The lymphoid microenvironment controls duration of T cell - DC interactions to promote accelerated effector cell generation

Abstract

Abstract Naïve T cells and dendritic cells (DCs) are drawn to lymphoid tissue by the chemokine receptor CCR7, where its ligands CCL19 and CCL21 are secreted by lymphoid stroma. There, CCR7 fuels the fast migration of naïve T cells to expedite encounters with DCs presenting cognate pMHC, leading to the formation of long-lasting contacts. Direct in situ observations in mouse models have shown that after approximately 12–24 h, activated T cells detach from DCs before undergoing cell division and effector T cell differentiation. Yet, the mechanisms underlying T cell release from DCs, and hence termination of TCR signal integration, are not well understood. Using a reporter system for TCR signaling, we show here that CD8+T cell detachment from DCs does not occur efficiently in the absence of CCR7 ligands, suggesting that T cells do not intrinsically cease TCR signal integration. In contrast, after a short period of unresponsiveness, ex vivo stimulated T cells increasingly separate from DCs in response to CCR7 ligands in line with in vivo kinetics of detachment. Using ex vivo and in vivo imaging, we identify a critical role for phosphoinositide-3-kinase and the Rac activator DOCK2 in calibrating CCR7-dependent duration of T cell-DC interactions. To assess the impact of enforced T cell-DC separation, we examined effector differentiation kinetics as a function of interaction duration with DCs. Environmentally triggered CD8+T cell detachment from DCs positively correlated with their entry into proliferation and granzyme B production while limiting PD-1 expression. In sum, our data assign a novel function to CCR7 ligands secreted by lymphoid stroma to limit the duration of CD8+T cell - DC interactions for accelerated effector T cell generation.