MEK kinase 1 is a negative regulator of virus-specific CD8(+) T cells.
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.
Labuda
Tord
T
Department of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark. t.labuda@immi.ku.dk
Christensen
Jan Pravsgaard
JP
Rasmussen
Susanne
S
Bonnesen
Barbara
B
Karin
Michael
M
Thomsen
Allan Randrup
AR
Odum
Niels
N
D000818:Animals; D000938:Antigen-Presenting Cells / Q000201:enzymology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D002678:Chimera; D046149:Embryo Culture Techniques; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D007113:Immunity, Innate / Q000276:immunology; D008099:Liver / Q000201:enzymology / Q000276:immunology; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018353:Rhabdoviridae Infections / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*
D048728:MAP Kinase Kinase Kinase 1