Older individuals have increased morbidity and mortality from infections. Vaccination holds the promise of a cost-effective intervention; however, vaccine responses are generally poor in the elderly and at best ameliorate disease. One major objective of immune aging research therefore is to identify defects in adaptive immune responses that impair the generation of immune memory and that can be successfully targeted. After vaccination or infection, antigen-specific T cells follow a typical sequence of events. First, they exponentially expand and differentiate into effector cells including follicular helper cells that control the activation of B cells and the generation of antibodies. While most of these effector cells undergo apoptosis, a small subset constitutes memory T cell precursors that differentiate into long-lived memory cells. We have provided evidence that reduced survival of effector T cells contributes to defective memory cell generation in older individuals. We have shown that CD39 identifies effector CD4 T cells that cannot differentiate into long-lived memory T cells and that generation of CD39+ CD4 T cells is increased in immune responses of older individuals. CD39 is not only a surrogate marker, but actively contributes to effector cell apoptosis through its ATP/Dase activity, implicating purinergic signaling in regulating T cell memory generation. Here, we propose to identify means to interfere with CD39 expression or to target purinergic signaling to improve generation of T memory cells.
Aim 1 will define the gene-regulatory networks that induce CD39 expression in a subset of CD4 T cells after activation and will identify the molecular basis of increased CD39 expression in older individuals.
Aim 2 will examine whether purinergic signaling can be targeted to improve survival of activated CD4 T cell.
While Aims 1 and 2 involve in vitro experiments, Aim 3 will examine the role of CD39 expression and purinergic signaling on memory T cell generation in vivo in individuals after varicella zoster vaccination.
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. This proposal will explore new pathways to improve the generation of immune memory after vaccination.
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