RT Journal Article
SR Electronic
T1 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
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1142
OP 1152
DO 10.1136/gutjnl-2012-302029
VO 62
IS 8
A1 Yasuhiro Nemoto
A1 Takanori Kanai
A1 Masahiro Takahara
A1 Shigeru Oshima
A1 Tetsuya Nakamura
A1 Ryuichi Okamoto
A1 Kiichiro Tsuchiya
A1 Mamoru Watanabe
YR 2013
UL http://gut.bmj.com/content/62/8/1142.abstract
AB 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.