72 The situation may differ at the maternal–fetal interface, however, because of the unique selleck inhibitor patterning
of MHC molecules in placental cells. Syncytiotrophoblast, which abundantly expresses B7-H1, represses virtually all MHC expression, effectively ruling out the possibility that in cis signaling to the T cell with MHC would occur from these cells. Our data suggest that these cells can in fact suppress TCR-mediated events on T cells in trans.71 Other trophoblast cells express B7-H1, including extravillous trophoblast cells, that express a restricted array of MHC. Although most investigators do not consider these cells to function as APCs, which possibility has not been formally ruled out. B7-H1 and HLA-G, for example, are co-expressed Alisertib on the surface of invading cytotrophoblast cells and those found in the chorion membrane (Fig. 2). Another possibility is that reverse-signaling through B7-H1 can occur, transmitting a signal not to the lymphocyte, but to the syncytiotrophoblast and/or cytotrophoblast itself. In the mouse, it is not entirely clear as yet whether the trophoblast, decidua, or both express B7-H1.40,48 Nonetheless, given its suppressive role in controlling self-reactive T cells and autoimmunity, we and others
tested whether maternal B7-H1 or PD-1 is mandatory for successful allogeneic pregnancy. Guleria and colleagues reported that systemic blockade of B7-H1 but not B7-DC disrupted allogeneic, but not syngeneic, pregnancy in mice.40 Fetal resorption was also observed in allogeneic pregnancies using CHIR-99021 mw B7-H1-deficient
mice. This group also found that B7-H1 may influence the local cytokine milieu at the maternal–fetal interface, as IFN-γ and IL-17 were increased, whereas IL-4 and IL-5 were reduced in the placenta of B7-H1-deficient mice.73 These authors additionally provide evidence to propose that the requirement for B7-H1 in allogeneic pregnancy lies in its utilization by maternal TRegs to control maternal anti-fetal T cells.73 On the other hand, we have shown in several models of pregnancy that genetic deletion or blockade of PD-1 has no obvious detrimental effect on pregnancy (Fig. 3).74 Similarly, in our hands, dams lacking B7-H1 carry allogeneic pups to term unimpeded.74 We carried these studies a step further to discern whether PD-1 on maternal T cells play any role in the maternal response to fetal antigen. Adopting a model of a defined fetal alloantigen, ovalbumin, combined with maternal anti-ovalbumin T cells, we showed that PD-1 prevents over-accumulation of fetal antigen-specific T cells in maternal lymphoid organs, possibly via a mechanism involving apoptosis.