Totsuka Teruji, Kanai Takanori, Nemoto Yasuhiro, Makita Shin, Okamoto Ryuichi, Tsuchiya Kiichiro, Watanabe Mamoru
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
J Immunol. 2007 Apr 15;178(8):4737-48. doi: 10.4049/jimmunol.178.8.4737.
Although IL-7 has recently emerged as a key cytokine involved in controlling the homeostatic turnover and the survival of peripheral resting memory CD4(+) T cells, its potential to be sustained pathogenic CD4(+) T cells in chronic immune diseases, such as inflammatory bowel diseases, still remains unclear. In this study, we demonstrate that IL-7 is essential for the development and the persistence of chronic colitis induced by adoptive transfer of normal CD4(+)CD45RB(high) T cells or colitogenic lamina propria (LP) CD4(+) memory T cells into immunodeficient IL-7(+/+) x RAG-1(-/-) and IL-7(-/-) x RAG-1(-/-) mice. Although IL-7(+/+) x RAG-1(-/-) recipients transferred with CD4(+)CD45RB(high) splenocytes developed massive inflammation of the large intestinal mucosa concurrent with massive expansion of Th1 cells, IL-7(-/-) x RAG-1(-/-) recipients did not. Furthermore, IL-7(-/-) x RAG-1(-/-), but not IL-7(+/+) x RAG-1(-/-), mice transferred with LP CD4(+)CD44(high)CD62L(-)IL-7Ralpha(high) effector-memory T cells (T(EM)) isolated from colitic CD4(+)CD45RB(high)-transferred mice did not develop colitis. Although rapid proliferation of transferred colitogenic LP CD4(+) T(EM) cells was observed in the in IL-7(-/-) x RAG-1(-/-) mice to a similar extent of those in IL-7(+/+) x RAG-1(-/-) mice, Bcl-2 expression was significantly down-modulated in the transferred CD4(+) T cells in IL-7(-/-) x RAG-1(-/-) mice compared with those in IL-7(+/+) x RAG-1(-/-) mice. Taken together, IL-7 is essential for the development and the persistence of chronic colitis as a critical survival factor for colitogenic CD4(+) T(EM) cells, suggesting that therapeutic approaches targeting IL-7/IL-7R signaling pathway may be feasible in the treatment of inflammatory bowel diseases.
尽管白细胞介素-7（IL-7）最近已成为参与控制外周静止记忆性CD4(+) T细胞的稳态更新和存活的关键细胞因子，但其在慢性免疫疾病（如炎症性肠病）中维持致病性CD4(+) T细胞的潜力仍不清楚。在本研究中，我们证明IL-7对于通过将正常CD4(+)CD45RB(high) T细胞或致结肠炎的固有层（LP）CD4(+)记忆T细胞过继转移到免疫缺陷的IL-7(+/+) x RAG-1(-/-)和IL-7(-/-) x RAG-1(-/-)小鼠中所诱导的慢性结肠炎的发生和持续存在至关重要。尽管用CD4(+)CD45RB(high)脾细胞过继转移的IL-7(+/+) x RAG-1(-/-)受体出现了大肠黏膜的大量炎症，同时Th1细胞大量扩增，但IL-7(-/-) x RAG-1(-/-)受体却没有。此外，用从结肠炎CD4(+)CD45RB(high)过继转移小鼠中分离出的LP CD4(+)CD44(high)CD62L(-)IL-7Ralpha(high)效应记忆T细胞（T(EM)）过继转移的IL-7(-/-) x RAG-1(-/-)小鼠，而非IL-7(+/+) x RAG-1(-/-)小鼠，并未发生结肠炎。尽管在IL-7(-/-) x RAG-1(-/-)小鼠中观察到过继转移的致结肠炎LP CD4(+) T(EM)细胞的快速增殖程度与IL-7(+/+) x RAG-1(-/-)小鼠中的相似，但与IL-7(+/+) x RAG-1(-/-)小鼠相比，IL-7(-/-) x RAG-1(-/-)小鼠中过继转移的CD4(+) T细胞中Bcl-2表达明显下调。综上所述，IL-7作为致结肠炎CD4(+) T(EM)细胞的关键存活因子，对于慢性结肠炎的发生和持续存在至关重要，这表明靶向IL-7/IL-7R信号通路的治疗方法在炎症性肠病的治疗中可能是可行的。
