At Embryo Implantation Site IL-35 Secreted by Trophoblast, Polarizing T Cells towards IL-35+ IL-10+ IL-4+ Th2-Type Cells, Could Favour Fetal Allograft Tolerance and Pregnancy Success

Abstract: We investigated the role of rhIL‐35, at low concentrations compatible with those produced by human trophoblast cells (less than 1 ng/mL), on human T helper (Th) cell functions and the presence of decidual IL‐35‐producing Th cells in human pregnancy. We found that human trophoblast cells produced IL‐35 but not IL‐4 or IL‐10. RhIL‐35, at concentrations produced by human trophoblasts, polarized T cells towards IL‐35+, IL‐10+, IL‐4+ Th2‐type cells and to Foxp3+ EBI3+ p35+ T reg cells producing IL‐35 but not IL‐10 and IL‐4. Moreover, rhIL‐35 at low concentrations did not suppress the proliferation of Th cells but stimulated IL‐4 and IL‐10 production by established Th clones. In particular, Th1‐type clones acquired the capacity to produce IL‐4. In addition, purified human trophoblast cell supernatants containing IL‐35 upregulated IL‐4 and IL‐10 production by Th clones. Finally, IL‐35+, IL‐10+, IL‐4+ Th2‐type cells, which were found to be induced by low concentrations of IL‐35 compatible with those produced by human trophoblasts, are exclusively present in the decidua of a successful pregnancy and at the embryo implantation site, suggesting their stringent dependence on trophoblast cells. Thus, the proximity of Th cells to IL‐35‐producing trophoblasts could be the determining factor for the differentiation of IL‐35+, IL‐10+, IL‐4+ Th2‐type cells that are crucial for human pregnancy success.