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 CD11b⁻CD103⁺ 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 CD11b⁺CD103⁻ 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 CD11b⁺CD103⁻ DCs and T_H17 cells, indicating that RA is a major inhibitory effector molecule against intestinal CD11b⁺CD103⁻ 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细胞的一种有效的共刺激受体，在各种非T细胞中都有表达，但对其在这些细胞中的调节功能知之甚少。在这项研究中，我们显示CD137信号传导，特别是在肠道CD11b ^- CD103 ⁺树突状细胞（DC）中，限制了急性结肠炎的进展。从机理上讲，CD137参与激活TAK1，随后刺激AMPK-PGC-1α轴，以增强编码视黄酸（RA）代谢酶RALDH2的Aldh1a2基因的表达。RA可以作用于CD11b ⁺ CD103 ^- DC并诱导SOCS3表达，进而抑制p38MAPK激活和白介素23（IL-23）的产生。DC特有的RA管理CD137 ^-/-小鼠抑制产生IL-23的CD11b ⁺ CD103 ^- DC和T _H 17细胞，表明RA是针对肠道CD11b ⁺ CD103 ^- DC的主要抑制效应分子。另外，在DC特异性CD137 ^-/-小鼠中消除了抗CD137抗体的治疗作用。两者合计，我们的结果定义了旁分泌免疫调节机制在肠道中的相邻DC子集之间运作。