澳大利亚墨尔本大学Ian A. Parish研究组发现，CD8⁺ T细胞耐受检查点触发一种由蛋白质翻译缺陷定义的独特分化状态。2024年5月21日，《免疫》杂志在线发表了这项成果。

利用流式细胞表型分析、单细胞RNA测序（scRNA-seq）和染色质可及性分析，研究人员证明了体内外周对自身抗原的耐受引发了一种根本不同的分化状态，这种状态不同于衰竭、记忆和功能效应细胞，但类似于对肿瘤有缺陷的细胞。耐受细胞很早就与效应细胞逐渐分化，在遇到抗原后的60小时内采用了转录和表观遗传学上的独特状态。

打破耐受性需要强大的T细胞受体（TCR）信号和炎症的协同作用，它们共同诱导基因模块，增强蛋白质翻译。由于效应基因表达与蛋白质翻译脱钩，旁观者感染期间的弱TCR信号不能突破耐受性。因此，耐受性涉及一个由蛋白质翻译缺陷强化的独特分化轨迹。

据悉，外周CD8⁺ T细胞耐受是自身免疫性疾病和抗癌免疫的一个检查点。尽管它很重要，但耐受诱导状态与其他CD8⁺ T细胞分化状态之间的关系仍不清楚。

附：英文原文

Title: The CD8+ T cell tolerance checkpoint triggers a distinct differentiation state defined by protein translation defects

Author: Willem Van Der Byl, Simone Nüssing, Timothy J. Peters, Antonio Ahn, Hanjie Li, Guy Ledergor, Eyal David, Andrew S. Koh, Mayura V. Wagle, Christian Deo T. Deguit, Maria N. de Menezes, Avraham Travers, Shienny Sampurno, Kelly M. Ramsbottom, Rui Li, Axel Kallies, Paul A. Beavis, Ralf Jungmann, Maartje M.C. Bastings, Gabrielle T. Belz, Shom Goel, Joseph A. Trapani, Gerald R. Crabtree, Howard Y. Chang, Ido Amit, Chris C. Goodnow, Fabio Luciani, Ian A. Parish

Issue&Volume: 2024-05-21

Abstract: Peripheral CD8+ T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity.Despite its importance, the relationship between tolerance-induced states and otherCD8+ T cell differentiation states remains unclear. Using flow cytometric phenotyping,single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, wedemonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiationstate separate from exhaustion, memory, and functional effector cells but analogousto cells defectively primed against tumors. Tolerant cells diverged early and progressivelyfrom effector cells, adopting a transcriptionally and epigenetically distinct statewithin 60 h of antigen encounter. Breaching tolerance required the synergistic actionsof strong T cell receptor (TCR) signaling and inflammation, which cooperatively inducedgene modules that enhanced protein translation. Weak TCR signaling during bystanderinfection failed to breach tolerance due to the uncoupling of effector gene expressionfrom protein translation. Thus, tolerance engages a distinct differentiation trajectoryenforced by protein translation defects.

DOI: 10.1016/j.immuni.2024.04.026

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00231-0