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

Abstract

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 (Mekkl ΔKD) exclusively in their hematopoietic system, we show that MEKK1 has a negative regulatory role in the generation of a virus-specific immune response. Mekk1 ΔKD 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 Mekk1 ΔKD mice following VSV infection is virus-specific and the frequency of virus-specific T cells is significantly higher (more than threefold) in Mekk1 ΔKD as compared to WT animals. Moreover, the hyper-expansion of T cells seen in Mekk1 ΔKD mice after VSV infection is a result of increased proliferation, since a significantly higher percentage of virus-specific Mekk1 ΔKD CD8+ T cells incorporated BrdU as compared to virus-specific WT CD8+ T cells. In contrast, similar levels of apoptosis were detected in Mekk1 ΔKD and WT T cells following VSV infection. These results strongly suggest that MEKK1 lays a negative regulatory role in the expansion of virus-specific CD8+ T cells in vivo. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.