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

Summary: 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 TH17 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. : Jin et al. demonstrate that CD137 signaling functions as an immune checkpoint by controlling the survival and function of regulatory intestinal CD11b−CD103+ dendritic cells to coordinate the balance between regulatory T cells and pathogenic IL-23 during acute colitis. Keywords: CD137, regulatory CD11b−CD103+ DC, Foxp3+ Treg, acute colitis, retinoic acid, RALDH2, IL-23, TH17, immune checkpoint, immune tolerance