MEK kinase 1 is a negative regulator of virus‐specific CD8+ T cells

• Published in: European journal of immunology 2006-08, Vol.36 (8), p.2076-2084
• Main Authors: Labuda, Tord, Christensen, Jan Pravsgaard, Rasmussen, Susanne, Bonnesen, Barbara, Karin, Michael, Thomsen, Allan Randrup, Ødum, Niels
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - enzymology; Antigen-Presenting Cells - immunology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - enzymology; CD8-Positive T-Lymphocytes - immunology; Cell Line; Cell Proliferation; Chimera; Embryo Culture Techniques; Female; Gene Amplification - genetics; Immunity, Innate - immunology; Knockout mice; Liver - enzymology; Liver - immunology; MAP Kinase Kinase Kinase 1 - genetics; MAP Kinase Kinase Kinase 1 - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Protein kinases; Rhabdoviridae Infections - enzymology; Rhabdoviridae Infections - immunology; Rhabdoviridae Infections - pathology; Rhabdoviridae Infections - virology; T cells; Vesicular stomatitis Indiana virus - immunology; Viral
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200535163

MEK kinase 1 (MEKK1) is a potent JNK‐activating kinase, a regulator of T helper cell differentiation, cytokine production and proliferation in vitro. Using mice deficient for MEKK1 activity (Mekk1ΔKD) exclusively in their hematopoietic system, we show that MEKK1 has a negative regulatory role in the generation of a virus‐specific immune response. Mekk1ΔKD mice challenged with vesicular stomatitis virus (VSV) showed a fourfold increase in splenic CD8+ T cell numbers. In contrast, the number of splenic T cells in infected WT mice was only marginally increased. The CD8+ T cell expansion in Mekk1ΔKD mice following VSV infection is virus‐specific and the frequency of virus‐specific T cells is significantly higher (more than threefold) in Mekk1ΔKD as compared to WT animals. Moreover, the hyper‐expansion of T cells seen in Mekk1ΔKD mice after VSV infection is a result of increased proliferation, since a significantly higher percentage of virus‐specific Mekk1ΔKD CD8+ T cells incorporated BrdU as compared to virus‐specific WT CD8+ T cells. In contrast, similar levels of apoptosis were detected in Mekk1ΔKD and WT T cells following VSV infection. These results strongly suggest that MEKK1 plays a negative regulatory role in the expansion of virus‐specific CD8+ T cells in vivo.