Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation

書誌事項

タイトル
Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation
タイトル別名
  • 抑制性免疫補助受容体LAG-3は細胞質領域に有する非定型モチーフを介してT細胞の活性化を抑制する
  • Inhibitory mechanisms of LAG-3–dependent T cell suppression
著者
Maeda, Takeo K.
著者
Sugiura, Daisuke
著者
Okazaki, Il-mi
著者
Maruhashi, Takumi
著者
Okazaki, Taku
学位授与大学
徳島大学
取得学位
博士(医学)
学位授与番号
甲第3319号
学位授与年月日
2019-02-13

説明

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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