B7 family molecules as regulators of the maternal immune system in pregnancy

Abstract

Placental and fetal growth and development are associated with chronic exposure of the maternal immune system to fetally derived, paternally inherited antigens. Because maternal lymphocytes are aware of fetal antigens, active tolerance mechanisms are required to ensure unperturbed progression of pregnancy and delivery of a healthy newborn. These mechanisms of tolerance may include deletion, receptor downregulation, and anergy of fetal antigen-specific cells in lymphoid tissues, as well as regulation at the maternal-fetal interface by a variety of locally expressed immunoregulatory molecules. The B7 family of costimulatory molecules comprises one group of immunoregulatory molecules present in the decidua and placenta. B7 family members mediate both inhibitory and stimulatory effects on T-cell activation and effector functions and may play a critical role in maintaining tolerance to the fetus. Here, we review the known functions of the B7 family proteins in pregnancy.

Fig. 1

Overview of expression patterns of B7 family proteins at the human maternal–fetal interface. Expression of the B7 proteins is indicated by +; variable expression of the protein is indicated by −/+; and absence of the protein is indicated by −. cTB, cytotrophoblast; evTB, extravillous cytotrophoblast; Mφ, macrophages; sTB, syncytiotrophoblast. Reprinted from Am J Pathol 2005, 167:465–473 with permission from the American Society for Investigative Pathology.

Fig. 2

Extravillous trophoblast cells express an unusual combination of HLA and B7 proteins. Term basal plate placenta from a normal pregnancy was subjected to dual color immunofluorescence using antibodies targeting HLA-G (clone MEM-G/9; alexa-flour 488 secondary antibody) and B7-H1 (clone MIH1). Near complete colocalization was observed in three separate basal plate placentas. Trophoblast cells of the term chorion membrane as well as invading trophoblast cells from first-trimester placentas exhibited similar colocalization. Isotype-matched controls yielded negligible fluorescence.

Fig. 3

Lack of effect of PD-1 depletion on viability of mid-gestation fetuses. Wild-type (WT) or PD-1-deficient female mice (n = 13 for both), both on the CBA genetic background, were allogeneically bred to C57Bl/6 males, and killed on gestation day (gd) 13.5 (day of copulation, gd 0.5). Viable and non-viable fetuses were counted.

Fig. 4

Trophoblast-derived B7 proteins may function in pregnancy in several different capacities. (a) B7s may regulate the outcome of interaction between trophoblast cells directly with T cells and other immune cells that express their counter-receptors. The implications for this are two-fold. (1) Trophoblast cells could provide both the first signal (MHC/antigen to TCR) and the second signal (B7 ligation of counter-receptor). This scenario is presumably only possible for those trophoblast cells that possess cell surface MHC – i.e. extravillous trophoblast cells that express HLA-C, -E, -F, and/or G. (2) A second possibility exists for trophoblast that lacks surface-associated MHC: the syncytiotrophoblast and possibly the villous cytotrophoblasts. The presence of copious quantities of B7 proteins on these cells together with the deficiency of MHC suggests that B7 ligates the counter-receptor on blood-borne lymphocytes and functions on its own, without concomitant MHC signaling. (b) B7s may also regulate the outcome of interactions between decidual APC with maternal lymphocytes. In this case, both signal 1 and signal 2 could be provided by the APC. With all of these scenarios, reverse-signaling can occur, transmitting a signal not to the lymphocyte, but rather to the syncytiotrophoblast, cytotrophoblast or decidual APC itself.