Colitis in mice lacking the common cytokine receptor γ chain is mediated by IL-6-producing CD4+ T cells
Colitis in mice lacking the common cytokine receptor γ chain is mediated by IL-6-producing CD4+ T cells
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DOI：
10.1053/j.gastro.2005.01.013
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发表时间：
2005-04-01
期刊：
影响因子：
29.4
通讯作者：
Kiyono, H
中科院分区：
文献类型：
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作者：
Kai, Y;Takahashi, I;Kiyono, H
背景与目的：已知具有常见细胞因子受体γ链（CR γ (-/Y)）截断突变的小鼠可自发发展为结肠炎。为了确定引发这种局部炎症性疾病的病理因素，我们在结肠炎CR γ (-/Y)小鼠中阐明并表征了异常T细胞及其肠致病性细胞因子。方法：观察固有层淋巴细胞的组织学形态、细胞群、t细胞受体V β的使用和细胞因子的产生。用抗白细胞介素(IL)-6受体单克隆抗体治疗CR γ (-/Y)小鼠，评估其控制结肠炎的能力，并将同一小鼠模型的脾CD4(+) T细胞过继转移到SCID小鼠体内，观察是否刺激结肠炎的出现。结果：我们发现，从8周龄开始，无胸腺CR γ (-/Y)小鼠的大肠明显增厚，隐窝深度增加，结肠固有层和粘膜下层有单核细胞浸润，而无胸腺CR γ (-/Y)小鼠则没有。高表达抗凋亡Bcl-x和Bcl-2的结肠CD4(+) T细胞使用选定的T细胞受体亚群（V β 14）并专门产生IL-6。用抗il -6受体单克隆抗体治疗CR γ (-/Y)小鼠通过诱导产生il -6的CD4(+) T细胞凋亡来阻止结肠炎的形成。病理性CD4(+) T细胞过继性转移诱导SCID小鼠结肠炎。结论：结肠产生il -6的胸腺源性CD4(+) T细胞与CR γ (-/Y)小鼠结肠炎的发生有关。
Background & Aims: Mice that have a truncated mutation of the common cytokine receptor gamma chain (CR gamma(-/Y)) are known to spontaneously develop colitis. To identify the pathologic elements responsible for triggering this localized inflammatory disease, we elucidated and characterized aberrant T cells and their enteropathogenic cytokines in CR gamma(-/Y) mice with colitis. Methods: The histologic appearance, cell population, T-cell receptor V beta usage, and cytokine production of lamina propria lymphocytes were assessed. CR gamma(-/Y) mice were treated with anti-interleukin (IL)-6 receptor monoclonal antibody to evaluate its ability to control colitis, and splenic CD4(+) T cells from the same mouse model were adoptively transferred into SCID mice to see if they spurred the appearance of colitis. Results: We found marked thickening of the large intestine, an increase in crypt depth, and infiltration of the colonic lamina propria and submucosa with mononuclear cells in the euthymic CR gamma(-/Y) mice, but not in the athymic CR gamma(-/Y) mice, starting at the age of 8 weeks. Colonic CD4(+) T cells with high expressions of antiapoptotic Bcl-x and Bcl-2 were found to use selected subsets (V beta 14) of T-cell receptor and to exclusively produce IL-6. Treatment of CR gamma(-/Y) mice with anti-IL-6 receptor monoclonal antibody prevented the formation of colitis via the induction of apoptosis in IL-6-producing CD4(+) T cells. Adoptive transfer of pathologic CD4(+) T cells induced colitis in the recipient SCID mice. Conclusions: Colonic IL-6-producing thymus-derived CD4(+) T cells are responsible for the development of colitis in CR gamma(-/Y) mice.