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Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases

Nature Immunology volume 7, pages 747–754 (2006)Cite this article

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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Figure 1: Phenotypic and functional characterization of NK clones.
Figure 2: Expression of Tyro3 receptors on NK cells and Tyro3 ligands on bone marrow stromal cells.
Figure 3: Impaired function of NK cells lacking Tyro3 receptors.
Figure 4: Tyro3 receptors in late differentiation of bone marrow and splenic NK cells.
Figure 5: Impaired maturation of NK cells lacking all three Tyro3 receptors.
Figure 6: Cell-autonomous defect of NK cells lacking Tyro3 receptors.
Figure 7: Interaction of Tyro3 receptors with their ligands induces NK cell differentiation in vitro.

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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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Author notes

  1. Anouk Caraux and Qingxian Lu: These authors contributed equally to this work.

Authors and Affiliations

  1. Département d'Immunologie, Laboratoire Cytokines et développement Lymphoïde, Institut Pasteur, Paris, 75724, Cedex 15, France

    Anouk Caraux & James P Di Santo

  2. Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, 92037, California, USA

    Qingxian Lu & Greg Lemke

  3. Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, 94720-3200, California, USA

    Nadine Fernandez & David H Raulet

  4. Département d'Immunologie, Laboratoire Immunité Cellulaire Antivirale, Institut Pasteur, Paris, 75724, Cedex 15, France

    Sylvain Riou & Claude Roth

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  1. Anouk Caraux
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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.

Corresponding author

Correspondence to Claude Roth.

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The authors declare no competing financial interests.

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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