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Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1

Author

Listed:
  • Eri Ishikawa

    (Medical Institute of Bioregulation, Kyushu University)

  • Hidetaka Kosako

    (Fujii Memorial Institute of Medical Sciences, Tokushima University)

  • Tomoharu Yasuda

    (Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences
    Present address: Max-Delbrück-Center for Molecular Medicine, Robert Rössel Street 10, 13125 Berlin, Germany)

  • Masaki Ohmuraya

    (Institute of Resource Development and Analysis, Kumamoto University)

  • Kimi Araki

    (Institute of Resource Development and Analysis, Kumamoto University)

  • Tomohiro Kurosaki

    (Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences
    Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center (iFReC), Osaka University)

  • Takashi Saito

    (Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences
    Laboratory for Cell Signaling, WPI Immunology Frontier Research Center (iFReC), Osaka University)

  • Sho Yamasaki

    (Medical Institute of Bioregulation, Kyushu University)

Abstract

Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. Here, we show that a serine/threonine kinase, protein kinase D (PKD), is crucial for thymocyte positive selection. In T cell-specific PKD-deficient (PKD2/PKD3 double-deficient) mice, the generation of CD4 single positive thymocytes is abrogated. This defect is likely caused by attenuated TCR signalling during positive selection and incomplete CD4 lineage specification in PKD-deficient thymocytes; however, TCR-proximal tyrosine phosphorylation is not affected. PKD is activated in CD4+CD8+ double positive (DP) thymocytes on stimulation with positively selecting peptides. By phosphoproteomic analysis, we identify SH2-containing protein tyrosine phosphatase-1 (SHP-1) as a direct substrate of PKD. Substitution of wild-type SHP-1 by phosphorylation-defective mutant (SHP-1S557A) impairs generation of CD4+ thymocytes. These results suggest that the PKD–SHP-1 axis positively regulates TCR signalling to promote CD4+ T cell development.

Suggested Citation

  • Eri Ishikawa & Hidetaka Kosako & Tomoharu Yasuda & Masaki Ohmuraya & Kimi Araki & Tomohiro Kurosaki & Takashi Saito & Sho Yamasaki, 2016. "Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12756
    DOI: 10.1038/ncomms12756
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