Impaired CD28-mediated Interleukin 2 Production and Proliferation in Stress Kinase SAPK/ERK1 Kinase (SEK1)/Mitogen-activated Protein Kinase Kinase 4 (MKK4)-deficient T Lymphocytes

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  • Hiroshi Nishina
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Martin Bachmann
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Antonio J. Oliveira-dos-Santos
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Ivona Kozieradzki
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Klaus D. Fischer
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Bernhard Odermatt
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Andrew Wakeham
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Arda Shahinian
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Hiroaki Takimoto
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Alan Bernstein
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Tak W. Mak
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • James R. Woodgett
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Pamela S. Ohashi
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland
  • Josef M. Penninger
    From the *Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada; ‡Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; §Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany; ‖Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ¶Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland

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<jats:p>The dual specific kinase SAPK/ERK1 kinase (SEK1; mitogen-activated protein kinase kinase 4/Jun NH2 terminal kinase [ JNK] kinase) is a direct activator of stress-activated protein kinases ([SAPKs]/JNKs) in response to CD28 costimulation, CD40 signaling, or activation of the germinal center kinase. Here we show that SEK1−/− recombination-activating gene (RAG)2−/− chimeric mice have a partial block in B cell maturation. However, peripheral B cells displayed normal responses to IL-4, IgM, and CD40 cross-linking. SEK1−/− peripheral T cells showed decreased proliferation and IL-2 production after CD28 costimulation and PMA/Ca2+ ionophore activation. Although CD28 expression was absolutely crucial to generate vesicular stomatitis virus (VSV)-specific germinal centers, SEK1−/−RAG2−/− chimeras mounted a protective antiviral B cell response, exhibited normal IgG class switching, and made germinal centers in response to VSV. Interestingly, PMA/Ca2+ ionophore stimulation, which mimics TCR–CD3 and CD28-mediated signal transduction, induced SAPK/JNK activation in peripheral T cells, but not in thymocytes, from SEK1−/− mice. These results show that signaling pathways for SAPK activation are developmentally regulated in T cells. Although SEK1−/− thymocytes failed to induce SAPK/JNK in response to PMA/Ca2+ ionophore, SEK1−/−RAG2−/− thymocytes proliferated and made IL-2 after PMA/Ca2+ ionophore and CD3/CD28 stimulation, albeit at significantly lower levels compared to SEK1+/+RAG2−/− thymocytes, implying that CD28 costimulation and PMA/Ca2+ ionophore–triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation. Our data provide the first genetic evidence that SEK1 is an important effector molecule that relays CD28 signaling to IL-2 production and T cell proliferation.</jats:p>

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