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Long-Lived Colitogenic CD4⁺ Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis¹

Yasuhiro Nemoto,^* Takanori Kanai,^2* Kaori Kameyama,^* Tamako Shinohara,^* Naoya Sakamoto,^* Teruji Totsuka,^* Ryuichi Okamoto,^* Kiichiro Tsuchiya,^* Tetsuya Nakamura,^* Tetsuo Sudo, Satoshi Matsumoto, and Mamoru Watanabe^*

^*Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; New Frontiers Research Laboratories, Toray Industries, Kanagawa, Japan; and Yakult Central Institute for Microbiological Research, Tokyo, Japan

To understand the perpetuation of inflammatory bowel disease (IBD), it is important to clarify whether the colitogenic CD4⁺ T cells are self-limited effector or long-lived memory T cells. We here investigate the latency of colitogenic CD4⁺ T cells in the remission stage of colitis under germfree (GF) conditions. We isolated splenic (SP) CD4⁺ T cells from colitic CD4⁺CD45RB^high T cell-injected SCID mice maintained under specific pathogen-free (SPF) conditions and transferred them into SPF or GF SCID mice. Donor colitic SP CD4⁺ T cells have a characteristic CD44^highCD62L^–IL-7R^high effector-memory T-type phenotype. Six weeks after transfer of cells to GF SCID mice, one group of mice was continued in GF conditions (GFGF), and the other was transferred into SPF conditions (GFSPF). GFSPF but not GFGF SCID mice developed colitis with elevated production of Th1 and Th17 cytokines at 4 wk after transfer. Surprisingly, a large number of CD4⁺ effector-memory T cells and a small but substantial number of central-memory T cells remained resident in SP and bone marrow, but not in lamina propria, of the GFGF SCID recipients. Consistent with this, GFSPF but not GFGF SCID mice rapidly developed colitis. Taken together, these findings suggest that long-lived colitogenic memory CD4⁺ cells can be established even in the presence of commensal Ags, reside outside the intestine in the absence of commensal bacteria, and participate in the perpetuation of colitis. Thus, blocking a stimulus of colitogenic memory CD4⁺ cells such as IL-7 may have therapeutic benefit for treatment of inflammatory bowel disease.

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; the Foundation for Advancement of International Science; the Terumo Life Science Foundation; the Ohyama Health Foundation; the Yakult Bio-Science Foundation; and the Research Fund of Mitsukoshi Health and Welfare Foundation.

² Address correspondence and reprint requests to Dr. Takanori Kanai, Department of Gastroenterology and Hematology, Tokyo Medical and Dental University, 1-5-45 Yeshiva, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: taka.gast{at}tmd.ac.jp

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; BM, bone marrow; CD62L, L-selectin; LP, lamina propria; MLN, mesenteric lymph node; SP, spleen or splenic; T_EM, effector-memory T; TSLP, thymic stromal lymphopoietin; WT, wild type.