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

ABSTRACT: 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 obse

SUBMITTER: Guy C 

PROVIDER: S-EPMC9106921 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature