Human NK Cells in Pregnant Uterus: Why There? Philippe Le Bouteiller 1 , Marie-Pierre Piccinni 2 1 INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; 2 Centre of Excellence for Research, Transfer and High Education DENOTHE of the University of Florence and Department of Internal Medicine – Immunoallergology unit, Florence, Italy Natural Killer (NK) cells are present in non-pregnant and pregnant uterus. 1–3 They must be there for spe- cific functions. Understanding the role of uterine NK (uNK) cells could thus be a major challenge in women reproduction. There is an ongoing discussion on this subject and the general agreement is that uNK cells phenotypically and functionally differ from their peripheral blood counterparts. 4 The major subset of NK cells in pregnant uterus is CD56 bright CD16 neg whereas in peripheral blood CD56 dim CD16 pos NK cells constitute the major subpopula- tion. 2 Recent studies have focused on the potential role of uNK cells in the control of trophoblast inva- sion and uterine vascular remodeling during preg- nancy. Moreover, as the NK cell population is the predominant decidual leukocyte population in the first trimester of a normal intrauterine pregnancy, it has been considered that uNK cells could play a major role in implantation and early placental devel- opment. The readers may refer to excellent reviews and discussions on this topic. 1,3,5,6 Here, we further highlight and discuss some important observations that may contribute to the debate. Uterine NK cell proliferation is synchronized with the cyclic surges of progesterone In humans, the cyclic appearance of NK cells in non-pregnant endometrium suggested hormonal reg- ulation. Several observations indeed indicate that their numbers parallel local progesterone levels. 1 In the pre-ovulatory, proliferative (follicular) phase of the menstrual cycle, few small and agranular NK cells are apparent in the endometrium. 2 Their num- bers increase dramatically after ovulation, under the influence of progesterone rise. In the mid-late secre- tory (luteal) phase, uNK cells very rapidly proliferate and become granulated and are found in contact with spiral vessels and endometrial glands. 7 Two days before menstruation, when progesterone levels Keywords Decidual NK cells, pregnancy, progesterone Correspondence Philippe Le Bouteiller, INSERM, U563, Ho ˆ pital Purpan, Ba ˆ timent A, BP3028, 31024 Toulouse Cedex 3, France. E-mail: philippe.le-bouteiller@toulouse.inserm.fr Submitted January 11, 2008; accepted February 11, 2008. Citation Le Bouteiller P, Piccinni M-P. Human NK cells in pregnant uterus: why there? Am J Reprod Immunol 2008; 59: 401–406 doi:10.1111/j.1600-0897.2008.00597.x Human Natural Killer (NK) cells are present in great number in preg- nant uterine mucosa. They must be there for specialized functions, but which ones? This review discusses important recent observations that further contribute to this fascinating debate. Firstly, an array of corro- borating findings indicates that uterine NK cell proliferation is synchro- nized with the cyclic surge of progesterone. Secondly, uterine NK cells are unlikely to exert a direct control on the embryo implantation. Thirdly, these NK cells influence the uterine vascular remodeling in early pregnancy but might not be the single key element that control trophoblast invasion. Finally, uterine NK cells are likely to be an impor- tant component of the local maternal immune response to pathogen infections. REVIEW ARTICLE American Journal of Reproductive Immunology 59 (2008) 401–406 ª 2008 The Authors Journal compilation ª 2008 Blackwell Munksgaard 401