title: High and low vitamin A therapies induce distinct FoxP3+ T-cell subsets and effectively control intestinal inflammation.
abstract: OBJECTIVE
  Retinoic acid plays a positive role in induction of FoxP3(+) regulatory T cells. Because retinoic acid is produced as a metabolite of vitamin A in the intestine and FoxP3(+) T cells regulate intestinal inflammation, we investigated the impact of vitamin A status on the regulatory T cells and inflammation in the intestine.
  
  
  METHODS
  The SAMP1/YP model is a mouse model of Crohn's disease. We made vitamin A-deficient, vitamin A-excessive, and normal SAMP1/YP mice and assessed the intestinal inflammation. We also investigated the phenotype and function of FoxP3(+) T cells induced in different levels of vitamin A availability in regulation of intestinal inflammation in a T-cell-induced inflammation model in SCID mice.
  
  
  RESULTS
  The limited and excessive vitamin A conditions induced distinct FoxP3(+) T-cell subsets in vivo, and both ameliorated the intestinal inflammation in SAMP1/YP mice. The limited vitamin A condition greatly induced unusual CD103(+)CCR7(+) FoxP3(+) cells, while the high vitamin A condition induced CCR9(+)alpha4beta7(+) FoxP3(+) T cells in the intestine. Both FoxP3(+) T-cell populations, when transferred into mice with ongoing intestinal inflammation, were highly effective in reversing the inflammation. Blockade or lack of occupancy of RARalpha is a mechanism to induce highly suppressive CD103(+)CCR7(+) FoxP3(+) cells in both the thymus and periphery in limited vitamin A availability.
  
  
  CONCLUSIONS
  Our results identify novel pathways of inducing highly suppressive FoxP3(+) regulatory T cells that can effectively control intestinal inflammation. The results have significant ramifications in treating inflammatory bowel diseases.
authors.affiliation: Department of Comparative Pathobiology, Laboratory of Immunology and Hematopoiesis, Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Seung G
authors.initials: SG
authors.lastname: Kang
authors.forename: Chuanwu
authors.initials: C
authors.lastname: Wang
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Chang H
authors.initials: CH
authors.lastname: Kim
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003424:Crohn Disease / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000032:analysis*; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D016130:Immunophenotyping; D039001:Integrin alpha Chains / Q000032:analysis; D007422:Intestines / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D054388:Receptors, CCR / Q000032:analysis; D054400:Receptors, CCR7 / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; C119309:CC chemokine receptor 9; C515371:Ccr7 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D005765:Gastrointestinal Agents; D039001:Integrin alpha Chains; C000607072:Rara protein, mouse; D054388:Receptors, CCR; D054400:Receptors, CCR7; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C091367:alpha E integrins; D014801:Vitamin A; D014212:Tretinoin