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* Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology and
Department of Basic Medical Sciences, Purdue Cancer Center, Bindley Bioscience Center and Birck Nanotechnology Center, Purdue University, West Lafayette, IN 47907; and
Department of Microbiology and Immunology, Walther Oncology Center, School of Medicine, Indiana University, Indianapolis, IN 46202
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 
and involves T cell activation driven by mucosal dendritic cells and costimulation through CD28. Retinoic acid can promote TGF-
1-dependent generation of FoxP3+ regulatory T cells but decrease the TGF-1- 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported, in part, from grants from the National Institutes of Health-National Institute of Allergy and Infectious Diseases (AI063064), the Sidney Kimmel Foundation, and the American Heart Association (to C.H.K.).
2 S.G.K. and H.W.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Chang H. Kim, Department of Comparative Pathobiology, Purdue University, 725 Harrison Street, West Lafayette, IN 47907. E-mail address: chkim{at}purdue.edu
4 Abbreviations used in this paper: DC, dendritic cell; ATRA, all-trans-retinoic acid; RAR, retinoic acid receptor; PP, Peyer’s patch; ChIP, chromatin immunoprecipitation; SEB, staphylococcal enterotoxin B; 7-AAD, 7-aminoactinomycin D; h, human; m, murine; RXR, retinoid X receptor; DEAB, diethylaminobenzaldehyde; PLN, peripheral lymph node.
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