A distinct priming phase regulates CD8 T cell immunity by orchestrating paracrine IL-2 signals

T cell priming is characterized by an initial activation phase that involves long-term interactions with dendritic cells (DC). How paracrine signals are spatiotemporally transmitted once activated T cells have disengaged from DC and resumed their migration is currently unclear. Here, we identified a separate phase that serves to expand high-affinity CD8 T cells in specific subfollicular niches in lymph nodes. CD8 T cells required stop signals mediated by CXCR3 and a high affinity TCR to re-engage with antigen-laden DC in restricted microdomains. There, CD4 T cells delivered paracrine IL-2 in a stop-and-go migration pattern and thereby played an essential role in scaling primary CD8 T cell responses. Our results revise the current paradigm of T cell priming and have direct implications for vaccinations and cellular immunotherapies. Foxp3-GFP-DTR mice were infected with Vaccinia virus subcutaneously in the foot hock and 28 hours later CD3+CD4+GFP+ regulatory T cells from the popliteal lymph node were sorted and analyzed by scRNAseq

T细胞启动（T cell priming）以包含与树突状细胞（dendritic cells, DC）长期相互作用的初始激活阶段为特征。目前，激活的T细胞脱离DC并恢复迁移后，旁分泌信号的时空传递机制仍不明确。本研究鉴定出一个独立阶段，该阶段可在淋巴结内特定的滤泡下微生境中扩增高亲和力CD8 T细胞。CD8 T细胞需要依赖CXCR3介导的制动信号与高亲和力T细胞受体（TCR），才能在受限的微域中重新结合携带抗原的DC。在此过程中，CD4 T细胞以“停-走”式迁移模式递送旁分泌白细胞介素-2（IL-2），进而在扩大初始CD8 T细胞应答中发挥核心作用。本研究结果修正了当前的T细胞启动范式，对疫苗接种与细胞免疫治疗具有直接的应用指导价值。实验中，我们将Foxp3-绿色荧光蛋白-白喉毒素受体（Foxp3-GFP-DTR）小鼠于跗关节皮下接种痘苗病毒（Vaccinia virus），于接种后28小时分离腘淋巴结中的CD3+CD4+GFP+调节性T细胞，并通过单细胞RNA测序（single-cell RNA sequencing, scRNAseq）完成分析。