TY - JOUR

T1 - MEK kinase 1 is a negative regulator of virus-specific CD8(+) T cells

AU - Labuda, Tord

AU - Christensen, Jan Pravsgaard

AU - Rasmussen, Susanne

AU - Bonnesen, Barbara

AU - Karin, Michael

AU - Thomsen, Allan Randrup

AU - Ødum, Niels

N1 - Keywords: Animals; Antigen-Presenting Cells; CD8-Positive T-Lymphocytes; Cell Line; Cell Proliferation; Chimera; Embryo Culture Techniques; Female; Gene Amplification; Immunity, Innate; Liver; MAP Kinase Kinase Kinase 1; Mice; Mice, Inbred C57BL; Mice, Transgenic; Rhabdoviridae Infections; Vesicular stomatitis Indiana virus

PY - 2006

Y1 - 2006

N2 - 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 (Mekk1(DeltaKD)) exclusively in their hematopoietic system, we show that MEKK1 has a negative regulatory role in the generation of a virus-specific immune response. Mekk1(DeltaKD) 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(DeltaKD) mice following VSV infection is virus-specific and the frequency of virus-specific T cells is significantly higher (more than threefold) in Mekk1(DeltaKD) as compared to WT animals. Moreover, the hyper-expansion of T cells seen in Mekk1(DeltaKD) mice after VSV infection is a result of increased proliferation, since a significantly higher percentage of virus-specific Mekk1(DeltaKD) CD8(+) T cells incorporated BrdU as compared to virus-specific WT CD8(+) T cells. In contrast, similar levels of apoptosis were detected in Mekk1(DeltaKD) 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.

AB - 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 (Mekk1(DeltaKD)) exclusively in their hematopoietic system, we show that MEKK1 has a negative regulatory role in the generation of a virus-specific immune response. Mekk1(DeltaKD) 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(DeltaKD) mice following VSV infection is virus-specific and the frequency of virus-specific T cells is significantly higher (more than threefold) in Mekk1(DeltaKD) as compared to WT animals. Moreover, the hyper-expansion of T cells seen in Mekk1(DeltaKD) mice after VSV infection is a result of increased proliferation, since a significantly higher percentage of virus-specific Mekk1(DeltaKD) CD8(+) T cells incorporated BrdU as compared to virus-specific WT CD8(+) T cells. In contrast, similar levels of apoptosis were detected in Mekk1(DeltaKD) 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.

U2 - 10.1002/eji.200535163

DO - 10.1002/eji.200535163

M3 - Journal article

C2 - 16761309

VL - 36

SP - 2076

EP - 2084

JO - European Journal of Immunology

JF - European Journal of Immunology

SN - 0014-2980

IS - 8

ER -