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IL-7 exacerbates chronic colitis with expansion of memory IL-7R^high CD4⁺ mucosal T cells in mice

¹Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo; Departments of ²Tropical Medicine and Parasitology and ⁴Internal Medicine, School of Medicine, Keio University, Tokyo; and ³Yakult Central Institute for Microbiological Research, Kunitachi City, Tokyo, Japan

Submitted 28 June 2004 ; accepted in final form 15 November 2004

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--deficient (TCR-^–/–), 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-^–/– mice. Conversely, the administration of anti-IL-7R monoclonal antibody significantly inhibited the development of TCR-^–/– 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.

interleukin-7; colitis; memory T cells; lamina propria lymphocytes; proliferation; high-level interleukin-7 receptor

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