title: Contrasting roles for all-trans retinoic acid in TGF-beta-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells.
abstract: 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-beta 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-beta-mediated Foxp3 induction, at-RA potently inhibits the TGF-beta-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.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, AL 35294, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Maynard
authors.forename: Robin D
authors.initials: RD
authors.lastname: Hatton
authors.forename: Whitney S
authors.initials: WS
authors.lastname: Helms
authors.forename: James R
authors.initials: JR
authors.lastname: Oliver
authors.forename: Charles B
authors.initials: CB
authors.lastname: Stephensen
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D060945:Inducible T-Cell Co-Stimulator Ligand; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000166:cytology; D011506:Proteins / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014212:Tretinoin / Q000276:immunology / Q000494:pharmacology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D011506:Proteins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D014212:Tretinoin