title: Occupancy of lymphocyte LFA-1 by surface-immobilized ICAM-1 is critical for TCR- but not for chemokine-triggered LFA-1 conversion to an open headpiece high-affinity state.
abstract: Lymphocyte arrest and spreading on ICAM-1-expressing APCs require activation of lymphocyte LFA-1 by TCR signals, but the conformational switches of this integrin during these critical processes are still elusive. Using Ab probes that distinguish between different LFA-1 conformations, we found that, unlike strong chemokine signals, potent TCR stimuli were insufficient to trigger LFA-1 extension or headpiece opening in primary human lymphocytes. Nevertheless, LFA-1 in these TCR-stimulated T cells became highly adhesive to both anchored and mobile surface-bound ICAM-1, although it failed to bind soluble ICAM-1 with measurable affinity. Rapid rearrangement of LFA-1 by immobilized ICAM-1 switched the integrin to an open headpiece conformation within numerous scattered submicron focal dots that did not readily collapse into a peripheral LFA-1 ring. Headpiece-activated LFA-1 microclusters were enriched with talin but were devoid of TCR and CD45. Notably, LFA-1 activation by TCR signals as well as subsequent T cell spreading on ICAM-1 took place independently of cytosolic Ca(2+). In contrast to LFA-1-activating chemokine signals, TCR activation of LFA-1 readily took place in the absence of external shear forces. LFA-1 activation by TCR signals also did not require internal myosin II forces but depended on intact actin cytoskeleton. Our results suggest that potent TCR signals fail to trigger LFA-1 headpiece activation unless the integrin first gets stabilized by surface-bound ICAM-1 within evenly scattered actin-dependent LFA-1 focal dots, the quantal units of TCR-stimulated T cell arrest and spreading on ICAM-1.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sara W
authors.initials: SW
authors.lastname: Feigelson
authors.forename: Ronit
authors.initials: R
authors.lastname: Pasvolsky
authors.forename: Saso
authors.initials: S
authors.lastname: Cemerski
authors.forename: Ziv
authors.initials: Z
authors.lastname: Shulman
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Tal
authors.initials: T
authors.lastname: Ilani
authors.forename: Adi
authors.initials: A
authors.lastname: Sagiv
authors.forename: Fabrice
authors.initials: F
authors.lastname: Lemaitre
authors.forename: Carlo
authors.initials: C
authors.lastname: Laudanna
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
mesh_terms: D000199:Actins / Q000235:genetics / Q000276:immunology; D000818:Animals; D018925:Chemokines / Q000276:immunology* / Q000494:pharmacology; D003599:Cytoskeleton / Q000235:genetics / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000199:Actins; D018925:Chemokines; C090509:Icam1 protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; C516770:Ptprc protein, mouse