Intracellular signaling pathways and the regulation of cell adhesion.

Adhesion molecules play an essential role in the host immune response by mediating the adhesive interactions that are essential for immune cell trafficking and activation. Integrins are one family of adhesion receptors that leukocytes utilize to interact with other cells and with components of the extracellular matrix. Since leukocytes rapidly alternate between adhesive and nonadhesive states, the functional activity of integrins expressed on leukocytes is carefully and precisely regulated. Resting T lymphocytes express integrin receptors, but they mediate minimal cell adhesion. However, activation of the T cell results within minutes in increased integrin functional activity that occurs without a change in the level of integrin expression on the cell surface. Increased integrin-mediated adhesion appears to be a general response of T cells to activation, since a diverse array of activation stimuli are capable of inducing this rapid increase in integrin functional activity. We have used DNA-mediated gene transfer and site-directed mutagenesis to elucidate the intracellular signaling pathways that regulate integrin-mediated cell adhesion. Our studies have revealed two important general themes. First, the lipid kinase phosphatidylinositol 3-kinase (PI 3-K) plays a role in integrin regulation mediated by many regulators of integrin function. Second, there are cell-specific differences in the signaling pathways that regulate integrin function. These studies illustrate the complex nature of the signaling pathways that regulate lymphocyte adhesion.