The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20080950
The Journal of Experimental Medicine, Vol. 206, No. 2, 343-357
The Rockefeller University Press, 0022-1007 $30.00
© Maynard et al.
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ARTICLE

 Contrasting roles for all-trans retinoic acid in TGF-β–mediated induction of Foxp3 and Il10 genes in developing regulatory T cells

Craig L. Maynard1, Robin D. Hatton1, Whitney S. Helms1, James R. Oliver1, Charles B. Stephensen4, and Casey T. Weaver1,2,3

1 Department of Pathology, 2 Department of Microbiology, and 3 Department of Medicine, University of Alabama at Birmingham, AL 35294
4 Nutrition Department, United States Department of Agriculture Western Human Nutrition Research Center, University of California, Davis, Davis, CA 95616

CORRESPONDENCE Casey T. Weaver: cweaver{at}uab.edu

Extrathymic induction of regulatory T (T reg) cells is essential to the regulation of effector T cell responses in the periphery. In addition to Foxp3, T reg cell expression of suppressive cytokines, such as IL-10, is essential for peripheral tolerance, particularly in the intestines. TGF-β has been shown to induce expression of Foxp3 as well as IL10 and the vitamin A metabolite; all-trans retinoic acid (RA [at-RA]) has been found to enhance the former. We report that in contrast to its enhancement of TGF-β–mediated Foxp3 induction, at-RA potently inhibits the TGF-β–mediated induction of Il10 in naive CD4 T cells. Thus, mucosal DC subsets that are active producers of at-RA inhibit induction of Il10 in naive CD4 T cells while promoting induction of Foxp3. Accordingly, mice with vitamin A deficiency have increased numbers of IL-10–competent T reg cells. Activation of DCs by certain Toll-like receptors (TLRs), particularly TLR9, suppresses T cell induction of Foxp3 and enables induction of Il10. Collectively, our data indicate that at-RA has reciprocal effects on the induction of Foxp3 and Il10 in developing CD4+ T reg cells and suggest that TLR9-dependent inhibition of at-RA production by antigen-presenting cells might represent one mechanism to promote the development of IL-10–expressing T cells.

Abbreviations used: at-RA, all-trans RA; Blimp-1, B lymphocyte–induced maturation protein-1; BMDC, BM-derived DC; cLP, colon lamina propria; GALT, gut-associated lymphoid tissue; ICOS, inducible costimulator; ICOSL, ICOS ligand; LTA, lipoteichoic acid; MDP, muramyl dipeptide; MLN, mesenteric LN; mRNA, messenger RNA; NOD, nucleotide oligomerization domain; RA, retinoic acid; RAR, RA receptor; RARi, RAR inhibitor; sLP, small intestine lamina propria; TLR, Toll-like receptor; TR1, T reg type 1; T reg cell, regulatory T cell; VAC, vitamin A control; VAD, vitamin A deficient; VAH, vitamin A high.

© 2009 Maynard et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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