Homeostatic proliferation of intestinal intraepithelial lymphocytes precedes their migration to extra-intestinal sites

Cells with the phenotype of intraepithelial lymphocytes (IEL) are present systemically and have been implicated in immune regulation. To determine whether IEL undergo homeostatic proliferation and migrate from the small intestine, we analysed the fate of congenic IEL transferred into lymphopenic mice. Donor IEL homed to the small intestinal epithelium, where they expanded in an IL-15-dependent manner and expressed CD69, CD44 and CD103; proliferation did not occur in the spleen, the main other site of IEL detection early after transfer. By 12 days after transfer, a small proportion of intestinal IEL had up-regulated the trafficking molecule CD62L. Four weeks after transfer, donor IEL with a CD69-CD44hiCD103- phenotype similar to memory T cells were present in spleen and other extra-intestinal sites. Treatment of mice with blocking antibody to CD62L reduced appearance of cells in mesenteric lymph nodes; treatment with FTY720, a sphingosine 1-phosphate receptor agonist that blocks egress of T cells from lymph nodes, reduced appearance of cells in spleen. The distribution of TCR alphabeta and gammadelta IEL varied between organs, alphabeta IEL being predominant. IEL proliferation and emigration under lymphopenic conditions suggests similar IEL turnover, albeit at a lower level, under physiological conditions.