The reduced ability of the aging immune system to mount adaptive immune responses compromises the efficacy of vaccinations and increases the morbidity from infections. Adaptive immune responses to exogenous or endogenous threats rely on the rapid expansion of an antigen-specific T cell population and acquisition of effector functions. In studying the effect of age on CD4 T memory cell function, we have identified a negative feedback loop mediated by the dual-specific phosphatase DUSP4 which is overactive in the elderly. DUSP4 is a nuclear phosphatase; its activity peaks two to four days after T cell activation and influences T cell differentiation by controlling nuclear ERK and JNK activity. In th current proposal we examine the hypothesis that the inappropriate activation of this feedback loop impairs T cell differentiation and effector function and that T cell responses in the elderly can be improved by identifying and correcting the mechanism of DUSP4 expression or by directly inhibiting DUSP4 activity.
Three specific aims have been designed to test this hypothesis.
In Aim 1, we will delineate the effect of DUSP4-mediated feedback loop on the kinetics of nuclear ERK and JNK activity in CD4 memory T cells. In a second step, we will then determine whether the age-associated attenuation of nuclear MAPK activities is universal for T cells or whether it is limited to selected T cell subpopulation depending on their differentiation and their replicative history.
In Aim 2, we will explore the mechanisms of increased DUSP4 expression in T cells from the elderly and determine whether the epigenetic or transcriptional control of DUSP4 changes with age. Of particular interest is the hypothesis that increased AMPK activation with age modifies the TCR-induced signaling cascade to favor DUSP4 transcription.
In Aim 3, we will examine the functional consequences of increased DUSP4 expression and explore how DUSP4 can be targeted to restore effector cell function.
With increasing age, the ability of the immune system to fend off infectious organisms or to control chronic infections declines. Consequences include the age-dependent reactivation of zoster infections, the increased morbidity and mortality from influenza, and the reduced response to vaccinations. With the changing demographics of the US population, this age-related immune incompetence is a major health problem. We hypothesize that a negative signaling feedback loop involving the dual specific phosphatase 4 is inappropriately activated in the elderly and can be targeted to correct defective T cell responses.
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