CD137 Signaling Regulates Acute Colitis via RALDH2-Expressing CD11b^-CD103⁺ DCs

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.