The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development

Abstract

T lymphocyte activation is associated with activation of diverse AGC serine kinases (named after family members protein kinase A, protein kinase G and protein kinase C). It has been difficult to assess the function of these molecules in T cell development with simple gene-deletion strategies because different isoforms of AGC kinases are coexpressed in the thymus and have overlapping, redundant functions. To circumvent these problems, we explored the consequences of genetic manipulation of phosphoinositide-dependent kinase 1 (PDK1), a rate-limiting 'upstream' activator of AGC kinases. Here we analyzed the effect of PDK1 deletion on T lineage development. We also assessed the consequences of reducing PDK1 levels to 10% of normal. Complete PDK1 loss blocked T cell differentiation in the thymus, whereas reduced PDK1 expression allowed T cell differentiation but blocked proliferative expansion. These studies show that AGC family kinases are essential for T cell development.

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Figure 1: Analysis of LckCre+Pdpk1−/− mice.
Figure 2: Analysis of CD4CD8 DN thymocytes from LckCre+Pdpk1−/− mice.
Figure 3: S6 phosphorylation in LckCre+Pdpk1−/− thymocytes.
Figure 4: Analysis of hypomorphic Pdpk1−/fl mice.
Figure 5: Development of Pdpk1−/fl T cells in a wild-type microenvironment.

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Acknowledgements

We thank N. Bailey, J. MacDonald, P. Hagger, G. Hutchinson, C Croucher and C. Watkins for mouse care; D. Davies, A. Eddaoudi, C. Simpson, G. Warnes and R. Clarke for help with flow cytometry; U. Marklund for discussions; P. Crocker for critical comments on the manuscript; and R. Spörri for help with the bone marrow chimera experiments and for critical comments on the manuscript. Supported by Cancer Research UK and a Wellcome Trust Principal Research Fellowship (D.A.C).

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Correspondence to Doreen A Cantrell.

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Hinton, H., Alessi, D. & Cantrell, D. The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development. Nat Immunol 5, 539–545 (2004). https://doi.org/10.1038/ni1062

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