title: Ligand-mediated friction determines morphodynamics of spreading T cells.
abstract: Spreading of T cells on antigen presenting cells is a crucial initial step in immune response. Spreading occurs through rapid morphological changes concomitant with the reorganization of surface receptors and of the cytoskeleton. Ligand mobility and frictional coupling of receptors to the cytoskeleton were separately recognized as important factors but a systematic study to explore their biophysical role in spreading was hitherto missing. To explore the impact of ligand mobility, we prepared chemically identical substrates on which molecules of anti-CD3 (capable of binding and activating the T cell receptor complex), were either immobilized or able to diffuse. We quantified the T cell spreading area and cell edge dynamics using quantitative reflection interference contrast microscopy, and imaged the actin distribution. On mobile ligands, as compared to fixed ligands, the cells spread much less, the actin is centrally, rather than peripherally distributed and the edge dynamics is largely altered. Blocking myosin-II or adding molecules of ICAM1 on the substrate largely abrogates these differences. We explain these observations by building a model based on the balance of forces between activation-dependent actin polymerization and actomyosin-generated tension on one hand, and on the frictional coupling of the ligand-receptor complexes with the actin cytoskeleton, the membrane and the substrate, on the other hand. Introducing the measured edge velocities in the model, we estimate the coefficient of frictional coupling between T Cell receptors or LFA-1 and the actin cytoskeleton. Our results provide for the first time, to our knowledge, a quantitative framework bridging T cell-specific biology with concepts developed for integrin-based mechanisms of spreading.
authors.affiliation: Adhesion & Inflammation, Aix-Marseille University, Inserm UMR 1067, CNRS UMR 7333, Marseille, France; CINAM, Aix-Marseille University, CNRS UMR 7325, Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dillard
authors.affiliation: Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD.
authors.forename: Rajat
authors.initials: R
authors.lastname: Varma
authors.affiliation: CINAM, Aix-Marseille University, CNRS UMR 7325, Marseille, France. Electronic address: sengupta@cinam.univ-mrs.fr.
authors.forename: Kheya
authors.initials: K
authors.lastname: Sengupta
authors.affiliation: Adhesion & Inflammation, Aix-Marseille University, Inserm UMR 1067, CNRS UMR 7333, Marseille, France. Electronic address: laurent.limozin@inserm.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Limozin
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D002465:Cell Movement; D048430:Cell Shape; D017276:Friction; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019169:Jurkat Cells; D008024:Ligands; D024462:Myosin Type II / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D008024:Ligands; D018799:Intercellular Adhesion Molecule-1; D024462:Myosin Type II