Submitted to: Journal of Experimental Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/16/2009
Publication Date: 2/9/2009
Publication URL: jem.rupress.org/content/206/2/343.full.pdf+html
Citation: Maynard, C.L., Hatton, R.D., Helms, W.S., Oliver, J.R., Stephensen, C.B., Weaver, C.T. 2009. Contrasting Roles For All-Trans Retinoic Acid in TGF-ß-mediated Induction of Foxp3 and Il10 genes in Developing Regulatory T Cells. J. Exp. Med. Vol. 206, No. 2 343-357. Interpretive Summary: Vitamin A deficiency impairs our ability to resist certain infectious diseases. This study demonstrates that vitamin D deficiency specifically increases the development of regulatory T lymphocytes in mice in response to stimulation of innate immune cells that mimic a viral infection. These results suggest that vitamin A deficiency may affect the host response to viral infections differently from other infections.
Technical Abstract: Extrathymic induction of regulatory T cells (Treg) is essential to the regulation of effector T cell responses in the periphery. TGF-ß has been shown to induce Foxp3-expressing Tregs both in vitro and in vivo. More recently, the vitamin A metabolite, all-trans retinoic acid (at-RA), has been found to enhance this process. In addition to Foxp3, Treg expression of suppressive cytokines, such as IL-10, is essential for peripheral tolerance, particularly in the intestines. TGF-ß also mediates peripheral induction of Il10, but the role of at-RA in this process has not been examined. Here we report that in contrast to its enhancement of TGF-ß-mediated Foxp3 induction, at-RA potently inhibits the TGF-ß-mediated induction of Il10 in naïve CD4 T cells. Thus, mucosal DC subsets that are active producers of at-RA inhibit induction of Il10 in naïve CD4 T cells, while promoting induction of Foxp3. Activation of DCs by certain toll-like receptors (TLRs), but particularly TLR9, suppresses T cell induction of Foxp3 and enables induction of Il10,through a MyD88-dependent, ICOS ligand-independent mechanism that involves inhibition of at-RA production by DCs. Accordingly, mice with vitamin A deficiency have increased numbers of IL-10 competent Tregs. Thus, at-RA has reciprocal effects on the induction of Foxp3 and Il10 in developing CD4 T cells, and TLR9-dependent inhibition of at-RA production by APCs represents one mechanism to promote the development of IL-10-expressing T cells.