The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/9/941/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 6, September 15, 1997 941-953

Articles

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

Hiroshi Nishina*, Martin Bachmann{ddagger}, Antonio J. Oliveira-dos-Santos*, Ivona Kozieradzki*, Klaus D. Fischer§, Bernhard Odermatt, Andrew Wakeham*, Arda Shahinian*, Hiroaki Takimoto*, Alan Bernstein||, Tak W. Mak*, James R. Woodgett{ddagger}, Pamela S. Ohashi{ddagger}, and 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; {ddagger} 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

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.

Address correspondence to Josef Penninger, Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, 620 University Ave., Suite 706, M5G 2C1 Toronto, Ontario, Canada. Phone: 416-204-2241; FAX: 416-204-2278; E-mail: jpenning{at}amgen.com

James R. Woodgett is supported by a grant from the Medical Research Council of Canada. Klaus-Dieter Fischer and Alan Bernstein are supported by the Medical Research Council and National Cancer Institute of Canada.

H. Nishina and M. Bachmann contributed equally to the work.

1 Abbreviations used in this paper: ERK, extracellular signal-regulated kinase; ES, embryonic stem; GCK, germinal center kinase; ICAM-1, intercellular adhesion molecule 1; JNK, Jun NH2 terminal kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MKK4, MAPK kinase; RAG, recombination-activating gene; SAPK, stress-activated protein kinase; SEK, SAPK/ERK kinase; sIg, surface Ig; VSV, vesicular stomatitis.


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