美国范德比尔特医学院Mary Philip团队近期取得重要工作进展，他们最新研究发现CD8⁺ T细胞功能障碍的标志在细胞分裂前肿瘤抗原相遇数小时内建立。相关研究成果2023年8月3日在线发表于《自然—免疫学》杂志上。

据介绍，癌症患者的肿瘤特异性CD8⁺ T细胞（TST）功能失调，无法阻止癌症的恶化。TST功能障碍，也称为衰竭，被认为是由几天到几周的慢性T细胞抗原受体（TCR）刺激引起的。然而，人们对CD8⁺ T细胞功能、细胞分裂和激活数小时内表观遗传学重塑之间的相互作用知之甚少。

研究人员评估了荷瘤小鼠和急性感染小鼠的早期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TST具有强大的激活和增殖能力，但即使在进行细胞分裂之前，其效应器功能也几乎完全受损，并且具有先前与后期功能障碍/衰竭相关的标志性染色质可及性特征。

此外，持续的肿瘤/抗原暴露驱动了进行性的表观遗传学重塑，“印记”了功能失调的状态。

总之，这一研究揭示了在肿瘤与感染的背景下，T细胞在细胞分裂前命运选择的快速差异。

附：英文原文

Title: Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division

Author: Rudloff, Michael W., Zumbo, Paul, Favret, Natalie R., Roetman, Jessica J., Detrs Romn, Carlos R., Erwin, Megan M., Murray, Kristen A., Jonnakuti, Sriya T., Dndar, Friederike, Betel, Doron, Philip, Mary

Issue&Volume: 2023-08-03

Abstract: 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.

DOI: 10.1038/s41590-023-01578-y

Source: https://www.nature.com/articles/s41590-023-01578-y