Colitogenic memory T cells are maintained by IL-7-producing cells in bone marrow.

致结肠炎记忆 T 细胞由骨髓中产生 IL-7 的细胞维持。

• 批准号: 20590736
• 负责人: NEMOTO Yasuhiro
• 金额: $ 3万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590736/
• 关键词: 炎症性腸疾患; IL-7; メモリーT細胞; 骨髄; 腸内細菌; 無菌マウス; 間葉系幹細胞; CD4^+ T細胞; CD4^+T細胞; CD4+T細胞

The aim of this study is to clarify the maintenance system of colitogenic memory CD4^+ T cells, which posses the "pathogenic memory" of inflammatory bowel disease, and to develop the epoch-making treatment for this disease.We have proved following things. 1) Although intestinal bacteria is essential for the development of colitis and cytokine production from effector T cells, it is not essential for the maintenance of colitogenic memory CD4^+ T cells. 2) IL-7^<-/-> x RAG-1^<-/-> mice were transplanted with BM cells of RAG-1^<-/-> (IL-7^<+/+>→IL-7^<-/->) or IL-7^<-/-> x RAG-1^<-/-> mice (IL-7^<-/->→IL-7^<-/->). IL-7 mRNA and protein were detected in BM, but not in colon, of in IL-7^<+/+>→IL-7^<-/-> mice, but not from IL-7^<-/->→IL-7^<-/-> mice. IL-7^<+/+>→IL-7^<-/->, but not IL-7^<-/->→IL-7^<-/-> recipients, transferred with CD4^+CD45RB^<high> T cells 4 weeks after transplantation, developed colitis. 3) Bone marrow mesenchymal stem cells (MSC), even over the 40^<th> passage, expressed ^<high>er levels of IL-7 mRNA and protein than those of freshly isolated IL-7^+ BM cells. 4) Co-culture with IL-7 producing MSC induced extensive proliferation of CFSE-labeled colitogenic CD4^+ T cells in vitro. 5) CD4^+CD45RB^<high> T cell-transferred IL-7^<-/-> x RAG-1^<-/-> mice previously transplanted with IL-7 producing MSC developed Th1/Th17-meidated colitis.Collectively, IL-7 producing bone marrow MSC play the important role in the maintenance system of colitogenic memory CD4^+ T cells. These findings are the progress in the investigation of IBD pathogenesis, suggesting the possibility of novel effective treatment, which targets this system.

本研究旨在阐明具有炎症性肠病“致病记忆”的结肠炎记忆CD4^+ T细胞的维持系统，并开发出具有划时代意义的治疗方法。我们已经证明了以下几点。1)虽然肠道细菌对结肠炎的发生和效应T细胞产生细胞因子至关重要，但它对维持结肠炎记忆CD4^+ T细胞并不是必不可少的。2) IL-7 ^ < - / - > x RAG-1 ^ < - / - >小鼠移植细胞的RAG-1 ^ < - / - > (IL-7 ^ < + / + >→IL-7 ^ < - / - >)或IL-7 ^ < - / - > x RAG-1 ^ < - / - >老鼠(IL-7 ^ < - / - >→IL-7 ^ < - / - >)。在IL-7^<+/+>→IL-7^<-/->小鼠的BM中检测到IL-7 mRNA和蛋白，而在结肠中未检测到，而在IL-7^<-/->→IL-7^<-/->小鼠中未检测到。IL-7^<+/+>→IL-7^<-/->，但IL-7^<-/->→IL-7^<-/->，移植后4周CD4^+CD45RB^<高> T细胞，发生结肠炎。3)骨髓间充质干细胞（MSC）即使经过40^< >传代，其IL-7 mRNA和蛋白表达水平也高于新分离的IL-7^+ BM细胞。4)与产生IL-7的MSC共培养可诱导cfse标记的结肠菌CD4^+ T细胞在体外广泛增殖。5) CD4^+CD45RB^<高> T细胞转移的IL-7^<-/-> x RAG-1^<-/->先前移植产生IL-7的MSC的小鼠发生Th1/ th17介导的结肠炎。总的来说，产生IL-7的骨髓间充质干细胞在结肠炎记忆CD4^+ T细胞维持系统中发挥重要作用。这些发现是对IBD发病机制研究的进展，提示了针对该系统的新型有效治疗的可能性。

项目成果

IL-7-producing mesenchymal stem cells sustain colitogenic memory CD4^+ T cells for the persistence of chronic colitis

产生 IL-7 的间充质干细胞维持致结肠炎记忆 CD4^ T 细胞，以维持慢性结肠炎的持续存在

• 发表时间: 2010
• 作者: 樋田信幸;堀和敏;松本譽之;Nemoto T
• 通讯作者: Nemoto T

Colitogenic CD4+ Effector-memory T Cells Actively Recirculate in Chronic Colitic Mice

• DOI: 10.1002/ibd.20636
• 发表时间: 2008-12-01
• 期刊: INFLAMMATORY BOWEL DISEASES
• 影响因子: 4.9
• 作者: Tomita, Takayuki;Kanai, Takanori;Watanabe, Mamoru
• 通讯作者: Watanabe, Mamoru

Continuous generation of colitogenic CD4+ T cells in persistent colitis

• DOI: 10.1002/eji.200737745
• 发表时间: 2008-05-01
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Tomita, Takayuki;Kanai, Takanori;Watanabe, Mamoru
• 通讯作者: Watanabe, Mamoru

Upregulated IL-7 Receptor {alpha} Expression on Colitogenic Memory CD4+ T Cells May Participate in the Development and Persistence of Chronic Colitis.

致结肠炎记忆 CD4 T 细胞上 IL-7 受体 {α} 表达的上调可能参与慢性结肠炎的发展和持续。

• 发表时间: 2011
• 期刊: J Immunol. in press
• 作者: Shinohara T;Nemoto Y;Kanai T;Kameyama K;Okamoto R;Tsuchiya K;Nakamura T;Totsuka T;Ikuta K;Watanabe M
• 通讯作者: Watanabe M

腸炎惹起性メモリーCD4+ T細胞再循環経路をターゲットとした炎症性腸疾患の治療戦略

针对肠病记忆 CD4+ T 细胞回收途径的炎症性肠病治疗策略

• 发表时间: 2010
• 作者: 根本泰宏;金井隆典;渡辺守;他
• 通讯作者: 他