Maynard Craig L, Hatton Robin D, Helms Whitney S, Oliver James R, Stephensen Charles B, Weaver Casey T
Department of Pathology, University of Alabama at Birmingham, AL 35294, USA.
J Exp Med. 2009 Feb 16;206(2):343-57. doi: 10.1084/jem.20080950. Epub 2009 Feb 9.
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.
胸腺外诱导调节性T（Treg）细胞对于外周效应T细胞反应的调节至关重要。除了Foxp3外，Treg细胞表达抑制性细胞因子（如IL-10）对于外周耐受至关重要，尤其是在肠道中。已证明转化生长因子-β（TGF-β）可诱导Foxp3以及IL-10和维生素A代谢产物的表达；已发现全反式视黄酸（RA [at-RA]）可增强前者。我们报告，与增强TGF-β介导的Foxp3诱导相反，at-RA强烈抑制TGF-β介导的幼稚CD4 T细胞中Il10的诱导。因此，作为at-RA活跃生产者的黏膜树突状细胞（DC）亚群在促进Foxp3诱导的同时，抑制幼稚CD4 T细胞中Il10的诱导。相应地，维生素A缺乏的小鼠具有更多能产生IL-10的Treg细胞。某些Toll样受体（TLR），特别是TLR9激活DC，可抑制T细胞诱导Foxp3并促进Il10的诱导。总体而言，我们的数据表明at-RA对发育中的CD4(+) Treg细胞中Foxp3和Il10的诱导具有相反的作用，并表明抗原呈递细胞对at-RA产生的TLR9依赖性抑制可能是促进表达IL-10的T细胞发育的一种机制。
