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

• DOI: 10.1038/s41590-022-01176-4
• Publication Date: 2022-04-18T16:04:49Z
• Authors: Clifford Guy; Diana M. Mitrea; Po-Chien Chou; Jamshid Temirov; Kate M. Vignali; Xueyan Liu; Hui Zhang; Richard Kriwacki; Marcel P. Bruchez; Simon C. Watkins; Creg J. Workman; Dario A. A. Vignali
• Keywords: CD3 Complex; Antigens, CD; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); CD8 Antigens; Histocompatibility Antigens Class II; Receptors, Antigen, T-Cell; CD8-Positive T-Lymphocytes; Lymphocyte Activation Gene 3 Protein; Signal Transduction

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.