Decidual RANKL/RANK interaction promotes the residence and polarization of TGF-β1-producing regulatory γδ T cells

Decidual gamma delta T (d gamma delta T) cells play an essential role during successful pregnancy; however, the residence and polarization of gamma delta T cells in decidua remain unclear. In this study, we observed higher levels of receptor activator for nuclear factor-kappa B ligand (RANKL) on decidual stromal cells (DSCs), and its receptor RANK on d gamma delta T cells in decidua from normal pregnancy compared with patients with recurrent spontaneous abortion (RSA). RANKL expressed by DSCs can induce the polarization of peripheral blood gamma delta T (p gamma delta T) and d gamma delta T cells to Foxp3 + gamma delta T cells, and upregulate the expression of transforming growth factor (TGF)-beta 1. This process is mediated through activation of nuclear factor kappa-light-chainenhancer of activated B cells (NF-kappa B). In addition, RANKL promotes the adhesion of d gamma delta T cells to DSCs in vitro, which is associated with the upregulation of ICAM-1 and VCAM-1 on DSCs and integrins on d gamma delta T cells. RANKL knockout leads to the decreased numbers of uterus total.d. cells, Foxp3+gamma delta T cells and the expression of TGF-beta 1, and the increased pregnancy loss in mice. These results suggest that RANKL is a pivotal regulator of maternal-fetal tolerance by triggering the polarization and residence of TGF-beta 1-producing Foxp3+gamma delta T cells in early pregnancy. The abnormal low level of RANKL/RANK results in pregnancy loss because of the dialogue disorder between DSCs and d gamma delta T cells. This observation provides a scientific basis on which a potential marker can be detected to early warning of pregnancy loss.