MECHANISMS OF CELLULAR IMMUNE RESPONSES

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Our studies continue to emphasize characterizing cell surface molecules which facilitate T cell function, as well as defining their regulation with T cell differentiation. Major advances have been made this year in the critical area of T cell adhesion to endothelium. Our work strengthens the model that binding occurs via a cascade of at least 3 steps: tether, trigger, strong adhesion. The triggering step for T cells has been the least well defined. We have discovered two "pro-adhesive" cytokines which promise to be physiologic triggers: MIP-1beta and HGF. MIP-1beta: l) induces T cell adhesion to the endothelial ligand VCAM-1; 2) can be retained on proteoglycan to mediate its adhesion-induction; 3) is found at the endothelial surface in tonsil and lymph node; and 4) is chemotactic for T cells. Although, hepatocyte growth factor (HGF) is structurally completely different from MIP-1beta and previously had no immunologic relevance, we find it is functionally similar: strongly chemotactic for T cells as well as inducing T cell adhesion. Immunohistologic studies identify HGF on endothelium at sites such as inflamed liver. We propose that these factors are retained at the endothelial surface by binding to proteoglycan. We have developed a broader physiologic model that such pro- adhesive cytokines are delivered to endothelium by a specialized fibroblastic reticular conduit system. In studies of the integrins which mediate strong adhesion to endothelium. Flow cytometry and 2D-gel analysis identifies predominantly alpha6beta1, alpha4beta1, alpha4beta7, and alpha5beta1 on T cells. Low uniform expression of integrins is seen on naive cells and higher more selective expression on memory cells, including a newly defined subset of CD4 cells virtually negative for alpha4. Finally, we have organized a major component of the upcoming Fifth International Workshop on Leukocyte Differentiation Antigen which will determine the level of expression of virtually all known leukocyte surface molecules on cells of many lineages.