The developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8⁺ T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1⁺ pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8⁺ T cells, coupled with elevated expression of multiple inhibitory receptors including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD5, and CD160. Genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62L^hi TCF-1⁺ subset and subsequent CD8⁺ T cell memory. Although central memory phenotype CD8⁺ T cells were formed in the absence of these cells, subsequent memory CD8⁺ T cell recall responses were compromised. Together, these results identify an important link between genome integrity maintenance and CD8⁺ T cell memory. Moreover, the data indicate a role for inhibitory receptors in preserving key memory CD8⁺ T cell precursors during initial activation and differentiation. Identification of this rare subpopulation within the memory CD8⁺ T cell precursor pool may help reconcile models of the developmental origin of long-term CD8⁺ T cell memory.

记忆 T 细胞的发育起源仍然不完全清楚。在急性病毒感染的扩张阶段，我们发现了一个独特的病毒特异性 CD8 ⁺ T 细胞亚群，它们具有不同的特征，包括 CD62L、T 细胞因子 1 (TCF-1) 和 Emesodermin 的表达；相对静止；激活标记的表达；和有限的效应分化特征。^{这些细胞是 TCF-1 +}池的一个数量上较小的亚群，表现出自我更新、增强的 DNA 损伤监测活动和优先的长期回忆能力。尽管在扩展阶段具有记忆特征和增殖有所抑制，但该子集显示出比其他响应 CD8 ^{+更强的 TCR 信号传导的证据}T 细胞，以及多种抑制性受体的表达升高，包括程序性细胞死亡 1 (PD-1)、淋巴细胞激活基因 3 (LAG-3)、细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4)、CD5 和 CD160 . PD-1 和 LAG-3 的基因消融损害了这种 CD62L ^hi TCF-1 ⁺亚群和随后的 CD8 ⁺ T 细胞记忆的形成。尽管在没有这些细胞的情况下形成了中央记忆表型 CD8 ⁺ T 细胞，但随后的记忆 CD8 ⁺ T 细胞回忆反应受到损害。^{总之，这些结果确定了基因组完整性维护和 CD8 +}之间的重要联系T细胞记忆。此外，数据表明抑制性受体在初始激活和分化过程中在保留关键记忆 CD8 ⁺ T 细胞前体中的作用。^{在记忆 CD8 +} T 细胞前体池中识别这种罕见的亚群可能有助于协调长期 CD8 ⁺ T 细胞记忆的发育起源模型。