title: F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse.
abstract: Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. Regulation of integrin function occurs via conformational change, which modulates ligand affinity, and receptor clustering, which modulates valency. Here, we show that conformational intermediates of leukocyte functional antigen 1 (LFA-1) form a concentric array at the immunological synapse. Using an inhibitor cocktail to arrest F-actin dynamics, we show that organization of this array depends on F-actin flow and ligand mobility. Furthermore, F-actin flow is critical for maintaining the high affinity conformation of LFA-1, for increasing valency by recruiting LFA-1 to the immunological synapse, and ultimately for promoting intracellular cell adhesion molecule 1 (ICAM-1) binding. Finally, we show that F-actin forces are opposed by immobilized ICAM-1, which triggers LFA-1 activation through a combination of induced fit and tension-based mechanisms. Our data provide direct support for a model in which the T cell actin network generates mechanical forces that regulate LFA-1 activity at the immunological synapse.
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors: William A
authors: WA
authors: Comrie
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors: Alexander
authors: A
authors: Babich
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 jburkhar@mail.med.upenn.edu.
authors: Janis K
authors: JK
authors: Burkhardt
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology*; D019012:Integrin beta1 / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism; D024462:Myosin Type II / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000199:Actins; D019012:Integrin beta1; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D024462:Myosin Type II