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The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-κB and activate T cells

Nature Immunology volume 10, pages 158–166 (2009)Cite this article

Abstract

In addition to ligation of the T cell antigen receptor (TCR), activation of the CD28 coreceptor by the costimulatory molecule B7 is required for induction of the transcription factor NF-κB and robust T cell activation, although the contribution of CD28 to this process remains incompletely understood. We show here that phosphoinositide-dependent kinase 1 (PDK1) is essential for integrating the TCR and CD28 signals. After we deleted PDK1 from T cells, TCR-CD28 signals were unable to induce activation of NF-κB or phosphorylation of protein kinase C-θ, although T cell survival and pathways dependent on the kinases p38 and Jnk or the transcription factor NFAT were unaffected. CD28 facilitated NF-κB activation by regulating recruitment and phosphorylation of PDK1, which are necessary for efficient binding of PDK1 to protein kinase C-θ and the adaptor CARMA1 and thus for NF-κB induction.

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Figure 1: PDK1 affects the activation, but not the survival, of mature thymocytes.
Figure 2: PDK1 is not required for CD4+ T cell survival.
Figure 3: PDK1 deletion specifically affects NF-κB activation in both primary and effector CD4+ T cells.
Figure 4: PDK1 is recruited by CD28 ligation and integrates CD28 and TCR signaling to activate NF-κB through phosphorylation-dependent binding to PKC-θ.
Figure 5: Phosphorylation of a conserved residue on PDK1 is central to θCBM-mediated activation of NF-κB.
Figure 6: Phosphorylation of Thr513 on PDK1 is central to CD4+ T cell activation.

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Acknowledgements

We thank Y. Wan (Yale University) for help with the Cre transgenic mice, C. Wilson (University of Washington) for the CD4-Cre mice, T.K. Harris (University of Miami) for antibody to Thr513-phosphorylated PDK1 and D.R. Littman (New York University) for the Prkcq knockout mice. Supported by the National Institutes of Health (R01-AI59440).

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Authors and Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Sung-Gyoo Park, Jan Schulze-Luehrman, Matthew S Hayden & Sankar Ghosh

  2. Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan

    Naoko Hashimoto, Wataru Ogawa & Masato Kasuga

  3. Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Sankar Ghosh

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Contributions

S.-G.P. designed and performed experiments, analyzed and interpreted data and wrote the paper; J.S.-L. performed and assisted with experiments; M.S.H. interpreted data and wrote the paper; N.H., W.O. and M.K. generated the Pdk1 conditional knockout mice; S.G. conceived the study, interpreted data and wrote the paper.

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Correspondence to Sankar Ghosh.

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Park, SG., Schulze-Luehrman, J., Hayden, M. et al. The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-κB and activate T cells. Nat Immunol 10, 158–166 (2009). https://doi.org/10.1038/ni.1687

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