Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba 305-8575, Japan.
Proc Natl Acad Sci U S A. 2021 May 25;118(21). doi: 10.1073/pnas.2021309118.
Regulatory T (Treg) cells that express forkhead box P3 (Foxp3) are pivotal for immune tolerance. Although inflammatory mediators cause Foxp3 instability and Treg cell dysfunction, their regulatory mechanisms remain incompletely understood. Here, we show that the transfer of Treg cells deficient in the activating immunoreceptor DNAM-1 ameliorated the development of graft-versus-host disease better than did wild-type Treg cells. We found that DNAM-1 competes with T cell immunoreceptor with Ig and ITIM domains (TIGIT) in binding to their common ligand CD155 and therefore regulates TIGIT signaling to down-regulate Treg cell function without DNAM-1-mediated intracellular signaling. DNAM-1 deficiency augments TIGIT signaling; this subsequently inhibits activation of the protein kinase B-mammalian target of rapamycin complex 1 pathway, resulting in the maintenance of Foxp3 expression and Treg cell function under inflammatory conditions. These findings demonstrate that DNAM-1 regulates Treg cell function via TIGIT signaling and thus, it is a potential molecular target for augmenting Treg function in inflammatory diseases.
表达叉头框蛋白 P3（Foxp3）的调节性 T（Treg）细胞对于免疫耐受至关重要。尽管炎症介质导致 Foxp3 不稳定和 Treg 细胞功能障碍，但它们的调节机制仍不完全清楚。在这里，我们表明，缺乏激活免疫受体 DNAM-1 的 Treg 细胞的转移比野生型 Treg 细胞更好地改善移植物抗宿主病的发展。我们发现，DNAM-1 与 T 细胞免疫受体 Ig 和 ITIM 结构域（TIGIT）竞争与它们共同配体 CD155 的结合，因此调节 TIGIT 信号转导，以在没有 DNAM-1 介导的细胞内信号转导的情况下下调 Treg 细胞功能。DNAM-1 缺乏会增强 TIGIT 信号转导；这随后抑制蛋白激酶 B-雷帕霉素靶蛋白复合物 1 通路的激活，导致 Foxp3 表达和 Treg 细胞功能在炎症条件下得以维持。这些发现表明，DNAM-1 通过 TIGIT 信号转导调节 Treg 细胞功能，因此它是增强炎症性疾病中 Treg 功能的潜在分子靶标。
