Gimme shelter: the immune system during pregnancy

Abstract

Antigen-presenting molecules vary between individuals of the same species, making it more difficult for pathogens to evade immune recognition and spread through the whole population. As a result of this genetic diversity, transplants between individuals are recognized as foreign and are rejected. This alloreactivity turns placental viviparity into a major immunological challenge. The maternal immune system has to balance the opposing needs of maintaining robust immune reactivity to protect both mother and fetus from invading pathogens, while at the same time tolerating highly immunogenic paternal alloantigens in order to sustain fetal integrity. Regulatory T cells are responsible for the establishment of tolerance by modulating the immune response, and uterine natural killer cells direct placentation by controlling trophoblast invasion. A variety of other cell types, including decidual stromal cells, dendritic cells, and immunomodulatory multipotent mesenchymal stromal cells, are found at the fetal-maternal interface. These cells conspire to establish a suitable environment for fetal development without compromising systemic immunity. Defects in any of these components can lead to gestational failure despite successful fertilization.

Semen Promotes the Differentiation of Tolerogenic Dendritic Cells

“…Increased numbers of Treg are found in pregnant mice and humans (47). Depletion of Treg induces resorption of the embryos in allogeneic matings in mice (46,48), whereas women with repeated spontaneous abortion show a decreased numbers of Treg (49,50). Tregs are identified as CD4 + CD25 + T cells expressing the signature transcription factor FOXP3 (51).…”

Variability in human semen content and its potential effects in the female reproductive tract

“…Additional studies suggest that semen may further bias a type 2 response by inducing the production of type 2 cytokines from local and intraepithelial T cells and dendritic cells (DCs), possibly through semen-associated prostaglandins [15,16]. These studies highlight the active role of semen in inducing the immune changes that prevent the semi-allograft fetus from being recognized as a foreign antigen and protect it from clearance [11].…”

“…Initially, semen is recognized by the local female innate immune system as a foreign entity due to the presence of paternalantigens and MHC class I and II on spermatozoa [10]. As a result, an inflammatory reaction is incited, characterized by a massive infiltration of neutrophils that are likely recruited by the high concentrations of IL-8 ( Table 1 and Supplementary Table S4) and GM-CSF ( Table 1 and Supplementary Table S5) found in seminal fluid [11]. The initial phase of inflammation is important to clear excess and abnormal sperm as well as various waste products found within semen [11,12].…”

“…As a result, an inflammatory reaction is incited, characterized by a massive infiltration of neutrophils that are likely recruited by the high concentrations of IL-8 ( Table 1 and Supplementary Table S4) and GM-CSF ( Table 1 and Supplementary Table S5) found in seminal fluid [11]. The initial phase of inflammation is important to clear excess and abnormal sperm as well as various waste products found within semen [11,12]. It is vital, however, that the inflammatory phase be quickly resolved, as uncontrolled inflammation could lead to the clearance of the healthy sperm cells by neutrophils and result in a reduced capacity for fertilization.…”

“…In order to suppress the female immune system and allow the paternal antigens to go unrecognized, a state of tolerance must be induced, likely mediated by the pleiotropic cytokine TGF-β. Both pro-TGF-β and active TGF-βare secreted into semen by the seminal vesicles and prostate, and arepresent at very high concentrations within the seminal fluid ( Table 1 and Supplementary Table S3) [11,13].…”