IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4+ mucosal T cells in mice.

Abstract

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.

• Authors: Eriko Okada, Motomi Yamazaki, Masanobu Tanabe, Tsutomu Takeuchi, Masanobu Nanno, Shigeru Oshima, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Takanori Kanai, Toshifumi Hibi, Mamoru Watanabe
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 288 Issue 4 Pg. G745-54 (Apr 2005) ISSN: 0193-1857 [Print] United States
• PMID: 15550560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Interleukin-7
• Rag2 protein, mouse
• Receptors, Antigen, T-Cell, alpha-beta
• Receptors, Interleukin-7
• V(D)J recombination activating protein 2

Topics

• Animals
• CD4-Positive T-Lymphocytes (metabolism, pathology)
• Chronic Disease
• Colitis (immunology, pathology)
• DNA-Binding Proteins (deficiency, genetics)
• Female
• Immunologic Memory
• Interleukin-7 (pharmacology, physiology)
• Intestinal Mucosa (metabolism, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, Antigen, T-Cell, alpha-beta (deficiency, genetics)
• Receptors, Interleukin-7 (metabolism)