LAG3 associates with TCR–CD3 complexes and suppresses signaling by driving co-receptor–Lck dissociation

LAG3 is an inhibitory receptor that is highly expressed on exhausted T cells. Although LAG3-targeting immunotherapeutics are currently in clinical trials, how LAG3 inhibits T cell function remains unclear. Here, we show that LAG3 moved to the immunological synapse and associated with the T cell receptor (TCR)-CD3 complex in CD4+ and CD8+ T cells, in the absence of binding to major histocompatibility complex class II—its canonical ligand. Mechanistically, a phylogenetically conserved, acidic, tandem glutamic acid–proline repeat in the LAG3 cytoplasmic tail lowered the pH at the immune synapse and caused dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor, which resulted in a loss of co-receptor–TCR signaling and limited T cell activation. These observations indicated that LAG3 functioned as a signal disruptor in a major histocompatibility complex class II-independent manner, and provide insight into the mechanism of action of LAG3-targeting immunotherapies. Vignali and colleagues show that the inhibitory receptor LAG3 interferes with TCR signaling and T cell activation by lowering the pH at the immune synapse, which causes the dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor.