The Role of DAP-kinase in T Cell Activation
Date Issued
2008
Date
2008
Author(s)
Chuang, Ya-Ting
Abstract
Death-associated protein kinase (DAP-kinase, DAPK) is a unique multi-domain kinase acting both as a tumor suppressor and an apoptosis inducer. The molecular mechanism underlying the effector function of DAPK is not fully understood, while the role of DAPK in T lymphocyte activation is mostly unknown. DAPK was activated after TCR stimulation, followed by DAPK degradation. Through the expression of a dominant negative form and a constitutively active form of DAPK in T cell lines and in transgenic mice, we found that DAPK negatively regulated T cell activation. DAPK markedly affected T cell proliferation and IL-2 production. We identified TCR-induced NF-κB activation as a target of DAPK. There was an increased PKCθ phosphorylation and an enhanced NF-κBp65 nuclear translocation in T cells with DAPK inhibited or down-regulated. In contrast, IL-1β- and TNF-α-triggered NF-κB activation was not affected by DAPK. We further found that DAPK selectively modulated the TCR-induced translocation of PKCθ, Bcl-10, and IKK into membrane rafts. Notably, the effect of DAPK on the raft entry was specific for NF-κB pathway, as other raft-associated molecules, such as LAT, were not affected. We further examined the possibility that, by negatively regulating T cell activation, DAPK contributes to the generation of T cell tolerance. DAPK mRNA expression was up-regulated when T cell anergy was induced either in vitro by calcium ionophore, or in vivo by intravenous administration of anti-CD3 antibody. There was a correlation between the amount of DAPK expression and the extent of T cell anergy, suggesting a role of DAPK in T cell tolerance induction. In addition, active DAPK transgene inhibited the induction and progression of autoimmune experimental autoimmune encephalomyelitis (EAE). Our results demonstrate that DAPK is a novel T cell regulator on TCR-activated NF-κB and T cell activation, and DAPK may contribute to maintenance of immune tolerance and avoidance of autoimmunity by promoting T cell anergy.
Subjects
DAP-kinase
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