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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. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.


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. CD137 Signaling Regulates Acute Colitis via RALDH2-Expressing CD11b-CD103+ DCs. Cell reports. 2020 Mar 24;30(12):4124-4136.e5

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PMID: 32209473

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