Marilen Benner

THREE TYPES OF TREG CONTROL PLACENTAL INFLAMMATION 53 3 INTRODUCTION During pregnancy, CD4 + CD25 HI FOXP3 + regulatory T cells (Tregs) are found at high levels in decidual tissue and have the ability to suppress fetus-specific and non-specific responses (1, 2). Most interestingly, HLA-Cmismatched pregnancies (where the fetus and extravillous trophoblasts (EVTs) express an HLA-C allotype that themother does not have) had increased levels of functional CD4 + CD25 HI Tregs in decidua, compared to HLA-C matched pregnancies (3). Furthermore, in vitro co-culture of naive CD4 + T cells with EVTs directly increased the proportion of CD4 + FOXP3 + Tregs, compared to CD4 + T cells cultured alone (4-6). This suggests that maternal T cells may specifically recognize fetal HLA-C, but its expression on EVTs promotes immune tolerance. The importance of maternal immune tolerance for fetal HLA-C is further illustrated by a recent study suggesting that HLA-C antibodies may contribute to the etiology of miscar riage (7). The proportion of circulating FOXP3 + Tregs was shown to be diminished in maternal blood obtained after spontaneous preterm birth (SPTB) (8-10)preeclampsia (PE)(11, 12) and in decidual tissue obtained after recurrent spontaneous miscarriage (13, 14). Furthermore, clonally expanded CD4 + CD25 HI CD127 – CD45RA – Treg populations were observed in healthy term pregnancy decidua, and failure of this clonal expansion may be related to development of preeclampsia (15). The importance of Tregs was also demonstrated in murine pregnancy models (16-19). Depletion of CD25 + Tregs during allogeneic matings, but not syngeneic matings, resulted in an increased resorption rate (16). Besides highlighting the role for Tregs, this also demonstrated that in the absence of Tregs, effector cells cause immunologic rejection of allogeneic fetal or placental tissues. A more recent murine study demonstrated that FOXP3 + Tregs with specificity to paternal antigens were generated extrathymically and accumulated in the placenta. In this study, females with impaired ability for extrathymic Treg induction showed increased fetal resorption rates and had increased influx of immune cells to the placenta in allogeneic matings, but not syngeneic matings (20).Other pathways and molecules have been demonstrated to play a role in Treg induction during pregnancy, including the blockade of the PD1-PDL1 pathway that led to reduced decidual CD25 + FOXP3 + Treg numbers and increased embryo resorption in mice, which could be abrogated by adoptive CD25 + FOXP3 + Treg transfer (21). This demonstrates the importance of PD1-PDL1 for decidual Treg induction. However, specific factors that contribute to diminished decidual Treg numbers or function during pregnancy complications have not been identified in human pregnancy. Thus far, research on the role of Tregs in human pregnancy has mainly focused on FOXP3 + Tregs (2, 8-10, 13-15, 22-24), while other types of FOXP3 – Tregs have not been studied in as much detail. Most importantly, only a handful of studies provide functional analysis of peripheral blood (11, 12) and decidual Tregs (2, 3)during human pregnancy. FOXP3, in combination with high expression of CD25 and HELIOS and the absence of CD127 expression, primarily identifies natural Tregs (nTregs), although whether HELIOS is a defining marker for human nTregs remains