Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon

M Kinoshita, H Kayama, T Kusu… - The Journal of …, 2012 - journals.aai.org
M Kinoshita, H Kayama, T Kusu, T Yamaguchi, J Kunisawa, H Kiyono, S Sakaguchi
The Journal of Immunology, 2012journals.aai.org
Dietary compounds as well as commensal microbiota contribute to the generation of a
unique gut environment. In this study, we report that dietary folic acid (FA) is required for the
maintenance of Foxp3+ regulatory T cells (Tregs) in the colon. Deficiency of FA in the diet
resulted in marked reduction of Foxp3+ Tregs selectively in the colon. Blockade of folate
receptor 4 and treatment with methotrexate, which inhibits folate metabolic pathways,
decreased colonic Foxp3+ Tregs. Compared with splenic Tregs, colonic Tregs were more …
Abstract
Dietary compounds as well as commensal microbiota contribute to the generation of a unique gut environment. In this study, we report that dietary folic acid (FA) is required for the maintenance of Foxp3+ regulatory T cells (Tregs) in the colon. Deficiency of FA in the diet resulted in marked reduction of Foxp3+ Tregs selectively in the colon. Blockade of folate receptor 4 and treatment with methotrexate, which inhibits folate metabolic pathways, decreased colonic Foxp3+ Tregs. Compared with splenic Tregs, colonic Tregs were more activated to proliferate vigorously and were highly sensitive to apoptosis. In colonic Tregs derived from mice fed with a FA-deficient diet, expression of anti-apoptotic molecules Bcl-2 and Bcl-xL was severely decreased. A general reduction of peripheral Tregs was induced by a neutralizing Ab against IL-2, but a further decrease by additional FA deficiency was observed exclusively in the colon. Mice fed with an FA-deficient diet exhibited higher susceptibility to intestinal inflammation. These findings reveal the previously unappreciated role of dietary FA in promotion of survival of Foxp3+ Tregs that are in a highly activated state in the colon.
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