NK Cell Tolerance and the Maternal–Fetal Interface

Natural killer (NK) cells play a fundamental role in the innate immune response through their ability to secrete cytokines and kill target cells without prior sensitization. These effector functions are central to NK cell anti-viral and anti-tumor abilities. Due to their cytotoxic nature, it is vital that NK cells have the capacity to recognize normal self-tissue and thus prevent their destruction. In addition to their role in host defense, NK cells accumulate at the maternal-fetal interface and are thought to play a critical role during pregnancy. The close proximity of uterine NK (uNK) cells to fetal trophoblast cells of the placenta would seemingly lead to catastrophic consequences, as the trophoblast cells are semi-allogeneic. A fundamental enigma of pregnancy is that the fetal cells constitute an allograft but, in normal pregnancies, they are in effect not perceived as foreign and are not rejected by the maternal immune system. Although the mechanisms involved in achieving NK cell tolerance are becoming increasingly well-defined, further clarification is required, given the clinical implications of this work in the areas of infection, transplantation, cancer and pregnancy. Herein, we discuss several mechanisms of NK cell tolerance and speculate as to how they may apply to uNK cells at the maternal–fetal interface.