Luminal CD4 + T cells penetrate gut epithelial monolayers and egress from lamina propria to blood circulation

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

Research output: Contribution to journalArticle

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Abstract

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 α-deficient mice were crossed with RAG-2 -/- (recombination-activating gene-2) mice to generate lymphotoxin α-deficient × 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.

Original languageEnglish
JournalGastroenterology
Volume141
Issue number6
DOIs
Publication statusPublished - 2011 Dec

Fingerprint

Blood Circulation
Mucous Membrane
Rectal Administration
T-Lymphocytes
CCR7 Receptors
Intestines
Lymphotoxin-alpha
Spleen
Lysosphingolipid Receptors
Intestinal Diseases
Enema
Colitis
Intestinal Mucosa
Green Fluorescent Proteins
Inbred C57BL Mouse
Genetic Recombination
Lymph Nodes
Lymphocytes
Electrons
Lung

Keywords

  • Chemokine
  • Localization
  • Mouse Model
  • T-Cell Migration
  • Treatment

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Luminal CD4 + T cells penetrate gut epithelial monolayers and egress from lamina propria to blood circulation. / Nemoto, Yasuhiro; Kanai, Takanori; Shinohara, Tamako; Ito, Takashi; Nakamura, Tetsuya; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Lipp, Martin; Eishi, Yoshinobu; Watanabe, Mamoru.

In: Gastroenterology, Vol. 141, No. 6, 12.2011.

Research output: Contribution to journalArticle

Nemoto, Y, Kanai, T, Shinohara, T, Ito, T, Nakamura, T, Okamoto, R, Tsuchiya, K, Lipp, M, Eishi, Y & Watanabe, M 2011, 'Luminal CD4 + T cells penetrate gut epithelial monolayers and egress from lamina propria to blood circulation', Gastroenterology, vol. 141, no. 6. https://doi.org/10.1053/j.gastro.2011.08.035
Nemoto, Yasuhiro ; Kanai, Takanori ; Shinohara, Tamako ; Ito, Takashi ; Nakamura, Tetsuya ; Okamoto, Ryuichi ; Tsuchiya, Kiichiro ; Lipp, Martin ; Eishi, Yoshinobu ; Watanabe, Mamoru. / Luminal CD4 + T cells penetrate gut epithelial monolayers and egress from lamina propria to blood circulation. In: Gastroenterology. 2011 ; Vol. 141, No. 6.
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AU - Nemoto, Yasuhiro

AU - Kanai, Takanori

AU - Shinohara, Tamako

AU - Ito, Takashi

AU - Nakamura, Tetsuya

AU - Okamoto, Ryuichi

AU - Tsuchiya, Kiichiro

AU - Lipp, Martin

AU - Eishi, Yoshinobu

AU - Watanabe, Mamoru

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AB - 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 α-deficient mice were crossed with RAG-2 -/- (recombination-activating gene-2) mice to generate lymphotoxin α-deficient × 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.

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KW - Mouse Model

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KW - Treatment

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