Abdullah Leena, Emiliani Francesco E, Vaidya Chinmay M, Stuart Hannah, Musial Shawn C, Kolling Fred W, Obar Joshua J, Rosato Pamela C, Ackerman Margaret E, Song Li, McKenna Aaron, Huang Yina H
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Immunity. 2025 Mar 11;58(3):601-615.e9. doi: 10.1016/j.immuni.2025.02.001. Epub 2025 Feb 27.
Generating balanced populations of CD8 effector and memory T cells is necessary for immediate and durable immunity to infections and cancer. Yet, a definitive understanding of how a diverse CD8 T cell repertoire differentiates remains unclear. We identified several hundred T cell receptor (TCR) clonotypes that constitute the polyclonal response against a single antigen and found that a majority of TCR clonotypes were highly biased toward memory or effector fates. TCR-intrinsic biases were not stochastic and were dominant over environmental cues. Differential gene expression analysis of memory- or effector-biased TCR clonotypes showed bifurcation of differential fates at the early effector stage. Additionally, phylogenetic analysis revealed that memory-biased clonotypes retain their fate preferences in subclonal populations but effector-biased subclones can switch to a memory fate. Our study highlights that the polyclonal CD8 T cell response is a composite of unbiased and biased clonotypes with varying capacity to incorporate environmental cues in their cell fate decisions.
产生平衡的CD8效应T细胞和记忆T细胞群体对于对感染和癌症产生即时和持久的免疫反应至关重要。然而，对于多样化的CD8 T细胞库如何分化，仍缺乏明确的认识。我们鉴定了数百种构成针对单一抗原的多克隆反应的T细胞受体（TCR）克隆型，发现大多数TCR克隆型高度偏向记忆或效应细胞命运。TCR内在偏向并非随机，且在环境线索之上占主导地位。对偏向记忆或效应细胞的TCR克隆型进行差异基因表达分析显示，在早期效应细胞阶段，不同命运出现分歧。此外，系统发育分析表明，偏向记忆的克隆型在亚克隆群体中保留其命运偏好，但偏向效应细胞的亚克隆可以转变为记忆细胞命运。我们的研究强调，多克隆CD8 T细胞反应是由无偏向和有偏向的克隆型组成的复合体，它们在细胞命运决定中整合环境线索的能力各不相同。
