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

The dual specific kinase SAPK/ERK1 kinase (SEK1; mitogen-activated protein kinase kinase 4/Jun NH(2) 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/Ca(2+) 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/Ca(2+) 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/Ca(2+) ionophore, SEK1(−/−)RAG2(−/−) thymocytes proliferated and made IL-2 after PMA/Ca(2+) ionophore and CD3/CD28 stimulation, albeit at significantly lower levels compared to SEK1(+/+)RAG2(−/−) thymocytes, implying that CD28 costimulation and PMA/Ca(2+) 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.