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 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|Jing|J|', 'Jung|In-Hyuk|IH|', 'Moon|Shin Hye|SH|', 'Jeon|Sejin|S|', 'Jeong|Se-Jin|SJ|', 'Sonn|Seong-Keun|SK|', 'Seo|Seungwoon|S|', 'Lee|Mi-Ni|MN|', 'Song|Eun Ju|EJ|', 'Kweon|Hyae Yon|HY|', 'Kim|Sinai|S|', 'Kim|Tae Kyeong|TK|', 'Kim|Juyang|J|', 'Cho|Hong Rae|HR|', 'Choi|Jae-Hoon|JH|', 'Kwon|Byungsuk|B|', 'Oh|Goo Taeg|GT|']
D000208:Acute Disease D000263:Adenylate Kinase D000445:Aldehyde Oxidoreductases D000818:Animals D015703:Antigens, CD D017209:Apoptosis D039481:CD11b Antigen D002454:Cell Differentiation D003092:Colitis D003713:Dendritic Cells D004198:Disease Susceptibility D051858:Forkhead Transcription Factors D039001:Integrin alpha Chains D007422:Intestines D020930:MAP Kinase Kinase Kinases D008810:Mice, Inbred C57BL D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha D015398:Signal Transduction D050378:T-Lymphocytes, Regulatory D058504:Th17 Cells D014212:Tretinoin D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
CD137 acute colitis retinoic acid RALDH2 IL-23 Foxp3(+) Treg T(H)17 immune checkpoint immune tolerance regulatory CD11b(−)CD103(+) DC