title: The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells.
abstract: Natural killer (NK) cells express inhibitory receptors for major histocompatibility complex (MHC) class I. If self-MHC is down-regulated or absent, lack of inhibition triggers "missing self" killing. NK cells developing in the absence of MHC class I are hypo-responsive, demonstrating that MHC class I molecules are required for NK-cell education. Here, we show that the number and the type of MHC class I alleles that are present during NK-cell education quantitatively determine the frequency of responding NK cells, the number of effector functions in individual NK cells, and the amount of interferon-gamma production in NK cells of specific Ly49 subsets. A relationship between the extent of inhibitory signals during education and functional responsiveness was corroborated by an enhanced probability of NK cells expressing more than one inhibitory receptor for a single host self-MHC class I allele to degranulate after activation. Our data suggest that the capacity of an individual NK cell to respond to stimulation is quantitatively controlled by the extent of inhibitory signals that are received from MHC class I molecules during NK-cell education.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Strategic Research Center for Studies of Integrative Recognition in the Immune System (IRIS), Karolinska Institutet, [corrected] Stockholm, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Brodin
authors.forename: Tadepally
authors.initials: T
authors.lastname: Lakshmikanth
authors.forename: Sofia
authors.initials: S
authors.lastname: Johansson
authors.forename: Klas
authors.initials: K
authors.lastname: Kärre
authors.forename: Petter
authors.initials: P
authors.lastname: Höglund
mesh_terms: D000483:Alleles; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D005805:Genes, MHC Class I; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000235:genetics / Q000378:metabolism; D054340:Receptors, KIR / Q000235:genetics / Q000502:physiology*; D055630:Receptors, NK Cell Lectin-Like / Q000235:genetics / Q000378:metabolism; D017634:Self Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology
chemical_list: D055650:NK Cell Lectin-Like Receptor Subfamily A; D054340:Receptors, KIR; D055630:Receptors, NK Cell Lectin-Like