Granulocytic myeloid-derived suppressor cells maintain feto-maternal tolerance by inducing Foxp3 expression in CD4+CD25-T cells by activation of the TGF-ß/ß-catenin pathway.

ABSTRACT

STUDY HYPOTHESIS: The transforming growth factor (TGF)-ß/ß-catenin pathway is involved in granulocytic myeloid-derived suppressor cell (G-MDSCs)-induced Foxp3 expression in CD4(+)CD25(-)T cells, which plays an essential role in maintaining feto-maternal tolerance. STUDY FINDING: Decidual G-MDSCs play an important role in promoting Foxp3 induction in CD4(+)CD25(-)T cells, which is dependent on TGF-ß/ß-catenin pathway. WHAT IS KNOWN ALREADY MDSCs contribute to the observed increase in regulatory T cells in animal cancer models. The TGF-ß/ß-catenin pathway is required for T cell development and survival. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: MDSC levels in deciduas from patients undergoing elective termination of pregnancy or spontaneous abortion were assessed by flow-cytometric analysis. The best characterized markers of G-MDSCs cells were examined by immunocytochemistry and flow-cytometric analysis. In vivo, fetus resorption and proportion of decidual immune cells were evaluated after depletion of G-MDSCs. In vitro, we established an antigen-non-specific (CD3/CD28) CD4(+)CD25(-)T and G-MDSC co-culture system and added TGF-ß, anti-TGFß, TGF-ß plus anti-TGFß or ß-catenin inhibitor ICG001 to the system. Protein levels were measured by western blot. MAIN RESULTS AND THE ROLE OF CHANCE G-MDSCs showed a significant decrease in spontaneous abortion compared with elective abortion in women with normal pregnancy (P < 0.01), whereas the numbers of monocytic MDSCs remained unchanged. The dynamics of G-MDSCs in mice revealed that few G-MDSCs were present in non-pregnant uteri. G-MDSCs expanded rapidly in CBA/J×BALB/c mice with normal pregnancy and decreased in CBA/J×DBA/2 mice with abortion-prone pregnancy. G-MDSCs were characterized by the expression of CD115, CD117, CD135, CD62L, CCR2, MHCII, CD80, Arginase I and iNOS, and a lack of F4/80 or CD11c expression. Specifically, depletion of G-MDSCs-induced severe embryo resorption and decreased the percentage of CD4(+)CD25(+)Foxp3(+)T cells. In vitro, G-MDSCs had an important role in promoting Foxp3 induction in CD4(+)CD25(-)T cells, dependent on TGF-ß/ß-catenin pathway. LIMITATIONS, REASONS FOR CAUTION It is not sufficient to examine the role of G-MDSCs in the maintenance of maternal-fetal tolerance by depleting G-MDSCs using neutralizing antibody. Further studies are needed to establish an animal model of G-MDSCs in order to elucidate their exact role at the maternal-fetal tolerance. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide novel insights into a new function and mechanism of action for G-MDSCs in mediating feto-maternal immune tolerance. LARGE-SCALE DATA Not applicable. STUDY FUNDING AND COMPETING INTERESTS This research was supported by the National Natural Science Foundation of China (Grant No. 81270715; 91442113). The authors have nothing to disclose.