Marilen Benner

GENERAL INTRODUCTION AND SCOPE OF THIS THESIS 15 1 that correct placenta formation and thus fetal development depends on the local actions of dNK cells (35). T cells Building up on Medawar’s initial question “How does the pregnant mother contrive to nourish within itself, for many weeks or months, a fetus that is an antigenically foreign body”, research on T cells in pregnancy started from a transplantation point of view. In a transplantation setting, if un- matched to the recipient, cells expressing allogeneic major histocompatibility complex (MHC) class I antigens fail to provide a self-signal (signal 1). In the presence of co-stimulatory signals (signal 2), cytolytic killing by CD8+ T cells is elicited (36). Additionally, MHC class II molecules may present the foreign antigens to CD4+ T cells, causing naïve T cells to differentiate into T helper (Th) cells. Th cells can in turn interact with B cells to initiate antibody-mediated killing, or directly promote the local immune reaction by secretion of pro-inflammatory cytokines (signal 3). Based on this key role in rejection, local T cells were initially suspected to pose a danger to the “fetal transplant” and thus it seemed logical that they need to be silenced after conception. However, during pregnancy, decidual T cells are responsive and can eradicate infections. In practice, maternal blood is merely in contact with syncytiotrophoblast and extravillous trophoblast cells (EVT), both of which have extraordinary MHC characteristics. Syncytiotrophoblast do not express any MHC rendering them inert to T cell-mediated response (37). EVT express human leucocyte antigen (HLA)-C,-E, and -G and of these, only HLA-C is highly polymorphic (HLA-A, and -B are the major polymorphic inducers of allograft rejection). Decidual T cells are indeed capable of reacting to an HLA mismatch but this does not lead to killing of trophoblast cells as shown in co-culture experiments (38, 39). On the contrary, upon encounter of an HLA-C mismatch, T cell activation was shown to induce increased abundance of regulatory T cells (Treg) (39). Additionally, rather than stimulating Th cells of pro-inflammatory cytokine profiles (Th1: IFN- γ , TNF- α , TNF- β ; Th17: IL-17, IL-22, IL-23), implantation provides signaling that allows for differentiation of Th cells that contribute to a tolerogenic environment (Th2: IL-4, IL-5, IL-10, IL- 13)(40, 41). Thus, with our improved understanding of T cell mediated immunity, the framework of inert T cells is set aside. Beyond NK- and T cell mediated immunity Still, also regarding the most studied cell types, we are still just beginning to collect the pieces of an unknown bigger picture. Many studies have pointed out that seeking to understand reproductive immunology goes beyond NK- and T cell mediated immunity. Interest in decidual myeloid cells (macrophages, dendritic cells, and granulocytes) is rising (42-47). As obtaining samples of the target site is challenging, few studies are available and research is still in its infancy.