LFA-1 in lymphocyte migration

University Of Rochester, Rochester NY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Although critical for both innate and adaptive immune responses, leukocyte migration is also involved in a wide range of pathologic conditions including vasculitis, atherosclerosis, stroke, rheumatoid arthritis, lupus, multiple sclerosis and Crohn's disease. In these diseases, a substantial components of vascular damage and injury to the underlying host tissue results from abnormal trafficking and massive infiltration of pro-inflammatory leukocytes. Central players in this process are the cell surface adhesion molecules called integrins, which regulate leukocyte extravasation and chemotaxis. The integrin lymphocyte function-associated antigen-1 (LFA- 1 or aLb2; CD11a/CD18) is expressed on most leukocytes and plays a major role in regulating leukocyte adhesion and recruitment to damaged or infected tissues during inflammatory responses. Insufficient LFA-1 activity contributes to recurrent infections and impaired wound healing, and excessive LFA-1 activity leads to an exaggerated inflammatory response and associated tissue damage. Although a great deal of information has been learned about the early steps in lymphocyte extravasation, including tethering, rolling and firm adhesion, little is known about the dynamic and spatial regulation of LFA-1 activation during T cell migration on and through the endothelium. We hypothesize that a localized chemokine signal is sufficient to induce a persistent balance between positive and negative regulatory signals for LFA-1 activation and to determine the direction of T cell migration in vivo. We will, (1) determine the mechanisms of how RhoH differentially regulates LFA-1 during chemokine-mediated T cell migration and TCR-dependent T cell activation, (2) investigate whether localized chemokine signals is sufficient to control LFA-1 activation and guide T cell migration in vivo, and (3) investigate the sequential control of LFA-1 activation and T cell extravasation by local adhesion molecules of the inflamed tissues. Throughout our work we will relate our findings to functional outcomes including T cell-antigen presenting cell (APC) interaction, T cell-endothelial cell interaction, T cell tissue- specific homing, and suppression o T cell migration. The integrin LFA-1 is an important drug target in inflammatory and autoimmune diseases, with one approved antibody antagonist and multiple small molecule antagonists in development. Thus, the molecular and cellular characterization of LFA-1 activation during T cell migration in vivo will enhance development of new therapeutics.