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

Jing Jin; In-Hyuk Jung; Shin Hye Moon; Sejin Jeon; Se-Jin Jeong; Seong-Keun Sonn; Seungwoon Seo; Mi-Ni Lee; Eun Ju Song; Hyae Yon Kweon; Sinai Kim; Tae Kyeong Kim; Juyang Kim; Hong Rae Cho; Jae-Hoon Choi; Byungsuk Kwon; Goo Taeg Oh

doi:10.1016/j.celrep.2020.02.103

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.

Authors

Jing Jin¹, In-Hyuk Jung², Shin Hye Moon¹, Sejin Jeon¹, Se-Jin Jeong², Seong-Keun Sonn¹, Seungwoon Seo¹, Mi-Ni Lee¹, Eun Ju Song¹, Hyae Yon Kweon¹, Sinai Kim¹, Tae Kyeong Kim¹, Juyang Kim³, Hong Rae Cho⁴, Jae-Hoon Choi⁵, Byungsuk Kwon⁶, Goo Taeg Oh⁷

Affiliations

¹ Immune and Vascular Cell Network Research Center, National Creative Initiatives, Department of Life Sciences, Ewha Womans University, Seoul 120-750, South Korea.
² Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
³ School of Biological Sciences and Biomedical Research Center, University of Ulsan, Ulsan 44610, South Korea.
⁴ Department of Surgery and Biomedical Research Center, Ulsan University Hospital, College of Medicine, University of Ulsan, Ulsan 44610, South Korea.
⁵ Department of Life Science, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, South Korea.
⁶ School of Biological Sciences and Biomedical Research Center, University of Ulsan, Ulsan 44610, South Korea. Electronic address: [email protected].
⁷ Immune and Vascular Cell Network Research Center, National Creative Initiatives, Department of Life Sciences, Ewha Womans University, Seoul 120-750, South Korea. Electronic address: [email protected].

PMID: 32209473
DOI: 10.1016/j.celrep.2020.02.103

Abstract

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.

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*

Substances

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