CELL BIOLOGY SYMPOSIUM: the immune system in pregnancy.

Pregnancy has often been likened to an allograft due to the genetic differences between the mother and her baby. Upon the discovery of the major histocompatibility complex antigens in the 1950s it was reasoned that in order for the mother to tolerate the fetus, the 2 must somehow prevent or suppress an immune response that could result because of their immunogenetic differences. Initial hypotheses of how the mother could tolerate the semiallogeneic fetus included maternal immune suppression, immunological immaturity of the fetus, and physical separation of the mother and fetus. The last 60 years of research have enlightened us greatly in the mechanisms by which this paradoxical situation flourishes; to varying degrees, all of Sir Peter Medawar’s hypotheses regarding the fetal “allograft” are true. The trophectoderm-derived placental trophoblast provides the physical interface between mother and baby, and although this tissue restricts expression of major histocompatibility complex molecules, there is no shortage of paternally-inherited minor histocompatibility antigens. These minor antigens, when mismatched between organ donor and recipient, cause chronic allograft rejection in transplantation; in pregnancy, minor antigens are expressed by the trohpoblast, and are detected and robustly tolerated by the maternal immune system. We have hypothesized that paternally-inherited as well as placenta-specific antigens are detected by the maternal immune system as a result of trophoblast expression, and moreover, by virtue of shedding of copious amounts of trophoblast microvesicles and exosomes into the maternal blood. The detection of feto-placental antigens by maternal CD4+ and CD8+ T lymphocytes occurs as a muted immune response that is controlled by placental factors co-expressed with the antigens. Despite this highly controlled lymphocyte response to the fetus, maternal memory T cells develop and can persist in women for decades. Although the physiological ramifications of these persistent T cells are not understood, they may include effects on long-term health of mothers. Supported by NIH R01HD045611 and P01HD049480.