Regulatory T cells and the immune pathogenesis of prenatal infection

Abstract

Pregnancy in placental mammals offers exceptional comprehensive benefits of in utero protection, nutrition, and metabolic waste elimination for the developing fetus. However, these benefits also require durable strategies to mitigate maternal rejection of fetal tissues expressing foreign paternal antigens. Since the initial postulate of expanded maternal immune tolerance by Sir Peter Medawar 60 years ago, an amazingly elaborate assortment of molecular and cellular modifications acting both locally at the maternal-placental interface and systemically have been shown to silence potentially detrimental maternal immune responses. In turn, simultaneously maintaining host defense against the infinite array of potential pathogens during pregnancy is equally important. Fortunately, resistance against most infections is preserved seamlessly throughout gestation. On the other hand, recent studies on pathogens with unique predisposition for prenatal infections have uncovered distinctive holes in host defense associated with the reproductive process. Using these infections to probe the response during pregnancy, the immune suppressive regulatory subset of maternal CD4 T cells has been increasingly shown to dictate the inter-workings between prenatal infection susceptibility and pathogenesis of ensuing pregnancy complications. Herein, the recent literature suggesting a necessity for maternal regulatory T cells (Tregs) in pregnancy-induced immunological shifts that sustain fetal tolerance is reviewed. Additional discussion is focused on how expansion of maternal Treg suppression may become exploited by pathogens that cause prenatal infections and the perilous potential of infection-induced immune activation that may mitigate fetal tolerance and inadvertently inject hostility into the protective in utero environment.

Figure 1

Shifts in the balance between immune stimulation and suppression during pregnancy or following infection may dictate the immune pathogenesis of pregnancy complications after prenatal infection. (a) The expansion of immune suppressive maternal Tregs essential for sustaining fetal tolerance during pregnancy can also compromise host defense against pathogens that cause prenatal infection. (b) Infection or inflammation induced reductions in Treg suppression unleash the activation of immune components required for optimal protection against infection. (c) However, with maternal infection during pregnancy, reductions in Treg suppression that unleash the activation of protective immune components can also fracture fetal tolerance with ensuing immune mediated pregnancy complications.

Figure 2

Proposed model for how pregnancy complications may occur with or without direct pathogen invasion of the placental-fetal unit. Infection induced reductions in maternal Treg suppression that unleash the activation of protective immune components fracture fetal tolerance unmasking normally tolerized fetal antigen. In turn, inflammation occurs at the maternal fetal interface containing the highest concentration of exposed fetal cells. With low dosage infection (a), circulating pathogen is eradicated, but pregnancy complications ensue from damage caused by activated maternal immune effector cells. With higher dosage infection (b), the persistence of circulating pathogen and inflammation at the maternal-fetal interface provides a conduit for invasion overriding the normally protective placental barrier.