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. Overall design: 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