A role for the src family kinase Fyn in NK cell activation and the formation of the repertoire of Ly49 receptors.
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.
Lowin-Kropf
Bente
B
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
Kunz
Béatrice
B
Schneider
Pascal
P
Held
Werner
W
D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis / Q000276:immunology; D016466:CHO Cells; D002352:Carrier Proteins / Q000096:biosynthesis / Q000276:immunology*; D006224:Cricetinae; D003412:Cricetulus; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006183:H-2 Antigens / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000502:physiology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000145:classification / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn; D011743:Pyrimidines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology* / Q000502:physiology; D055630:Receptors, NK Cell Lectin-Like; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017634:Self Tolerance / Q000502:physiology*; D014407:Tumor Cells, Cultured
C412373:AG 1879; D000950:Antigens, Ly; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; C527088:Klra1 protein, mouse; C527086:Klrk1 protein, mouse; D037181:Lectins, C-Type; C452844:Ly49G2 receptor; C408248:Ly49I antigen; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins; C494960:Fyn protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn