IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4+ mucosal T cells in mice
IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4+ mucosal T cells in mice
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DOI：
10.1152/ajpgi.00276.2004
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发表时间：
2005-04-01
影响因子：
4.5
通讯作者：
Watanabe, M
中科院分区：
文献类型：
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作者：
Okada, E;Yamazaki, M;Watanabe, M
我们先前已经证明，黏膜中高水平表达IL-7受体(IL-7R(High))的CD4(+)T细胞是慢性结肠炎的致病细胞。在这里，我们研究了IL-7是否直接参与了IL-7R(高记忆性)粘膜T细胞的扩张和结肠炎的恶化。我们首次发现，来自野生型、T细胞受体α缺陷(TCR-α(-/-))和重组酶激活基因(RAG)-2(-/-)转移的小鼠的CD4(+)固有层淋巴细胞(LPL)显示出记忆细胞的表型，但只有来自结肠炎小鼠的CD4(+)LPL显示出IL-7R(高)。在体外，IL-7(而不是IL-15和胸腺基质淋巴生成素)刺激能显著增强结肠炎CD4(+)淋巴细胞的增殖反应和存活率，但不能促进正常的CD4(+)LPL的存活。重要的是，体内注射IL-7小鼠加速了IL-7R(高记忆性)CD4(+)LPL的扩张，从而加重了从结肠炎TCR-α(-/-)小鼠转移来的CD4(+)LPL的RAG-2(-/-)小鼠的慢性结肠炎。相反，给予抗IL-7R单抗可显著抑制TCR-α(-/-)结肠炎的发展，并减少CD4(+)LPL的扩张。综上所述，目前的数据表明，在病理条件下，IL-7对于致病记忆CD4(+)T细胞的扩张是必不可少的。因此，针对IL-7R途径的治疗方法在治疗人类炎症性肠病方面可能是可行的。
We have previously demonstrated that mucosal CD4(+) T cells expressing high levels of IL-7 receptor (IL-7R(high)) are pathogenic cells responsible for chronic colitis. Here we investigate whether IL-7 is directly involved in the expansion of IL-7R(high) memory CD4(+) mucosal T cells and the exacerbation of colitis. We first showed that CD4(+) lamina propria lymphocytes (LPLs) from wild-type, T cell receptor-alpha-deficient (TCR-alpha(-/-)), and recombinase-activating gene (RAG)- 2(-/-)-transferred mice with or without colitis showed phenotypes of memory cells, but only CD4(+) LPLs from colitic mice showed IL-7R(high). In vitro stimulation by IL-7, but not by IL-15 and thymic stromal lymphopoietin, enhanced significant proliferative responses and survival of colitic CD4(+), but not normal CD4(+) LPLs. Importantly, in vivo administration of IL-7 mice accelerated the expansion of IL-7R(high) memory CD4(+) LPLs and thereby exacerbated chronic colitis in RAG-2(-/-) mice transferred with CD4(+) LPLs from colitic TCR-alpha(-/-) mice. Conversely, the administration of anti-IL-7R monoclonal antibody significantly inhibited the development of TCR-alpha(-/-) colitis with decreased expansion of CD4(+) LPLs. Collectively, the present data indicate that IL-7 is essential for the expansion of pathogenic memory CD4(+) T cells under pathological conditions. Therefore, therapeutic approaches targeting the IL-7R pathway may be feasible in the treatment of human inflammatory bowel disease.