Role of Uterine Natural Killer Cells and Interferon γ in Placental Development

Large granular lymphocytes migrate in large numbers to the pregnant uteri of a wide variety of mammalian species (1). These cells, also known as granulated metrial gland cells in rodents and endometrial granulocytes in primates, will for the purposes of this review all be referred to as uterine (u)NK cells. uNK cells are bone marrow–derived leukocytes, but their immediate precursors may migrate from the spleen. Cells expressing a similar panel of activation antigens are found in the spleens of pregnant but not nonpregnant mice, and only splenocytes derived from pregnant donors can populate the uteri of uNK-deficient recipients during pregnancy (1, 2). The signals that regulate migration of uNK to the uterus are not known. Homing precedes implantation in rodents and primates, so it is unlikely that the fetus plays a direct role. Circumstantial evidence implicates ovarian steroids and uterine decidualiza-tion, a metaplastic process that modifies the placental implantation site during pregnancy (3). Mice lacking genes for chemokines known to attract NK cells at other sites show no defects in uNK localization (1). After migration, uNK cells proliferate, differentiate, and accumulate in large numbers in specific areas of the uterus between days 2.5 and 12 of murine pregnancy (implantation occurs on day 4 and delivery on day 19). After day 12, uNK cells undergo extensive apoptosis (as defined by morphology and TdT tailing) and are dramatically decreased in number and activation through the remainder of pregnancy (4–6). uNK granules contain lytic molecules such as perforin and granzymes A and B, matrix components including os-teopontin, and vasoactive factors such as inducible nitric oxide synthase (iNOS) and endothelial (e)NOS (6–8). Factors expressed in the uterus that are either bound by or otherwise implicated in the regulation of uNK cells include IL-15 (9), decidual prolactin-related peptide B (10), and IFN-␥. uNK cells can also be activated to secrete a variety of cytokines including GM-CSF, CSF-1, leukemia inhibi-tory factor, TGF-␤ 1, TNF-␣ , and most importantly for the purposes of this discussion, IFN-␥ (8). What is the justification for assigning uterine large gran-ular lymphocytes to the NK lineage? Murine uNK cells express Thy 1.1, asialo-GM1, IL-15R ␣ , and at least two members of the CD94/NKG2 C-type lectin–like family of class I MHC receptors, NKR-P1 (NK1.1) and Ly49G2 (LGL-1), and can lyse YAC-1 target cells (5, 6). Human uNK cells express CD56 (polysialylated neural cell adhesion molecule), members of the CD94/NKG2 and killer inhibitory …