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.
Immunol Lett. 2013 Nov-Dec;156(1-2):82-93. doi: 10.1016/j.imlet.2013.09.001. Epub 2013 Sep 23.
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.
致炎 CD4(+)T 细胞记忆细胞在炎症性肠病（IBD）发病机制中起重要作用。尽管最近在人和小鼠中均鉴定出具有高存活和自我更新能力的记忆干细胞，但在慢性结肠炎小鼠中是否存在类似的亚群尚不清楚。我们试图鉴定和纯化致炎记忆 CD4(+)T 细胞的长寿亚群，这可能是治疗 IBD 的靶点。我们使用长期培养系统纯化了致炎记忆 CD4(+)T 细胞的长寿亚群。评估了这些细胞的特征。白细胞介素（IL）-7 促进先前注射过 CD4(+)CD45RB(high)T 细胞的结肠炎 SCID 小鼠的固有层（LP）CD4(+)T 细胞在体外存活超过 8 周。这些细胞处于静止状态，在 4 周内最多分裂 5 次。LP CD4(+)T 细胞在培养后表达更高水平的 Bcl-2、整合素-α4β7、CXCR3 和 CD25，并且在响应肠道细菌抗原时分泌高浓度的 IL-2 和低浓度的 IFN-γ和 IL-17。用 IL-7 培养 8 周的结肠炎小鼠 LP CD4(+)T 细胞比培养 4 周的 LP CD4(+)T 细胞诱导更严重的结肠炎。我们开发了一种新的培养系统，从活化的 LP CD4(+)T 细胞中纯化出一种长寿、高致病性的记忆亚群。IL-7 促进了该亚群在静止状态下的长期体外存活。该亚群将成为治疗 IBD 的一种新的、有效的靶点。
