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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cells, Cultured
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Dendritic Cells / enzymology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Gene Expression Regulation, Enzymologic* / genetics
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Glyceraldehyde-3-Phosphate Dehydrogenases / biosynthesis*
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Glyceraldehyde-3-Phosphate Dehydrogenases / genetics
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Intestinal Mucosa / enzymology
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Intestinal Mucosa / immunology
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Intestinal Mucosa / metabolism
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Lymph Nodes / cytology
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Mesentery / cytology
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Mesentery / immunology
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Mesentery / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Retinal Pigment Epithelium / enzymology
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Retinal Pigment Epithelium / immunology*
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Retinal Pigment Epithelium / metabolism*
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / deficiency
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / physiology*
Substances
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TNFRSF9 protein, human
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Glyceraldehyde-3-Phosphate Dehydrogenases