Abstract
Immunosenescence, described as the loss of normal immune function with age is a risk-factor culpable in age-related disease, susceptibility to infection, and reduced vaccine response. Increased immunosenescence is linked with the accumulation of TEMRA cells. Interestingly, these cells express increased β2-Adrenergic Receptor (β2AR) gene and protein compared to other T-cells. Previous work in the murine model found β2AR-stimulation induced p38-signalling, reactive oxygen species (ROS) generation and DNA damage, which are all senescent characteristics of TEMRA-cells. Furthermore, β2AR-stimulation decreases T-cell functionality including proliferation and IFNγ-production. Whether β2AR-signalling plays a causative role in the TEMRA senescence phenotype and/or reduced cellular functionality is not known. The overall aim of this PhD project is to explore the link between the increased β2AR expression observed with greater differentiation of human T-cells, and the significance of this relationship within the context of increased senescent characteristics exhibited by TEMRA cells.
Primary human CD8+/CD4+ T-cells were subjected to acute and chronic βAR-stimulation protocols, and downstream DNA damage, senescent-related signalling pathways and T-cell functionality were assessed by Flow Cytometry and Western Blotting.
Senescent TEMRA cells demonstrated the greatest β2AR-signalling response. The senescence signalling molecules, p-p38 MAPK and ROS, increased proportionally with β2AR expression in T-cells. Furthermore, T-cell functionality (IL-2, TNFα, IFNγ expression and proliferation) was also impaired in T-cells exhibiting greater β2AR expression. Finally, daily adrenergic stimulation of sorted CD8+ T-cells led to increased p-p38, p53, p-p53 and γH2AX (DNA damage) expression accompanied by prolonged cytokine suppression in TEMRA cells, importantly highlighting their susceptibility to adrenergic-induced senescence.
These findings demonstrate, for the first time, a molecular link between β2AR-signalling, T-cell senescence phenotype and reduced T-cell immune function. A greater understanding of the relationship between sympathetic nervous system activity, β2AR-stimulation and immunosenescence, may identify future therapeutic (βAR-antagonism) and prophylactic (stress-reduction) interventions aimed at improving the aged immune response.