A lymphoid tissue chemokine checkpoint prevents loss of CD8 ⁺ T cell functionality

The generation of effector CD8 ⁺ T cells (T _EFF ) requires activation of naive CD8 ⁺ T cells (T _N ) by dendritic cells (DCs) within lymphoid tissue. To date, it remains elusive how the duration of T _N -DC interactions and integration of activation signals are controlled in vivo . Here, we report that lymphoid stroma-secreted ligands for CCR7 constrained interaction duration by gradually inducing CD8 ⁺ T cell release from DCs. At late time points of interactions, CCR7 ligands repositioned the F-actin-promoting factor DOCK2 away from the DC interface to enable CD8 ⁺ T cell detachment, proliferation onset and acquisition of cytotoxicity. Lack of CCR7 signaling, as during ex vivo activation or in chronically inflamed lymphoid tissue, caused sustained T cell-DC interactions, and generated dysfunctional T _EFF with high expression of inhibitory receptors, impaired antimicrobial activity, and poor recall responses. In sum, our findings uncover that lymphoid stromal chemokines act as built-in “disruptors” of T cell-DC interactions for long-term preservation of T _EFF functionality.