title: Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells.
abstract: OBJECTIVE
  Interleukin (IL)-7 is mainly produced in bone marrow (BM) that forms the niche for B cells. We previously demonstrated that BM also retains pathogenic memory CD4 T cells in murine models of inflammatory bowel disease (IBD). However, it remains unknown whether BM-derived IL-7 is sufficient for the development of IBD and which cells form the niche for colitogenic memory CD4 T cells in BM.
  
  
  METHODS
  To address these questions, we developed mice in which IL-7 expression was specific for BM, and identified colitis-associated IL-7-expressing mesenchymal stem cells (MSC) in the BM.
  
  
  RESULTS
  IL-7-/-×RAG-1-/- mice injected with BM cells from IL-7+/+×RAG-1-/- mice, but not from IL-7-/-×RAG-1-/- mice, expressed IL-7 in BM, but not in their colon, and developed colitis when injected with CD4+CD45RBhigh T cells. Cultured BM MSC stably expressed a higher level of IL-7 than that of primary BM cells. IL-7-sufficient, but not IL-7-deficient, BM MSC supported upregulation of Bcl-2 in, and homeostatic proliferation of, colitogenic memory CD4 T cells in vitro. Notably, IL-7-/-×RAG-1-/- mice transplanted with IL-7-sufficient, but not IL-7-deficient, BM MSC expressed IL-7 in BM, but not in their colon, and developed colitis when transplanted with CD4+CD45RBhigh T cells.
  
  
  CONCLUSIONS
  We demonstrate for the first time that BM MSC are a major source of IL-7 and play a pathological role in IBD by forming the niche for colitogenic CD4 memory T cells in BM.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nemoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takahara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Oshima
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okamoto
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D015851:Interleukin-7; D012333:RNA, Messenger
keywords: Ibd Basic Research; Immunology; T Lymphocytes