IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4+ mucosal T cells in mice.
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.
Okada
Eriko
E
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Yamazaki
Motomi
M
Tanabe
Masanobu
M
Takeuchi
Tsutomu
T
Nanno
Masanobu
M
Oshima
Shigeru
S
Okamoto
Ryuichi
R
Tsuchiya
Kiichiro
K
Nakamura
Tetsuya
T
Kanai
Takanori
T
Hibi
Toshifumi
T
Watanabe
Mamoru
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D007156:Immunologic Memory; D015851:Interleukin-7 / Q000494:pharmacology / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000378:metabolism*
D004268:DNA-Binding Proteins; D015851:Interleukin-7; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D020395:Receptors, Interleukin-7; C064655:V(D)J recombination activating protein 2