IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4+ T cells in chronic colitis mice.
Colitogenic memory CD4(+) T cells are important in the pathogenesis of inflammatory bowel disease (IBD). Although memory stem cells with high survival and self-renewal capacity were recently identified in both mice and humans, it is unclear whether a similar subset is present in chronic colitis mice. We sought to identify and purify a long-lived subset of colitogenic memory CD4(+) T cells, which may be targets for treatment of IBD. A long-lived subset of colitogenic memory CD4(+) T cells was purified using a long-term culture system. The characteristics of these cells were assessed. Interleukin (IL)-7 promoted the in vitro survival for >8 weeks of lamina propria (LP) CD4(+) T cells from colitic SCID mice previously injected with CD4(+)CD45RB(high) T cells. These cells were in a quiescent state and divided a maximum of 5 times in 4 weeks. LP CD4(+) T cells expressed higher levels of Bcl-2, integrin-α4β7, CXCR3 and CD25 after than before culture, as well as secreting high concentrations of IL-2 and low concentrations of IFN-γ and IL-17 in response to intestinal bacterial antigens. LP CD4(+) T cells from colitic mice cultured with IL-7 for 8 weeks induced more severe colitis than LP CD4(+) T cells cultured for 4 weeks. We developed a novel culture system to purify a long-lived, highly pathogenic memory subset from activated LP CD4(+) T cells. IL-7 promoted long-term in vitro survival of this subset in a quiescent state. This subset will be a novel, effective target for the treatment of IBD.
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558, Japan.
Masahiro
M
Takahara
Yasuhiro
Y
Nemoto
Shigeru
S
Oshima
Yu
Y
Matsuzawa
Takanori
T
Kanai
Ryuichi
R
Okamoto
Kiichiro
K
Tsuchiya
Tetsuya
T
Nakamura
Kazuhide
K
Yamamoto
Mamoru
M
Watanabe
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007156:Immunologic Memory / Q000276:immunology; D039441:Integrin alpha4 / Q000276:immunology / Q000378:metabolism; D039641:Integrin beta Chains / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017493:Leukocyte Common Antigens; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
C515188:Cxcr3 protein, mouse; D016207:Cytokines; D039641:Integrin beta Chains; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D054367:Receptors, CXCR3; C091368:integrin beta7; D039441:Integrin alpha4; D017493:Leukocyte Common Antigens
BM; CD4; Cell culture; IBD; IL-7; Inflammatory bowel disease; LP; MLNs; Memory T cells; SP; T(CM); T(EM); T(reg); bone marrow; central memory T (cells); effector memory T (cells); inflammatory bowel disease; lamina propria; mesenteric lymph nodes; regulatory T (cells); spleen