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Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell–mediated immune responses

Nature Immunology volume 8, pages 84–91 (2007)Cite this article

Abstract

HPK1 is a Ste20-related serine-threonine kinase that inducibly associates with the adaptors SLP-76 and Gads after T cell receptor (TCR) signaling. Here, HPK1 deficiency resulted in enhanced TCR-induced phosphorylation of SLP-76, phospholipase C-γ1 and the kinase Erk, more-persistent calcium flux, and increased production of cytokines and antigen-specific antibodies. Furthermore, HPK1-deficient mice were more susceptible to experimental autoimmune encephalomyelitis. Although the interaction between SLP-76 and Gads was unaffected, the inducible association of SLP-76 with 14-3-3τ (a phosphorylated serine–binding protein and negative regulator of TCR signaling) was reduced in HPK1-deficient T cells after TCR stimulation. HPK1 phosphorylated SLP-76 and induced the interaction of SLP-76 with 14-3-3τ. Our results indicate that HPK1 negatively regulates TCR signaling and T cell–mediated immune responses.

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Figure 1: Lymphoid development in Map4k1−/− mice.
Figure 2: Map4k1−/− T cells are hyperproliferative in response to TCR stimulation.
Figure 3: Enhanced in vivo T cell activation in Map4k1−/− mice.
Figure 4: Enhanced susceptibility of Map4k1−/− mice to EAE induction.
Figure 5: HPK1 is a negative regulator of TCR-induced Erk activation.
Figure 6: Enhanced proximal TCR signaling in Map4k1−/− T cells.
Figure 7: Regulation of SLP-76 signaling by HPK1.

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Acknowledgements

We thank J. Belmont for assistance with embryonic stem cell culture; F.J. DeMayo (Baylor College of Medicine Transgenic Core Facility) for embryonic stem cell microinjection; K.M. Stehling for technical assistance; and D.A. Guzman and R. Cuthbert for secretarial assistance. Mouse 129/Sv/Ev embryonic stem cells (clone AB2.2) were provided by A. Bradley (The Sanger Institute); GST–14-3-3τ plasmid was provided by W.C. Lin (University of Alabama at Birmingham); and Flag–SLP-76 plasmid was provided by G. Koretzky (University of Pennsylvania). Supported by the National Institutes of Health (R01-AI42532, R01-AI066895 and R01-CA87076 to T.-H.T; and T32-AI07495 to J.-W.S., J.S.B. and G.A.D) and the American Heart Association Texas Affiliate (0465456Y to G.Z.).

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Authors and Affiliations

  1. Department of Immunology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Jr-Wen Shui, Jonathan S Boomer, Jin Han, Jun Xu, Gregory A Dement, Guisheng Zhou & Tse-Hua Tan

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Contributions

J.-W.S. designed and did experiments and prepared the manuscript; J.S.B. designed and did experiments and edited the manuscript; J.H., J.X. and G.A.D. did experiments; G.Z. assisted in experiments; and T.-H.T. established the initial scientific questions, designed and supervised experiments and composed the manuscript.

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Correspondence to Tse-Hua Tan.

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Supplementary information

Supplementary Figure 1

Generation of Mapk41−/− mice. (PDF 173 kb)

Supplementary Figure 2

A schematic model of SLP-76 regulation by HPK1 during T cell signaling. (PDF 89 kb)

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Shui, JW., Boomer, J., Han, J. et al. Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell–mediated immune responses. Nat Immunol 8, 84–91 (2007). https://doi.org/10.1038/ni1416

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