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IL-7 Is Essential for the Development and the Persistence of Chronic Colitis¹

Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

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^highCD62L^–IL-7R^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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported in part by grants-in-aid for Scientific Research, Scientific Research on Priority Areas, Exploratory Research, and Creative Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology; the Japanese Ministry of Health, Labor and Welfare; the Japan Medical Association; Foundation for Advancement of International Science; Terumo Life Science Foundation; Ohyama Health Foundation; Yakult Bio-Science Foundation; and Research Fond of Mitsukoshi Health and Welfare Foundation.

² Address correspondence and reprint requests to Dr. Takanori Kanai, Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan. E-mail address: taka.gast{at}tmd.ac.jp

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; HPF, high power field; IEL, intraepithelial cell; LP, lamina propria; T_EM, effector-memory T.

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