Aging is associated with reduced protective cellular as well as systemic immune responses. Protective cellular immunity against invading pathogens depends on the ability of T cells to detect processed pathogen-derived peptides that are bound to MHC proteins on the surface of antigen- presenting cells (APCs). In young people and mice binding of the T cell receptor (TCR), on the membrane of the T cells, to such peptides-MHC proteins on the APCs causes localized spatial- temporal membrane rearrangements that recruit and activate receptor-proximal intracellular signaling proteins. The engaged receptors and their associated intracellular proteins rapidly form highly organized Immunological-Synapses (IS). These membrane-proximal events within the IS initiate multiple intracellular signaling cascades that propagate from the membrane to the nucleus, modify gene transcription and cause effective T cell immune responses. In aging people and mice both na?ve and memory T cells respond poorly to antigenic stimulation by APCs and form defective immune synapses. The causes for these age-dependent defects are still unknown. In this project we will study membrane-associated events in T cells from aging mice. We propose to investigate the connection between declines in immune response with aging to changes in TCR organization, IS dynamics and membrane lipid composition. Our hypothesis is that declines in CD4+ T cell responses reflect changes in TCR organization, which reduce effective antigen recognition. We further speculate that the changes in receptor organization are a consequence of changes plasma membrane lipid composition with age. We will test our hypothesis by: 1) using engineered nano-particles, quantum-dots, to probe and analyze TCR organization in the plasma membrane of T cells from young and old animals 2) 4D live cell imaging of immune synapse formation to capture subtle kinetic changes in antigen recognition consequent to aging and 3) determining the lipid composition of T cells from young and aged mice and using this as a guide to lipid modulation of TCR organization and dynamics of IS formation. The experiments proposed can lead to a better understanding of age-dependent changes in immune responses at the cellular and molecular level. They can also point the way to relatively simple interventions, for example dietary changes, which can enhance immune responses in older individuals. Immune responses decline with age resulting in decreased resistance to infectious diseases and reduced protection by vaccines. In this application we intend to investigate the causes for age- dependent reduced immunity. Our experiments can point the way to simple approaches, changes in diet, for modulating and enhancing immune responses in aged individuals. If these declines could be arrested or reduced the large population of older Americans would be less susceptible to infection with profound social and economic consequences. ? ? ?
