The overall objective of this proposal is to investigate the modulation of T-cell function by catecholamines. The importance of these studies can be found in the observation that catecholamines participate in the stress response and thus have the potential to be immunomodulatory. This gives rise to the possibility that the immune potential of patients with Acquired Immunodeficiency Syndrome (AIDS) can be modulated by catecholamines interacting with their T-cells. The proposed studies will focus on defining how stimulation of the beta adrenergic receptor (BAR) alters the activation of T-cells and their subsets by a variety of specific and non- specific stimuli. Initial experiments are designed to quantify the ability of T-cells to respond to phytohemagglutinin (PHA) and anti-T3 monoclonal antibody (mab) in presence of the beta adrenergic agonist isoproterenol (ISO). Moreover, ISO will be added at various times to stimulated T- cells to define the temporal action of BAR stimulation on the activation of these cells. Concurrent with these studies the status of the BAR on T- cells at various times during culture will be assessed by ligand binding studies. Further experiments will be performed with T-cell subsets (CD8+, CD4+ and CD4+ naive and memory cells.) These will include their mitogen responsiveness in the presence of ISO added at various times to the cell cultures. Furthermore, the BAR density and affinity will be determined by ligand binding studies. Experiments also are planned to evaluate the modulatory effects of BAR stimulation on more selective and physiological activators T-cell (soluble antigen, autologous and allogeneic cells). In other experiments the influence of stimulating the BAR on accessory cell function will be defined. The final series of studies are concerned with investigating the biologic mechanisms responsible for the effects of ISO on T-cell activation. These included quantitation of the consequences of BAR stimulation on the subsequent modulation of the TCR by anti-T3 mab; the production of interleukin 2 (IL-2) and expression of the IL-2 receptor (IL- 2) by activated T-cells. Finally, the role of cell adherence in the process of T-cell activation will be studied in the context of the stimulation of the BAR.
