Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases.
Although understanding of the function and specificity of many natural killer (NK) cell receptors is increasing, the molecular mechanisms regulating their expression during late development of NK cells remain unclear. Here we use representational difference analysis to identify molecules required for late NK cell differentiation. Axl protein tyrosine kinase, together with the structurally related receptors Tyro3 and Mer, were essential for NK cell functional maturation and normal expression of inhibitory and activating NK cell receptors. Also, all three receptors were expressed in maturing NK cells, the ligands of these receptors were produced by bone marrow stromal cells, and recombinant versions of these ligands drove NK cell differentiation in vitro. These results collectively suggest that Axl, Tyro3 and Mer transmit signals that are essential for the generation of a functional NK cell repertoire.
Caraux
Anouk
A
Laboratoire Cytokines et Développement Lymphoïde, Département d'Immunologie, Institut Pasteur, 75724 Paris Cedex 15, France.
Lu
Qingxian
Q
Fernandez
Nadine
N
Riou
Sylvain
S
Di Santo
James P
JP
Raulet
David H
DH
Lemke
Greg
G
Roth
Claude
C
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D002478:Cells, Cultured / Q000166:cytology / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000502:physiology*; D007113:Immunity, Innate / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D010641:Phenotype; D017293:Protein S / Q000502:physiology; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017634:Self Tolerance / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D017154:Stromal Cells / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D000943:Antigens, Differentiation; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D015513:Oncogene Proteins; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C490767:Mertk protein, mouse; C513478:Tyro3 protein, mouse; C000722290:AXL receptor tyrosine kinase, mouse