title: Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Allorecognition through the Activating Receptor during Development.
abstract: Little is known about how the prenatal interaction between NK cells and alloantigens shapes the developing NK cell repertoire toward tolerance or immunity. Specifically, the effect on NK cell education arising from developmental corecognition of alloantigens by activating and inhibitory receptors with shared specificity is uncharacterized. Using a murine prenatal transplantation model, we examined the manner in which this seemingly conflicting input affects NK cell licensing and repertoire formation in mixed hematopoietic chimeras. We found that prenatal NK cell tolerance arose from the elimination of phenotypically hostile NK cells that express an allospecific activating receptor without coexpressing any allospecific inhibitory receptors. Importantly, the checkpoint for the system appeared to occur centrally within the bone marrow during the final stage of NK cell maturation and hinged on the instructive recognition of allogeneic ligand by the activating receptor rather than through the inhibitory receptor as classically proposed. Residual nondeleted hostile NK cells expressing only the activating receptor exhibited an immature, anergic phenotype, but retained the capacity to upregulate inhibitory receptor expression in peripheral sites. However, the potential for this adaptive change to occur was lost in developmentally mature chimeras. Collectively, these findings illuminate the intrinsic process in which developmental allorecognition through the activating receptor regulates the emergence of durable NK cell tolerance and establishes a new paradigm to fundamentally guide future investigations of prenatal NK cell-allospecific education.
authors.affiliation: Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Amir M
authors.initials: AM
authors.lastname: Alhajjat
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Strong
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Lee
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Lucas E
authors.initials: LE
authors.lastname: Turner
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Ram K
authors.initials: RK
authors.lastname: Wadhwani
authors.affiliation: Experimental Therapeutics Section, National Cancer Institute, Frederick, MD 21702;
authors.forename: John R
authors.initials: JR
authors.lastname: Ortaldo
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110; and Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Heusel
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229; aimen.shaaban@cchmc.org.
authors.forename: Aimen F
authors.identifier: http://orcid.org/0000-0002-9459-107X
authors.initials: AF
authors.lastname: Shaaban
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D006706:Homeostasis; D007108:Immune Tolerance; D016130:Immunophenotyping; D007519:Isoantigens / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D023421:Models, Animal; D010641:Phenotype; D011971:Receptors, Immunologic / Q000378:metabolism*; D018183:Transplantation Chimera
chemical_list: D006183:H-2 Antigens; D007519:Isoantigens; D011971:Receptors, Immunologic