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Natural Killer Cells in Pregnancy and Recurrent Pregnancy Loss: Endocrine and Immunologic Perspectives

Division of Endocrinology and Metabolism (C.D.), Department of Medicine; and Division of Reproductive Endocrinology and Infertility (L.C.G.), Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, California 94305

Correspondence: Address all correspondence and requests for reprints to: Linda C. Giudice, M.D., Ph.D., Department of Gynecology and Obstetrics, Stanford University Medical Center, Stanford, California 94305. E-mail: giudice{at}stanford.edu

The endocrine system and the immune system interact closely during implantation and maintenance of pregnancy. One of the most striking examples of this communication is at the level of the decidua (endometrium of pregnancy). Here, under the influence of sex steroids, there is a dramatic increase of a unique population of lymphocytes, the uterine natural killer (uNK) cells, in early pregnancy. These cells derive predominantly from a subset of peripheral blood NK cells, which under hormonal influence gets recruited to the uterus. In mice, uNK cells play an important role in the development of placental vasculature. The role of these cells in human pregnancy is still not definitively established; however, they are believed to promote placental and trophoblast growth and provide immunomodulation at the maternal-fetal interface. In contrast to their presumptive role in the maintenance of a healthy pregnancy, uNK cells and peripheral NK cells are dysregulated in unexplained recurrent pregnancy loss. Herein, we review NK cell populations, their changes in number and function in altered endocrine environments during the menstrual cycle and pregnancy, the current data on their potential role in unexplained recurrent pregnancy loss, and mechanisms for potential therapies targeted to NK cell function for this enigmatic disorder.

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