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

Y Nemoto, T Kanai, M Takahara, S Oshima… - Gut, 2013 - gut.bmj.com
Y Nemoto, T Kanai, M Takahara, S Oshima, T Nakamura, R Okamoto, K Tsuchiya…
Gut, 2013gut.bmj.com
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 …
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–/–ŚRAG-1–/– mice injected with BM cells from IL-7+/+ŚRAG-1–/– mice, but not from IL-7–/–ŚRAG-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–/–ŚRAG-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.
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