Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells.
In this study, we report a novel biological function of vitamin A metabolites in conversion of naive FoxP3- CD4+ T cells into a unique FoxP3+ regulatory T cell subset (termed "retinoid-induced FoxP3+ T cells") in both human and mouse T cells. We found that the major vitamin A metabolite all-trans-retinoic acid induces histone acetylation at the FoxP3 gene promoter and expression of the FoxP3 protein in CD4+ T cells. The induction of retinoid-induced FoxP3+ T cells is mediated by the nuclear retinoic acid receptor alpha and involves T cell activation driven by mucosal dendritic cells and costimulation through CD28. Retinoic acid can promote TGF-beta1-dependent generation of FoxP3+ regulatory T cells but decrease the TGF-beta1- and IL-6-dependent generation of inflammatory Th17 cells in mouse T cells. Retinoid-induced FoxP3+ T cells can efficiently suppress target cells and, thus, have a regulatory function typical for FoxP3+ T cells. A unique cellular feature of these regulatory T cells is their high expression of gut-homing receptors that are important for migration to the mucosal tissues particularly the small intestine. Taken together, these results identify retinoids as positive regulatory factors for generation of gut-homing FoxP3+ T cells.
Kang
Seung G
SG
Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue Cancer Center, Bindley Bioscience Center and Birck Nanotechnology Center, Purdue University, West Lafayette, IN 47907, USA.
Lim
Hyung W
HW
Andrisani
Ourania M
OM
Broxmeyer
Hal E
HE
Kim
Chang H
CH
D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006131:Growth Inhibitors / Q000378:metabolism / Q000502:physiology; D006801:Humans; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism / Q000502:physiology*; D014801:Vitamin A / Q000378:metabolism* / Q000502:physiology; D000097768:Retinoic Acid Receptor gamma; D000093242:Interleukin-6 Inhibitors