Lymphocyte function-associated (LFA) molecules and intercellular adhesion molecules (ICAMs) are important both in antigen-specific interactions in immune responses and in interactions with endothelial cells during leukocyte localization in inflammation. LFA-1 is an alpha/beta heterodimer and a member of the integrin family. It binds to 3 ICAMs, (ICAM-1, ICAM-2, and ICAM-3) that are members of the Ig superfamily (IgSF) and are closely related (35-55%) to one another. CD2 and LFA-3 bind to each other, and each contains 2 IgSF domains. The physiologic importance of these molecules is demonstrated by effect of deficiency of LFA-1 in an inherited disease, LAD; effect of ICAM-1 deficiency in mice; and effect of mAb to these molecules in inhibiting antigen-specific T lymphocyte responses, graft rejection, and animal models of disease. Studies of the function of these molecules in health and disease, the regulation of adhesiveness and signaling through them, and the structure of their interaction sites is of great importance, and may lead to the development of novel anti-inflammatory agents. We will examine the regions of the LFA-1 alpha and beta subunits that bind to ICAMs by construction of chimeric and mutant molecules and mapping binding sites of function-blocking mAb. We will prepare and examine the 3-dimensional structure of the LFA-1 alphabeta complex, the isolated LFA-1 beta subunit, and ICAM-2. We will examine the mechanism of regulation of adhesiveness of LFA-1, measure its affinity for ICAM-1, and study the role of cytoplasmic domains and interacting proteins within the cell. We will characterize the binding sites of ICAM-3 and ICAM-2, and signaling through ICAM-3. We will characterize the function of ICAM-2 and ICAM-3 in the mouse with blocking mAb, and study in deficient mice the function of the LFA-1 alpha and beta subunits. We will examine the kinetics of the interactions of CD2 with LFA-3 and LFA- 1 with ICAM-1 by plasmon resonance spectroscopy.
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