title: Continuous engagement of a self-specific activation receptor induces NK cell tolerance.
abstract: Natural killer (NK) cell tolerance mechanisms are incompletely understood. One possibility is that they possess self-specific activation receptors that result in hyporesponsiveness unless modulated by self-major histocompatability complex (MHC)-specific inhibitory receptors. As putative self-specific activation receptors have not been well characterized, we studied a transgenic C57BL/6 mouse that ubiquitously expresses m157 (m157-Tg), which is the murine cytomegalovirus (MCMV)-encoded ligand for the Ly49H NK cell activation receptor. The transgenic mice were more susceptible to MCMV infection and were unable to reject m157-Tg bone marrow, suggesting defects in Ly49H(+) NK cells. There was a reversible hyporesponsiveness of Ly49H(+) NK cells that extended to Ly49H-independent stimuli. Continuous Ly49H-m157 interaction was necessary for the functional defects. Interestingly, functional defects occurred when mature wild-type NK cells were adoptively transferred to m157-Tg mice, suggesting that mature NK cells may acquire hyporesponsiveness. Importantly, NK cell tolerance caused by Ly49H-m157 interaction was similar in NK cells regardless of expression of Ly49C, an inhibitory receptor specific for a self-MHC allele in C57BL/6 mice. Thus, engagement of self-specific activation receptors in vivo induces an NK cell tolerance effect that is not affected by self-MHC-specific inhibitory receptors.
authors.affiliation: Gastroenterology Division, Department of Medicine, Washington University School of Medicine and Howard Hughes Medical Institute, St. Louis, MO 63110, USA.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Tripathy
authors.forename: Peter A
authors.initials: PA
authors.lastname: Keyel
authors.forename: Liping
authors.initials: L
authors.lastname: Yang
authors.forename: Jeanette T
authors.initials: JT
authors.lastname: Pingel
authors.forename: Tammy P
authors.initials: TP
authors.lastname: Cheng
authors.forename: Achim
authors.initials: A
authors.lastname: Schneeberger
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D016026:Bone Marrow Transplantation / Q000276:immunology; D002454:Cell Differentiation; D006566:Herpesviridae Infections / Q000276:immunology; D007108:Immune Tolerance; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology / Q000821:virology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000821:virology; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011971:Receptors, Immunologic / Q000378:metabolism*; D055630:Receptors, NK Cell Lectin-Like; D014181:Transplantation Immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D000950:Antigens, Ly; C527091:Klra3 protein, mouse; C527096:Klra8 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D014764:Viral Proteins