Lymphoid Chemokine Checkpoint: CD8+ T Cell Guard. A lymphoid tissue chemokine checkpoint safeguards effector CD8+ T cell differentiation

Activation of naive CD8+ T cells (TN) by pMHC-presenting dendritic cells (DCs) in lymphoid tissue is key to effector CD8+ T cell (TEFF) generation. How the duration of TN-DC interactions, and thereby integration of activation signals, is controlled in vivo remains elusive. Here, we report that lymphoid stroma-secreted ligands for CCR7, a TN-expressed chemokine receptor, act as rheostat of interaction duration by gradually inducing CD8+ T cell release from DCs. At late time points of interactions, CCR7 ligands promoted redistribution of the F-actin-promoting factor DOCK2 away from the immunological synapse to enable CD8+ T cell detachment, onset of proliferation and acquisition of cytotoxic capacity. Defects in the CCR7 rheostat caused sustained TN-DC interactions, yielding TEFF with high inhibitory receptor expression and impaired antimicrobial activity. In sum, our results uncover an evolutionarily conserved lymphoid tissue chemokine checkpoint that restricts TN-DC interactions to safeguard TEFF differentiation and to prevent imprinting of dysfunctional traits.

在淋巴组织中，呈递肽-主要组织相容性复合体（pMHC）的树突状细胞（DC）激活初始CD8+T细胞（TN，naive CD8+ T cells），这是效应CD8+T细胞（TEFF，effector CD8+ T cells）生成的核心环节。目前，体内如何调控TN与DC的交互时长、进而整合激活信号的机制仍未明确。本研究发现，淋巴基质分泌的CCR7配体（CCR7为TN表达的趋化因子受体）可作为交互时长的调控变阻器，通过逐步诱导CD8+T细胞脱离DC来发挥作用。在交互的后期阶段，CCR7配体可促进F-肌动蛋白促进因子DOCK2从免疫突触处重新分布，从而介导CD8+T细胞脱离、增殖启动以及细胞毒性功能的获得。CCR7调控变阻器的缺陷会导致TN与DC的交互持续时间延长，最终生成的TEFF会高表达抑制性受体，且抗菌活性受损。综上，本研究揭示了一种进化保守的淋巴组织趋化因子检查点，该检查点通过限制TN与DC的交互时长，保障TEFF的分化进程，并防止功能异常性状的印记形成。