My laboratory studies the structure and function of cell surface adhesion molecules in the immune system. Adhesion receptors on lymphocytes together with their ligands on vascular endothelial cells are critical for the traffic of lymphocytes from blood into lymphoid organs and into inflamed tissues. They may also play an important role in the metastasis of malignant cells into distal tissue sites. We use protein chemistry and cell and molecular biology in conjunction with in vitro and in vivo models of adhesion to characterize these receptor/ligand interactions. With these studies we hope to gain better understanding of their role in biological systems and of the intracellular signalling pathways necessary for receptor activation.
Effector and/or memory T cells are known to express increased surface levels of the receptor CD44. We have shown that following the recognition of cognate antigen by a T cell receptor, CD44 is converted to a conformationally activated form able to bind its ligand the glycosaminoglycan hyaluronan (HA). As a result, activated CD44 can mediate the primary adhesion (rolling) of T cells under conditions of physiologic shear stress on microvascular endothelial cells expressing HA. This interaction results in the extravasation of activated lymphocytes at inflammatory sites, including tissues that are the target of autoimmune damage. We have demonstrated a role for this interaction in human autoimmune diseases, showing a correlation between disease exacerbation and expression of activated CD44 on peripheral blood lymphocytes in patients with juvenile arthritis or systemic lupus erythematosus. We are currently studying activated CD44 on T cells as a contributing mechanism in several murine models of autoimmune inflammation, including Type I (autoimmune) diabetes, arthritis, and SLE. In addition, using molecular methods, we are identifying small molecular weight inhibitors of this interaction as potential diagnostic and therapeutic aids. Parallel studies on vascular endothelial cells have demonstrated that HA expression is regulated in response to proinflammatory cytokines. The intracellular signaling pathways for induction and regulation of both the activated form of CD44 and HA expression are actively under investigation.
