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.
Atherosclerosis is a chronic inflammatory disease. CD4+ and CD8+ T cells are abundantly present in atherosclerotic lesions, where they produce a wide array of cytokines that can exert pro-inflammatory effects. These pro-inflammatory cytokines of the interleukin family are considered to be key players in the chronic vascular inflammation that is typical of atherosclerosis. Therefore, recruitment of T cells to the atherosclerotic plaques has emerged as a key factor in the pathogenesis of atherosclerosis. During T cell recruitment, LFA-1 acts as the feet by supporting adhesion to other cells and by linking the outside adhesion with the inside actin filaments via adapter proteins. Insufficient LFA-1 activity contributes to recurret infections and impaired wound healing, and excessive LFA-1 activity leads to an exaggerated inflammatory response and associated tissue damage. This makes LFA-1 a promising therapeutic target. This study will determine the molecular mechanisms that regulate LFA-1 activation in T cells, which would lead to the design of a novel therapeutic approach to treat the disease.
|Xu, Yuexin; Hyun, Young-Min; Lim, Kihong et al. (2014) Optogenetic control of chemokine receptor signal and T-cell migration. Proc Natl Acad Sci U S A 111:6371-6|
|Stevenson, Catherine; de la Rosa, Gonzalo; Anderson, Christopher S et al. (2014) Essential role of Elmo1 in Dock2-dependent lymphocyte migration. J Immunol 192:6062-70|
|Overstreet, Michael G; Gaylo, Alison; Angermann, Bastian R et al. (2013) Inflammation-induced interstitial migration of effector CD4? T cells is dependent on integrin ?V. Nat Immunol 14:949-58|
|Hu, Xuebo; Kang, Sungkwon; Lefort, Craig et al. (2010) Combinatorial libraries against libraries for selecting neoepitope activation-specific antibodies. Proc Natl Acad Sci U S A 107:6252-7|
|Lefort, Craig T; Kim, Minsoo (2010) Human T lymphocyte isolation, culture and analysis of migration in vitro. J Vis Exp :|
|Elphick, Gwendolyn F; Sarangi, Pranita P; Hyun, Young-Min et al. (2009) Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood 113:4078-85|
|Quinn, Jeffrey A; Graeber, C Thomas; Frackelton Jr, A Raymond et al. (2009) Coordinate regulation of estrogen-mediated fibronectin matrix assembly and epidermal growth factor receptor transactivation by the G protein-coupled receptor, GPR30. Mol Endocrinol 23:1052-64|
|Hyun, Young-Min; Lefort, Craig T; Kim, Minsoo (2009) Leukocyte integrins and their ligand interactions. Immunol Res :|
|Lefort, Craig T; Hyun, Young-Min; Schultz, Joanne B et al. (2009) Outside-in signal transmission by conformational changes in integrin Mac-1. J Immunol 183:6460-8|
|Hyun, Young-Min; Chung, Hung-Li; McGrath, James L et al. (2009) Activated integrin VLA-4 localizes to the lamellipodia and mediates T cell migration on VCAM-1. J Immunol 183:359-69|
Showing the most recent 10 out of 12 publications