下发布。
Tumor-specific CD8+ T cells (TST) in patients with cancer are dysfunctional and unable to halt cancer progression. TST dysfunction, also known as exhaustion, is thought to be driven by chronic T cell antigen receptor (TCR) stimulation over days to weeks. However, we know little about the interplay between CD8+ T cell function, cell division and epigenetic remodeling within hours of activation. Here, we assessed early CD8+ T cell differentiation, cell division, chromatin accessibility and transcription in tumor-bearing mice and acutely infected mice. Surprisingly, despite robust activation and proliferation, TST had near complete effector function impairment even before undergoing cell division and had acquired hallmark chromatin accessibility features previously associated with later dysfunction/exhaustion. Moreover, continued tumor/antigen exposure drove progressive epigenetic remodeling, 'imprinting' the dysfunctional state. Our study reveals the rapid divergence of T cell fate choice before cell division in the context of tumors versus infection.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.