DIRECT EVIDENCE TO SUPPORT THE ROLE OF HLA-G IN PROTECTING THE FETUS FROM MATERNAL UTERINE NATURAL-KILLER CYTOLYSIS

HLA-G is a nonclassical major histocompatibility complex class I molec ule selectively expressed on cytotrophoblasts at the fete-maternal int erface, where it may play an important role in maternal tolerance of t he fetus. We pro,ide direct evidence under physiological conditions th at supports the role of HLA-G in protecting cytotrophoblasts against n atural killer (NK) cytolysis in 6 semiallogenic combinations of matern al uterine NK cells and their own trophoblast counterparts, as well as in 20 allogenic combinations of maternal uterine NK cells and trophob lasts from different mothers. We show that, in all cases studied, this HLA-G-mediated protection was abolished by treatment of cytotrophobla sts with an HLA-G-specific mAb. The HLA class I-negative K562 cell lin e transfected with the predominant HLA-G1 isoform results in similar p rotection and abolition from maternal uterine NK lysis. Because matern al uterine NK cells express killer inhibitory receptors for HLA-G, we conclude that their interactions contribute to the survival of the fet al semiallograft by confering immunological tolerance to its tissues.