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

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 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.

Keywords: CD137; Foxp3(+) Treg; IL-23; RALDH2; T(H)17; acute colitis; immune checkpoint; immune tolerance; regulatory CD11b(−)CD103(+) DC; retinoic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adenylate Kinase / metabolism
  • Aldehyde Oxidoreductases / metabolism*
  • Animals
  • Antigens, CD / metabolism*
  • Apoptosis
  • CD11b Antigen / metabolism*
  • Cell Differentiation
  • Colitis / immunology
  • Colitis / pathology*
  • Dendritic Cells / metabolism*
  • Disease Susceptibility
  • Forkhead Transcription Factors / metabolism
  • Integrin alpha Chains / metabolism*
  • Intestines / pathology
  • MAP Kinase Kinase Kinases / metabolism
  • Mice, Inbred C57BL
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Signal Transduction*
  • T-Lymphocytes, Regulatory / immunology
  • Th17 Cells / cytology
  • Tretinoin / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / deficiency
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism*


  • Antigens, CD
  • CD11b Antigen
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Integrin alpha Chains
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • alpha E integrins
  • Tretinoin
  • Aldehyde Oxidoreductases
  • RALDH2 protein, mouse
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Adenylate Kinase