Immune and Vascular Cell Network Research Center, National Creative Initiatives, Department of Life Sciences, Ewha Womans University, Seoul 120-750, South Korea.
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell Rep. 2020 Mar 24;30(12):4124-4136.e5. doi: 10.1016/j.celrep.2020.02.103.
CD137, a potent costimulatory receptor for CD8 T cells, is expressed in various non-T cells, but little is known about its regulatory functions in these cells. In this study, we show that CD137 signaling, specifically in intestinal CD11bCD103 dendritic cells (DCs), restricts acute colitis progression. Mechanistically, CD137 engagement activates TAK1 and subsequently stimulates the AMPK-PGC-1α axis to enhance expression of the Aldh1a2 gene encoding the retinoic acid (RA) metabolizing enzyme RALDH2. RA can act on CD11bCD103 DCs and induce SOCS3 expression, which, in turn, suppresses p38MAPK activation and interleukin-23 (IL-23) production. Administration of RA in DC-specific CD137 mice represses IL-23-producing CD11bCD103 DCs and T17 cells, indicating that RA is a major inhibitory effector molecule against intestinal CD11bCD103 DCs. Additionally, the therapeutic effect of the anti-CD137 antibody is abrogated in DC-specific CD137 mice. Taken together, our results define a mechanism of paracrine immunoregulation operating between adjacent DC subsets in the intestine.
CD137 是 CD8 T 细胞的一种有效共刺激受体，在各种非 T 细胞中表达，但关于其在这些细胞中的调节功能知之甚少。在这项研究中，我们表明 CD137 信号转导，特别是在肠道 CD11bCD103 树突状细胞（DC）中，限制了急性结肠炎的进展。从机制上讲，CD137 结合激活 TAK1，随后刺激 AMPK-PGC-1α 轴，增强编码视黄酸（RA）代谢酶 RALDH2 的 Aldh1a2 基因的表达。RA 可以作用于 CD11bCD103 DC 并诱导 SOCS3 的表达，SOCS3 反过来抑制 p38MAPK 的激活和白细胞介素-23（IL-23）的产生。RA 在 DC 特异性 CD137 小鼠中的给药抑制了产生 IL-23 的 CD11bCD103 DC 和 T17 细胞，表明 RA 是针对肠道 CD11bCD103 DC 的主要抑制效应分子。此外，抗 CD137 抗体的治疗效果在 DC 特异性 CD137 小鼠中被消除。总之，我们的结果定义了一种旁分泌免疫调节机制，该机制在肠道中相邻的 DC 亚群之间发挥作用。
