Molecular Basis of Ionic Suppression of ZAP-70 Dependent T Cell Receptor Activation

Ionic imbalance in the tumor microenvironment alters the tumor-infiltrating T lymphocyte function. High extracellular K ⁺ suppresses T cell function by negatively regulating T cell receptor (TCR) signaling. In contrast, elevated extracellular Na ⁺ enhances T cell effector function by boosting the phosphorylation of TCR signaling modules. Here, we presented a mechanism explaining how the two monovalent cations differently regulate TCR function. At rest, high intracellular K ⁺ uncouples allosteric recruitment of ZAP-70, a key signaling module, to the TCR complex. The formation of antigen TCR complex induces K ⁺ efflux, causing spontaneous recruitment of ZAP-70 to the TCR. Increasing extracellular K ⁺ perturbs K ⁺ efflux and slows ZAP-70 recruitment to the TCR complex, even upon antigen binding. This leads to defects in T cell development and arthritis-like symptoms in juvenile mice. We conclude that K ⁺ dynamics is integral to T cell ligand discrimination and fundamental to turning off the signaling during T cell quiescence.