Contribution of macrophages to fetomaternal immunological tolerance

Abstract

The semi-allogeneic fetus develops in a uniquely immune tolerant environment within the uterus. For successful pregnancy, both the innate and adaptive immune systems must favor acceptance of the fetal allograft. Macrophages are the second most abundant immune cells after natural killer (NK) cells in the decidua. In coordination with decidual NK cells and dendritic cells, macrophages aid in implantation, vascular remodeling, placental development, immune tolerance to placental cells, and maintenance of tissue homeostasis at the maternal-fetal interface. Decidual macrophages show the classical activated (M1) and alternatively activated (M2) phenotypes under the influence of the local milieu of growth factors and cytokines, and appropriate temporal regulation of the M1/M2 switch is vital for successful pregnancy. Disturbances in the mechanisms that control the M1/M2 balance and associated functions during pregnancy can trigger a spectrum of pregnancy complications ranging from preeclampsia and fetal growth restriction to preterm delivery. This review addresses various mechanisms of tolerance, focusing on the basic biology of macrophages, their plasticity and polarization, and their protective roles at the immune-privileged maternal-fetal interface, including direct and indirect roles in promoting fetomaternal immune tolerance.

Keywords: Decidua; Immune tolerance; Macrophages; Maternal-fetal interface; Placenta; Pregnancy.

Figure 1:. Crosstalk between decidual macrophages, decidual NK, and T cells

Decidual macrophages secrete IL-15 inducing differentiation of endometrial NK cells into active decidual NK cells. dNK cells suppress maternal alloreactive immune responses through induction of Tregs. Macrophages by effect of dNK-secreted IFN-γ produce IDO which further suppress T cell activation and induces differentiation of Tregs. Decidual macrophages interact with PD-1 on T cells through B7-H1 and B7-DC (B7 family costimulatory molecules) and negatively modulate the activity of T cells.

Figure 2:. Macrophage polarization and M1/M2 macrophages during pregnancy

Macrophages polarize to M1 and M2a, M2b, M2c, and M2d phenotypes under different cytokine milieu (A). Macrophages display different phenotypes during pregnancy. M1 macrophages are dominant during peri-implantation stage. M1 and M2 both phenotypes are present during implantation and early 1^st trimester. M2 phenotypes predominate during late first trimester and maintenance of pregnancy during 2^nd trimester. M2 begin to decline and M1 again increase during 3^rd trimester and parturition (B).