Abstract
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.
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Acknowledgements
We thank L. Gresh for advice in preparing the differential library; J. Hash for genotyping of knockout mice and wild-type littermates; and F. Lemonnier and A. Cumano for discussions. Supported by the Pasteur Institute, the Salk Institute, the Ligue Nationale contre le Cancer and the Lupus Research Institute.
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Contributions
A.C. did the representational difference analysis; Q.L. collaborated in the analysis of wild-type and knockout mice; N.F., S.R. and J.P.D. participated in critical revision of the paper; D.H.R. participated in study design and contributed to writing of the manuscript; G.L. maintained the allelic series of Tyro3, Axl and Mertk mouse mutants and contributed to writing of the manuscript; and C.R. designed and conceptualized the research, analyzed data and wrote the manuscript.
Note: Supplementary information is available on the Nature Immunology website.
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Supplementary information
Supplementary Fig. 1
Impaired NK repertoire in mice lacking all three Tyro 3 receptors. (PDF 125 kb)
Supplementary Table 1
Primer sequences used to detect transcripts for NK cell receptors, adaptors and effector molecules in NK clones. (PDF 76 kb)
Supplementary Table 2
Primer sequences used to detect transcripts for NK cell receptors, adaptors, effector molecules, transcription factors, Tyro 3 receptors and ligands in NK cells and BM stromal cells. (PDF 77 kb)
Supplementary Table 3
Expression of Ly49 receptors by colonies derived from wild-type or Tyro3−/−Axl−/−Mertk−/− c-Kit+ Sca2+ Lin− precursor cells at limiting dilution on OP9 stroma and 3T3 fibroblasts expressing Gas6 and Protein S. (PDF 101 kb)
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Caraux, A., Lu, Q., Fernandez, N. et al. Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases. Nat Immunol 7, 747–754 (2006). https://doi.org/10.1038/ni1353
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DOI: https://doi.org/10.1038/ni1353
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