Directed lymphocyte migration requires the interaction of specific receptors, present on the lymphocyte cell surface, with ligands present on the surface of other cells or the extracellular matrix. The overall objective of this proposal is to understand how thymus-derived lymphocytes and their progenitors interact with the extracellular matrix. CD44 is a cell-surface molecule that is expressed on the earliest T- lymphocyte progenitors, on memory T-lymphocytes, and on certain lymphoid tumor cells that exhibit metastatic behavior. Several lines of evidence indicate that CD44 mediates binding to extracellular matrix components. Hyaluronic acid (HA) is one ligand for CD44. Although most normal hematopoietic cells express a CD44 isoform which potentially binds hyaluronic acid, most hematopoietic cells that express this CD44 isoform do not bind hyaluronic acid. This result implies that whether this CD44 isoform binds hyaluronic acid only under very specific conditions and under strict cellular control. The specific objective of this proposal is to determine the factors that determine whether the CD44 isoform on hematopoietic cells binds HA or not. This work has implications for understanding normal lymphocyte development, mechanisms of inflammation and lymphocyte migration in disease states, and the mechanisms underlying tumor cell metastasis. To accomplish the specific objective, we propose to: 1) Determine structural features of the CD44 molecule that are required for HA binding. 2) Determine how some CD44-specific monoclonal antibodies enhance the binding of HA. 3) Investigate the role of the cytoskeleton in binding HA and in the enhancement of HA-binding by CD44-specific antibodies. 4) Determine why some cell lines cannot be induced to bind HA by CD44- specific antibodies. 5) Investigate consequences of the activation of HA binding by CD44- specific antibodies on lymphocyte adhesion to epithelial cells and on thymocyte progenitor migration in vivo.
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