Cutting edge: 4-1BB controls regulatory activity in dendritic cells through promoting optimal expression of retinal dehydrogenase.
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.
Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Seung-Woo
SW
Lee
Yunji
Y
Park
So-Young
SY
Eun
Shravan
S
Madireddi
Hilde
H
Cheroutre
Michael
M
Croft
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008643:Mesentery / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055213:Retinal Pigment Epithelium / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases