Luminal CD4+ T Cells Penetrate Gut Epithelial Monolayers and Egress From Lamina Propria to Blood Circulation
Luminal CD4+ T Cells Penetrate Gut Epithelial Monolayers and Egress From Lamina Propria to Blood Circulation
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DOI：
10.1053/j.gastro.2011.08.035
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发表时间：
2011-12-01
期刊：
影响因子：
29.4
通讯作者：
Watanabe, Mamoru
中科院分区：
文献类型：
--
作者：
Nemoto, Yasuhiro;Kanai, Takanori;Watanabe, Mamoru
背景与目的：记忆T细胞从肺、皮肤等外周组织进入引流淋巴结需要CC趋化因子受体7(CCR7)的表达。在肠道中，肠道固有层(LP)中的常驻记忆T细胞不表达CCR7，这表明它们是与组织结合的，不会离开肠道。方法：建立C57BL/6小鼠淋巴细胞直肠注射细胞移植系统。将淋巴毒素α缺陷小鼠与RAG-2(-/-)(重组激活基因-2)小鼠杂交，产生淋巴毒素α缺陷xRAG-2(-/-)小鼠。结果：重度联合免疫缺陷(SCID)或RAG-2(-/-)小鼠经直肠注射正常小鼠脾中的CD4(+)T细胞后出现结肠炎，细胞不仅在LP中增殖，而且在脾中也有增殖。给SCID或RAG-2(-/-)小鼠直肠注射表达绿色荧光蛋白(GFP(+))的CD4(+)T细胞(GFP(+)CD4(+)T细胞)，这些细胞在6小时内定位于LP，但直到给药后24小时才在脾中发现。免疫组织化学和电子显微镜分析在直肠给药后仅3小时在上皮内间隙检测到CD4(+)T细胞。然而，CCR7缺乏和鞘氨醇-1-磷酸受体激动剂Fingolimod都不会损害CD4(+)T细胞从LP到体循环的输出。结论：CD_4~(+)T细胞不仅能从肠腔进入肠壁，而且能主动地从肠腔进入循环系统。我们开发了一种直肠给药系统，可以用来进一步研究肠道粘膜中的细胞运输，并开发基于灌肠的肠道疾病治疗方法。
BACKGROUND & AIMS: The egress of memory T cells from peripheral tissues, such as lung and skin, into the draining lymph nodes requires their expression of CC chemokine receptor 7 (CCR7). In the intestine, resident memory T cells in the intestinal lamina propria (LP) do not express CCR7, indicating that they are tissue bound and do not exit the intestine. METHODS: We developed a cell transfer system, using rectal administration of lymphocytes to C57BL/6 mice. Lymphotoxin alpha-deficient mice were crossed with RAG-2(-/-) (recombination-activating gene-2) mice to generate lymphotoxin alpha-deficient x RAG-2(-/-) mice. RESULTS: Severe combined immunodeficient (SCID) or RAG-2(-/-) mice given rectal administration of splenic CD4(+) T cells from normal mice developed colitis; the cells proliferated not only in the LP but also in spleen. SCID or RAG-2(-/-) mice given rectal administrations of CD4(+) T cells that expressed green fluorescent protein (GFP(+)CD4(+) T cells) localized to the LP within 6 hours but were not found in the spleen until 24 hours after administration. Immunohistochemical and electron microscopic analyses detected CD4(+) T cells in the intraepithelial space just 3 hours after intrarectal administration. However, neither CCR7 deficiency nor the sphingosine-1-phosphate receptor agonist Fingolimod impaired the egress of CD4(+) T cells from LP to systemic circulation. CONCLUSIONS: CD4(+) T cells not only penetrate from the luminal side of the intestine to the LP but also actively egress from the LP into the circulation. We developed a rectal administration system that might be used to further investigate cell trafficking in intestinal mucosa and to develop enema-based therapeutics for intestinal diseases.