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

作者：Nemoto Yasuhiro^*; Kanai Takanori; Takahara Masahiro; Oshima Shigeru; Nakamura Tetsuya; Okamoto Ryuichi; Tsuchiya Kiichiro; Watanabe Mamoru

来源：Gut, 2013, 62(8): 1142-1152.

DOI：10.1136/gutjnl-2012-302029

• Ibd Basic Research
• Immunology
• T Lymphocytes

Objective %26lt;br%26gt;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. %26lt;br%26gt;Design %26lt;br%26gt;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. %26lt;br%26gt;Results %26lt;br%26gt;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. %26lt;br%26gt;Conclusions %26lt;br%26gt;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.

• 出版日期2013-8