CXCL12 enhances exogenous CD4+CD25+ T cell migration and prevents embryo loss in non-obese diabetic mice

Objective: To investigate the possible role of CXCL12 in the migration of regulatory T (Treg) cells. Design: Animal model-based study. Setting: Academic. Animal(s): Pregnant non-obese diabetic (NOD) mice were compared with non-immunodeficient mice. Intervention(s): In vivo and in vitro CXCL 12 induction. Main Outcome Measure(s): Flow cytometric analysis and Treg cell migratory assay. Result(s): A significantly high percentage of spontaneous embryo resorption was observed in both syngeneic and allogeneic pregnant NOD mice. The percentage of embryo loss in allogeneic pregnant NOD mice was significantly decreased by treatment with Treg cells and CXCL12 injection; however, no such effect was observed in syngeneic pregnant NOD mice. In addition, the migration of Treg cells induced by CXCL12 was confirmed by both in vitro and in vivo migratory assays. CXCR4, the specific receptor for CXCL12, was expressed more intensively on Treg cells than on non-Treg CD3(+) T cells, whereas CXCL12 was dominantly expressed in cytokeratin 7(+) trophoblast cells at an early stage of gestation, and its expression reduced gradually during pregnancy. Conclusion(s): The higher level of embryo loss in allogeneic pregnant NOD mice may be due to the lack of Treg cells. CXCL12 can cause CXCR4(+) Treg cells to migrate into the pregnant uterus and establish a beneficial micro-environment for the fetus. (Fertil Steril (R) 2009;91:2687-96. (C)2009 by American Society for Reproductive Medicine.)