NK cells in the female reproductive tract; biology and protection against HIV-1

Natural killer (NK) cells are innate immune cells which have been shown to kill tumors and cells infected with viruses. This knowledge however is based on studies carried out with natural killer cells isolated from blood. The female reproductive tract (FRT) mucosa is a unique site because it allows the growth of the fetus and at the same time is the major entry site of human immunodeficiency virus-1 (HIV-1) in the majority of women worldwide. The biology of natural killer cells in the FRT and their role in protection against HIV infection is unknown.;To examine the presence, phenotype and function of human NK cells throughout the female reproductive tract we used Fallopian tube, endometrium, cervix and ectocervix tissues obtained from women undergoing hysterectomy at Dartmouth Hitchcock Medical Center. These studies show that NK cells are present throughout the FRT and the phenotype of FRT NK cells is unique and distinct from blood NK cells. The upper FRT NK cells have a regulatory phenotype and respond to the menstrual cycle changes, where as the lower FRT NK cells have a cytolytic phenotype and do not vary with menstrual cycle changes.;We used uterine NK (uNK) cell clones to determine the ability of FRT NK cell secretions to inhibit HIV-1 infection. Our studies demonstrated that uNK cell secretions inhibited HIV-1 infection. Specifically, the uNK cell secretions inhibited HIV-1IIIB, HIV-1 NL4.3 and HIV-1 HCN, which are X4-tropic viruses, but did not inhibit infection with HIV-1BaL (R5-tropic) virus. The anti-HIV activity of uNK cell secretions was associated with production of CXCL12, but not IFN-gamma. Stimulation of uNK cells with IL-12 and IL-15 increased anti-HIV activity, indicating that the anti-HIV potential of FRT NK cells can be modulated by cytokines.;Our studies show that FRT NK cells are unique from blood and other mucosal NK cells, and that they can inhibit HIV-1 infection by X4-tropic viruses through the secretion of CXCL12. Thus NK cells present in the FRT can potentially play a role in preventing HIV-1 transmission and these cells may be targeted in the design of novel anti-HIV-1 microbicides.