Memory CD8 T cells provide durable protection against diverse intracellular pathogens and can be broadly segregated into distinct circulating and tissue-resident populations. Paradigmatic studies have demonstrated that circulating memory cells can be further divided into effector memory (Tem) and central memory (Tcm) populations based on discrete functional characteristics. Following resolution of infection, we identified a persisting antigen-specific CD8 T cell population that was terminally fated with potent effector function but maintained memory T cell qualities and conferred robust protection against reinfection. Notably, this terminally differentiated effector memory CD8 T cell population (terminal-Tem) was conflated within the conventional Tem population, prompting redefinition of the classical characteristics of Tem cells. Murine terminal-Tem were transcriptionally, functionally, and developmentally unique compared to Tem cells. Through mass cytometry and single-cell RNA sequencing (RNA-seq) analyses of human peripheral blood from healthy individuals, we also identified an analogous terminal-Tem population of CD8 T cells that was transcriptionally distinct from Tem and Tcm. Key findings from this study show that parsing of terminal-Tem from conventionally defined Tem challenge the reported characteristics of Tem biology, including enhanced presence in lymphoid tissues, robust IL-2 production, and recall potential, greater than expected homeostatic fitness, refined transcription factor dependencies, and a distinct molecular phenotype. Classification of terminal-Tem and clarification of Tem biology hold broad implications for understanding the molecular regulation of memory cell states and harnessing immunological memory to improve immunotherapies.

记忆 CD8 T 细胞提供针对多种细胞内病原体的持久保护，并且可以广泛分为不同的循环和组织驻留群体。范式研究表明，循环记忆细胞可以根据离散的功能特征进一步分为效应记忆（T em）和中央记忆（T cm ）群体。感染消退后，我们鉴定出了持续存在的抗原特异性 CD8 T 细胞群，该细胞群最终具有强大的效应功能，但仍保持记忆 T 细胞质量，并提供针对再次感染的强大保护。值得注意的是，这种终末分化的效应记忆 CD8 T 细胞群 (terminal-T em)与传统 T em细胞群混为一谈，促使人们重新定义 T em细胞的经典特征。与 T em细胞相比，小鼠末端 T em在转录、功能和发育上都是独特的。通过对健康个体的人外周血进行质谱流式分析和单细胞 RNA 测序 (RNA-seq) 分析，我们还鉴定了类似的CD8 T 细胞终末 T em群体，其在转录上与 T em和 T cm不同。这项研究的主要发现表明，从传统定义的T em中解析末端 T em挑战了已报道的 T em生物学特征，包括淋巴组织中的存在增强、IL-2 产生强劲、回忆潜力、高于预期的稳态适应性、精细的转录因子依赖性和独特的分子表型。终末温度的分类和温度生物学的澄清对于理解记忆细胞状态的分子调节和利用免疫记忆来改善免疫疗法具有广泛的意义。