Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis

  • Nathalie Rouas-Freiss
    Service de Recherches en Hémato-Immunologie, Commissariat à l’Energie Atomique-CEA-DRM-DSV, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75475 Paris cedex 10, France; and Fondation Jean Dausset, 27, rue Juliette-Dodu, 75010 Paris cedex, France
  • Rachel Marchal-Bras Gonçalves
    Service de Recherches en Hémato-Immunologie, Commissariat à l’Energie Atomique-CEA-DRM-DSV, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75475 Paris cedex 10, France; and Fondation Jean Dausset, 27, rue Juliette-Dodu, 75010 Paris cedex, France
  • Catherine Menier
    Service de Recherches en Hémato-Immunologie, Commissariat à l’Energie Atomique-CEA-DRM-DSV, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75475 Paris cedex 10, France; and Fondation Jean Dausset, 27, rue Juliette-Dodu, 75010 Paris cedex, France
  • Jean Dausset
    Service de Recherches en Hémato-Immunologie, Commissariat à l’Energie Atomique-CEA-DRM-DSV, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75475 Paris cedex 10, France; and Fondation Jean Dausset, 27, rue Juliette-Dodu, 75010 Paris cedex, France
  • Edgardo D. Carosella
    Service de Recherches en Hémato-Immunologie, Commissariat à l’Energie Atomique-CEA-DRM-DSV, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75475 Paris cedex 10, France; and Fondation Jean Dausset, 27, rue Juliette-Dodu, 75010 Paris cedex, France

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<jats:p>HLA-G is a nonclassical major histocompatibility complex class I molecule selectively expressed on cytotrophoblasts at the feto–maternal interface, where it may play an important role in maternal tolerance of the fetus. We provide direct evidence under physiological conditions that supports the role of HLA-G in protecting cytotrophoblasts against natural killer (NK) cytolysis in 6 semiallogenic combinations of maternal uterine NK cells and their own trophoblast counterparts, as well as in 20 allogenic combinations of maternal uterine NK cells and trophoblasts from different mothers. We show that, in all cases studied, this HLA-G-mediated protection was abolished by treatment of cytotrophoblasts with an HLA-G-specific mAb. The HLA class I-negative K562 cell line transfected with the predominant HLA-G1 isoform results in similar protection and abolition from maternal uterine NK lysis. Because maternal uterine NK cells express killer inhibitory receptors for HLA-G, we conclude that their interactions contribute to the survival of the fetal semiallograft by confering immunological tolerance to its tissues.</jats:p>

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