title: Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon.
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.
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Hisako
authors.initials: H
authors.lastname: Kayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Kusu
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Jun
authors.initials: J
authors.lastname: Kunisawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
mesh_terms: D000821:Animal Feed; D000818:Animals; D002470:Cell Survival / Q000276:immunology; D003106:Colon / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005492:Folic Acid / Q000008:administration & dosage* / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000502:physiology; D055879:Gene Knock-In Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000502:physiology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D014803:Vitamin B Complex; D005492:Folic Acid