The ability of leukocytes to traffic throughout the host and to localize at sites of antigen deposition and tissue injury is critically important in normal immune and inflammatory responses. Leukocyte migration is controlled by a series of cell surface adhesion molecules which mediate the recognition of complementary ligands on vascular endothelial cells. The investigator has shown that CD8 cells activated by alloantigen in vivo modulate these adhesion molecules, with the down regulation of L-selectin and concomitant up-regulation of proinflammatory integrins and CD44. As activated CD8 T-cells differentiate into memory cells, they undergo additional changes in expression of these adhesive receptors. The first objective of this research is to examine further the regulated changes in expression of T lymphocyte adhesion receptors that occur as activated cells differentiate into effector and memory cells. Using both normal and T-cell receptor transgenic mouse models, the following specific points will be addressed: (1) Examination of the regulation of adhesion molecules by activated effector and memory T-cells and determination of the role of L-selectin in the targeting of T lymphocytes to sites of inflammation will be examined. (2) The lineage relationships of naive, activated effector, and memory T-cells responding to allografts will be determined, testing the hypothesis that CD8 memory T-cells arise from activated effector cell precursors. (3) Antigen-specific and bystander-activated T-cells will be examined, comparing the regulation of adhesion molecule expression and traffic, their rate of long-term persistence, and the mechanisms that affect their clonal elimination. The second objective is to examine the rapid PKC-regulated proteolytic cleavage and shedding of L-selectin. The major focus of these studies will be to examine the physiological function of receptor shedding with respect to T-cell adhesion, transendothelial migration, and cell traffic in vivo. The role of L-selectin shedding in the transregulation of integrin activation will also be investigated, as will the structural basis by which the protease recognizes substrate in the plane of the plasma membrane.
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