title: Luminal CD4⁺ T cells penetrate gut epithelial monolayers and egress from lamina propria to blood circulation.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nemoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Tamako
authors.initials: T
authors.lastname: Shinohara
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okamoto
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001775:Blood Circulation; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D003093:Colitis, Ulcerative / Q000097:blood / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008854:Microscopy, Electron; D009092:Mucous Membrane / Q000276:immunology*; D054400:Receptors, CCR7 / Q000378:metabolism
chemical_list: D054400:Receptors, CCR7