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

Gut. 2013 Aug;62(8):1142-52. doi: 10.1136/gutjnl-2012-302029. Epub 2012 Nov 9.

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.

Design: 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.

Keywords: Ibd Basic Research; Immunology; T Lymphocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Bone Marrow Cells / immunology*
  • Bone Marrow Transplantation
  • CD4-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Coculture Techniques
  • Colitis, Ulcerative / immunology*
  • Colitis, Ulcerative / pathology
  • Colon / immunology
  • Disease Models, Animal
  • Gene Expression Regulation / immunology
  • Immunologic Memory / immunology
  • Interleukin-7 / biosynthesis*
  • Interleukin-7 / genetics
  • Lymphocyte Activation / immunology
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger / genetics

Substances

  • Interleukin-7
  • RNA, Messenger