期刊
GUT
卷 62, 期 8, 页码 1142-1152出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2012-302029
关键词
Ibd Basic Research; Immunology; T Lymphocytes
资金
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Japanese Ministry of Health, Labour and Welfare
- Japan Medical Association
- Foundation for Advancement of International Science
- Terumo Life Science Foundation
- Ohyama Health Foundation
- Yakult Bio-Science Foundation
- Research Fund of the Mitsukoshi Health and Welfare Foundation
- Japan Intractable Disease Research Foundation
- Grants-in-Aid for Scientific Research [24590935, 24659375, 24590936, 23659394, 24590933, 23130506, 22229005, 23790777, 23102003] Funding Source: KAKEN
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(-/-)xRAG-1(-/-) mice injected with BM cells from IL-7(+/+)xRAG-1(-/-) mice, but not from IL-7(-/-)xRAG-1(-/-) mice, expressed IL-7 in BM, but not in their colon, and developed colitis when injected with CD4(+)CD45RB(high) 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(-/-)xRAG-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(+)CD45RB(high) 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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