Mast cells as novel regulators of tolerance at the fetal-maternal interface: their role in pregnancy success as "Treg-helpers" and study of their therapeutic potential in spontaneous abortions
Mast cells (MCs) are largely known as primary responders in allergic reactions and important cells of the innate immune system. However, recent studies reveal that MCs in fact also play a critical role in the Treg-dependent allograft tolerance by secreting interleukin-9 (IL)-9. In the light of this breaking role for MCs we embarked on a series of studies aiming to analyze whether MCs may be implicated in tolerance towards the semiallogenic fetus growing within the maternal uterus. We confirmed the presence of MCs at the fetal-maternal interface preferentially in maternal decidua. Their peak is observed around implantation. Fetal rescue by means of antigen-specific Treg was associated with an augmented number of MCs as well as with enhanced expression of MC-related molecules (Tph-1, Mcpt-1 and Mcpt-5) at the fetal-maternal interface and in other organs. Treg treatment was further associated with an increase in the levels of well-known MC growth factors mSCF and IL-3, while IL-9 remained unaltered. Anti-IL-10 treatment abrogated the protective effect of Treg and down-regulated the levels of Mcpt-1, highlighting a possible function of IL-10 as MC regulator at the fetal-maternal interface. The strongest data in support of a role for MCs during pregnancy were provided by our experiments with MC-deficient KitW-sh/W-sh mice. Adult pregnant KitW-sh/W-sh females showed severely impaired implantation and pregnancy outcome as compared to their wild type counterparts. Reconstitution with BMMCs prior to pregnancy totally rescued the phenotype. Our results indicate that as already observed in transplantation, MCs and their associated molecules might contribute to Treginduced tolerance at the fetal-maternal interface. Here, we aim to unravel the novel role of MCs as cells promoting tolerance towards the semiallogenic fetus and to elucidate whether this is achieved as the result of interplay between MCs and Treg. The main aims of the present project are 1) to study the participation of MCs in reproductive processes such as ovulation, receptivity, implantation, trophoblast growth, placentation and pregnancy maintenance, 2) to investigate the mechanisms as to why MC determine pregnancy success, especially focussing in the interactions of MC with Treg during pregnancy using intravital microscopy as well as with in vitro methods and 3) to identify MCs and their metabolites as potential candidates for therapeutic approaches in a murine model of abortion, which may later help women suffering from spontaneous abortions, a still unsolved problem with social and economical consequences. We do believe that our study will contribute to the knowledge of the basic mechanisms regulating immune tolerance during pregnancy and to bring to light a further role for MCs as disease modulators.