Lymphocyte function-associated molecules LFA-1, CD2, LFA-3, and ICAM-1 a both cell-cell interactions in immune responses and in leukocyte localization in inflammation. LFA-1 is an alpha beta heterodimer, a member of the integrin family, and binds to ICAM-1, a member of the Ig superfamily related to NCAM. CD2 and LFA-3 bind to one another; each contains 2 Ig domains. The physiologic importance of these molecules is demonstrated by effect of deficiency of LFA-1 in an inherited disease, LAD, effect of MAb in vivo on graft rejection and leukocyte localization, and effect of MAb to LFA-1, ICAM-1, CD2, and LFA-3 in inhibiting antigen-specific CTL-mediated killing and T helper responses as well as antigen-independent interactions of lymphocytes with target cells, endothelium, epithelium, and fibroblasts. Lymphocyte activation stimulates increased adhesion via the LFA-l:ICAM-1 and CD2:LFA-3 pathways. We will investigate the molecular structure and ligand binding sites of these and novel related molecules, and define the molecular mechanisms which regulate their adhesion and signalling activity. We will examine effect of phosphorylation and cytoskeletal association on avidity of LFA-1 for ligand. Site directed mutagenesis will define regions of the transmembrane and cytoplasmic domains of alpha and beta subunits that transduce changes in avidity. The ligand binding sites of LFA-1 and ICAM-1 will be studied using chimaeric molecules and site directed mutagenesis. A novel LFA-1 ligand, ICAM-2, will be characterized. Mechanisms including glycosylation, elevation above the glycocalyx, and mobility which regulate CD2:LFA-3 association will be examined. Associations important in signalling between CD2 and CD3 and between CD2 and LFA-3 will be examined. We will examine the strength of the CD2/LFA-3 and LFA-l/ICAM-1 pathways under shear stress, and will define further pathways of lymphocyte-endothelium interaction.
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