F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse.
| Autor: | Comrie WA; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Babich A; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Burkhardt JK; 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. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of cell biology [J Cell Biol] 2015 Feb 16; Vol. 208 (4), pp. 475-91. Date of Electronic Publication: 2015 Feb 09. |
| DOI: | 10.1083/jcb.201406121 |
| Abstrakt: | 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. (© 2015 Comrie et al.) |
| Databáze: | MEDLINE |
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