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

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 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-/-mice to generate LT{alpha}-/-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 h, but were not found in spleen until 24 h after administration. Immunohistochemical and electron microscopic analyses detected CD4+ T cells in the intraepithelial space just 3 h after intrarectal administration. However, neither CCR7 deficiency nor the sphingosine-1-phosphate receptor agonist FTY720 impaired the egress of CD4+ T cells from LP to systemic circulation. CONCLUSION: 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