期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 15, 页码 6017-6026出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.007455
关键词
immunology; T cell; T cell receptor (TCR); inhibition mechanism; immunotherapy; monoclonal antibody; cytokine induction; co-receptor; immune checkpoint; LAG-3
资金
- Core Research for Evolutional Science and Technology Program of the Japan Science and Technology Agency
- Basic Science and Platform Technology Program for Innovative Biological Medicine of the Japan Agency for Medical Research and Development [JP18am0301007]
- Japan Society for the Promotion of Science [JP18H05417]
T cell activation is tightly regulated by both stimulatory and inhibitory co-receptors and has been a focus in the development of interventions for managing cancer or autoimmune diseases. Targeting the inhibitory co-receptors programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) has successfully eradicated tumors but induced immune-related adverse events in humans and mice. The beneficial and adverse effects of targeting these co-receptors highlight their importance in cancer immunity and also autoimmunity. Although the therapeutic potencies of other inhibitory co-receptors are under extensive investigation, their inhibitory mechanisms and their functional differences are not well understood. Here we analyzed the inhibitory mechanisms of lymphocyte activation gene-3 (LAG-3), another inhibitory co-receptor, by using an in vitro T cell activation system and a high-affinity anti-LAG-3 antibody that strongly interferes with the binding of LAG-3 to its ligand. We found that the expression level of LAG-3 strongly correlates with the inhibitory function of LAG-3, suggesting that LAG-3 functions as a rheostat rather than as a breaker of T cell activation. By evaluating the inhibitory capacities of various LAG-3 variants relative to their expression levels, we found that LAG-3 transduces two independent inhibitory signals through an FXXL motif in the membrane-proximal region and the C-terminal EX repeat. These motifs have not been reported previously for inhibitory co-receptors, suggesting that LAG-3 inhibits T cell activation through a nonredundant inhibitory mechanisms along with the other inhibitory co-receptors. Our findings provide a rationale for combinatorial targeting of LAG-3 and the other inhibitory co-receptors to improve cancer immunotherapy.
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