Immune function declines in the elderly resulting in a greater susceptibility to disease, particularly of viral origin. Recent studies suggest the hypothesis that this decline involves alterations in the abilit of leukocytes to migrate from the bloodstream, through basement membranes, and into tissues to sites of infection. Because T lymphocytes (T-Ly) are the primary leukocytes that fight viral infections and because T-Ly migration through three-dimensional collagen gels (a model for cell migration through basement membranes into tissues) requires the presence in the gels of the extracellular matrix protein laminin, the proposed studies focus on aging-associated alterations in the interactions of T-Ly with laminin. Indeed, experiments already performed strongly support the hypothesis: T-Ly from senior individuals migrate much less well through collagen/laminin gels than do T-Ly from young individuals. Moreover, Alzheimer's Disease may be an extreme example of altered T lymphocyte-laminin interactions in that Alzheimer's T-Ly migrate even less well than control senior T-Ly. To test the hypothesis further, we will: 1) Use flow cytometry to compare the expression of markers for various classes of T-Ly in senior and young individuals. These experiments will indicate if functional differences between senior and young T-Ly result from the amplification of a specific subpopulation of T-Ly in seniors. 2) Use biochemical methods to compare the expression of laminin receptors by senior and young T-Ly. We have already demonstrated that the alpha-6 and alpha-7 integrin subunits are functional laminin receptors in T-Ly. These experiments will suggest which laminin receptors are responsible for the differential interaction of senior and young T-Ly with laminin. 3) Because protein kinase C (PKC) plays a major role in regulating T-Ly migration, we will compare the expression and subcellular localization of PKC isoforms in migrating senior and young T-Ly and the role of the interaction of laminin with specific receptors in regulating the expression and localization of PKC isoforms. These experiments will reveal if functional differences between senior and young T-Ly result from differences in the linkage of laminin receptors to signaling mechanisms involving PKC. The better understanding of the role of cell migration in immune deficits associated with aging that will result from these studies should allow new strategies for fighting infectious diseases in the elderly to be proposed and tested.
