Cutting Edge: 4-1BB Controls Regulatory Activity in Dendritic Cells through Promoting Optimal Expression of Retinal Dehydrogenase |
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Authors: | Seung-Woo Lee Yunji Park So-Young Eun Shravan Madireddi Hilde Cheroutre Michael Croft |
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Institution: | Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; |
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Abstract: | Dendritic cells (DC) in the gut promote immune tolerance by expressing retinal dehydrogenase (RALDH), an enzyme that promotes retinoic acid, which aids differentiation of Foxp3(+) inducible regulatory T cells (iTreg) in the intestinal mucosa. How RALDH expression is regulated is unclear. We found that 4-1BB (CD137), a member of the TNFR family, together with CD103, marked mesenteric lymph node DC with the highest level of RALDH activity, and ligation of 4-1BB maintained RALDH expression in these gut DC. Moreover, 4-1BB signals synergized with those through TLR2 or GM-CSFR to promote RALDH activity in undifferentiated DC. Correspondingly, 4-1BB-deficient mice were impaired in their ability to generate iTreg in the GALT when exposed to oral Ag, and 4-1BB-deficient mesenteric lymph node DC displayed weak RALDH activity and were poor at promoting iTreg development. Thus, our data demonstrate a novel activity of 4-1BB in controlling RALDH expression and the regulatory activity of DC. |
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