This laboratory has discovered and works on families of adhesion and chemoattractant receptors that regulate specific cell interactions, localization, migration, and differentiation of cells of the immune system. The importance of integrins on leukocytes in vivo has been demonstrated by an inherited disease, leukocyte adhesion deficiency, in which mutations affect the common b subunit that associates with three different a subunits to form ab heterodimers. The leukocyte integrins LFA-1 and Mac-1 bind to members of the immunoglobulin supergene family called intercellular adhesion molecules (ICAMs).
The adhesiveness of LFA-1 for ICAM-1 is regulated by T cell activation by antigen; thus, LFA-1 acts as an adhesion servomotor under the control of the T cell recptor for antigen. High avidity of LFA-1 is transient, providing a mechanism for de-adhesion. Truncation of the cloned b subunit cytoplasmic domain abrogates the high avidity state. We have predicted the structure of several integrin domains, including a G protein-like b-propeller domian. We are working on the structure of integrins to obtain a molecular model of how signals that regulate ligand binding and cell proliferation are propagated by conformational changes.
Mutagenesis studies are defining the regions in the extracellular domains of integrins and ICAMs involved in ligand binding. We have determined the crystal structure of ICAM-1, ICAM-2, and MAdCAM-1 and are using this information to guide mutagenesis to study their binding sites for integrins. ICAM-1 is subverted as a receptor by rhinoviruses, and novel chimaeric molecules are being constructed to neutralize rhinoviruses, and to understand how receptor binding leads to host cell penetration.
Selectins that bind carbohydrate ligands mediate the initial tethering of flowing lekocytes to the vessel wall and subsequent rolling. The a4b1 and a4b7 integrins can also mediate rolling by binding VCAM-1 on MAdCAM-1. We are examining leukocyte interactions with purified adhesion molecules, or with a monolayer of platelets or endothelial cells, in a flow system at physiologic shear stress. The biophysics that regulate rolling are being explored.
Work on chemoattractants and their receptors focuses on their function in lymphocyte trafficking, as HIV co-receptors, and structure.
A multi-step model suggests specificity of leukocyte trafficking is due to combinatorial diversity in signals from selectins, chemoattractants, and integrin ligands that are displayed on vascular endothelium.