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Luminal CD4+ T Cells Penetrate Gut Epithelial Monolayers and Egress From Lamina Propria to Blood Circulation

2011; Elsevier BV; Volume: 141; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2011.08.035

1528-0012

Yasuhiro Nemoto, Takanori Kanai∥, Tamako Shinohara, Takashi Ito, Tetsuya Nakamura, Ryuichi Okamoto, Kiichiro Tsuchiya, Martin Lipp, Yoshinobu Eishi, Mamoru Watanabe,

Immunotherapy and Immune Responses

Background & AimsThe 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.MethodsWe developed a cell transfer system, using rectal administration of lymphocytes to C57BL/6 mice. Lymphotoxin α-deficient mice were crossed with RAG-2−/− (recombination-activating gene-2) mice to generate lymphotoxin α-deficient × RAG-2−/− mice.ResultsSevere 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.ConclusionsCD4+ 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. 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. We developed a cell transfer system, using rectal administration of lymphocytes to C57BL/6 mice. Lymphotoxin α-deficient mice were crossed with RAG-2−/− (recombination-activating gene-2) mice to generate lymphotoxin α-deficient × RAG-2−/− mice. 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. 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.