A role for the src family kinase Fyn in NK cell activation and the formation of the repertoire of Ly49 receptors

Eur J Immunol. 2002 Mar;32(3):773-82. doi: 10.1002/1521-4141(200203)32:3<773::AID-IMMU773>3.0.CO;2-U.

Abstract

NK cell function is regulated by a dual receptor system, which integrates signals from triggering receptors and MHC class I-specific inhibitory receptors. We show here that the src family kinase Fyn is required for efficient, NK cell-mediated lysis of target cells, which lack both self-MHC class I molecules and ligands for NKG2D, an activating NK cell receptor. In contrast, NK cell inhibition by the MHC class I-specific receptor Ly49A was independent of Fyn, suggesting that Fyn is specifically required for NK cell activation via non-MHC receptor(s). Compared to wild type, significantly fewer Fyn-deficient NK cells expressed the inhibitory Ly49A receptor. The presence of a transgenic Ly49A receptor together with its H-2(d) ligand strongly reduced the usage of endogenous Ly49 receptors in Fyn-deficient mice. These data suggest a model in which the repertoire of inhibitory Ly49 receptors is formed under the influenced of Fyn-dependent NK cell activation as well as the respective MHC class I environment. NK cells may acquire Ly49 receptors until they generate sufficient inhibitory signals to balance their activation levels. Such a process would ensure the induction of NK cell self-tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / biosynthesis
  • Antigens, Ly / immunology
  • CHO Cells
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / immunology*
  • Cricetinae
  • Cricetulus
  • Crosses, Genetic
  • Cytotoxicity, Immunologic
  • Enzyme Inhibitors / pharmacology
  • H-2 Antigens / immunology
  • Histocompatibility Antigen H-2D
  • Killer Cells, Lymphokine-Activated / immunology
  • Killer Cells, Natural / immunology*
  • Lectins, C-Type
  • Lymphocyte Activation / physiology*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / deficiency
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / classification
  • Membrane Glycoproteins / immunology*
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Transgenic
  • NK Cell Lectin-Like Receptor Subfamily A
  • NK Cell Lectin-Like Receptor Subfamily K
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-fyn
  • Pyrimidines / pharmacology
  • Receptors, Immunologic / biosynthesis
  • Receptors, Immunologic / immunology*
  • Receptors, Immunologic / physiology
  • Receptors, NK Cell Lectin-Like
  • Receptors, Natural Killer Cell
  • Recombinant Fusion Proteins / physiology
  • Self Tolerance / physiology*
  • Tumor Cells, Cultured

Substances

  • AG 1879
  • Antigens, Ly
  • Carrier Proteins
  • Enzyme Inhibitors
  • H-2 Antigens
  • Histocompatibility Antigen H-2D
  • Klra1 protein, mouse
  • Klrk1 protein, mouse
  • Lectins, C-Type
  • Ly49G2 receptor
  • Ly49I antigen
  • Membrane Glycoproteins
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily A
  • NK Cell Lectin-Like Receptor Subfamily K
  • Proto-Oncogene Proteins
  • Pyrimidines
  • Receptors, Immunologic
  • Receptors, NK Cell Lectin-Like
  • Receptors, Natural Killer Cell
  • Recombinant Fusion Proteins
  • Fyn protein, mouse
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Proto-Oncogene Proteins c-fyn