title: Ly49-dependent NK cell licensing and effector inhibition involve the same interaction site on MHC ligands.
abstract: NK cells become functionally competent to be triggered by their activation receptors through the interaction of NK cell inhibitory receptors with their cognate self-MHC ligands, an MHC-dependent educational process termed "licensing." For example, Ly49A(+) NK cells become licensed by the interaction of the Ly49A inhibitory receptor with its MHC class I ligand, H2D(d), whereas Ly49C(+) NK cells are licensed by H2K(b). Structural studies indicate that the Ly49A inhibitory receptor may interact with two sites, termed site 1 and site 2, on its H2D(d) ligand. Site 2 encompasses the α1/α2/α3 domains of the H2D(d) H chain and β(2)-microglobulin (β2m) and is the functional binding site for Ly49A in effector inhibition. Ly49C functionally interacts with a similar site in H2K(b). However, it is currently unknown whether this same site is involved in Ly49A- or Ly49C-dependent licensing. In this study, we produced transgenic C57BL/6 mice expressing wild-type or site 2 mutant H2D(d) molecules and studied whether Ly49A(+) NK cells are licensed. We also investigated Ly49A- and Ly49C-dependent NK licensing in murine β2m-deficient mice that are transgenic for human β2m, which has species-specific amino acid substitutions in β2m. Our data from these transgenic mice indicate that site 2 on self-MHC is critical for Ly49A- and Ly49C-dependent NK cell licensing. Thus, NK cell licensing through Ly49 involves specific interactions with its MHC ligand that are similar to those involved in effector inhibition.
authors.affiliation: Rheumatology Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Taewoong
authors.initials: T
authors.lastname: Choi
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Ferris
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Jennifer
authors.initials: J
authors.lastname: Poursine-Laurent
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000235:genetics / Q000378:metabolism*; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D008024:Ligands; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055654:NK Cell Lectin-Like Receptor Subfamily C; D001613:beta 2-Microglobulin