4.7 Article

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

Journal

NATURE IMMUNOLOGY
Volume 23, Issue 5, Pages 757-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41590-022-01176-4

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Funding

  1. SJCRH
  2. National Institutes of Health [P01 AI108545, R01 AI129893, R01 AI144422]
  3. NCI Comprehensive Cancer Center Support CORE grant [CA047904]
  4. ALSAC
  5. NCI [P30 CA021765]

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This study reveals that the inhibitory receptor LAG3 interferes with TCR signaling and T cell activation by lowering the pH at the immune synapse, providing insights into the mechanism of action of LAG3 in inhibiting T cell function.
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. 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.

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