title: Kindlin-3 is required for the stabilization of TCR-stimulated LFA-1:ICAM-1 bonds critical for lymphocyte arrest and spreading on dendritic cells.
abstract: Kindlin-3 is a key lymphocyte function-associated antigen-1 (LFA-1) coactivator deleted in leukocyte adhesion deficiency-III (LAD-III). In the present study, we investigated the involvement of this adaptor in lymphocyte motility and TCR-triggered arrest on ICAM-1 or on dendritic cells (DCs). Kindlin-3-null primary T cells from a LAD-III patient migrated normally on the major lymph node chemokine CCL21 and engaged in normal TCR signaling. However, TCR activation of Kindlin-3-null T lymphocytes failed to trigger the robust LFA-1-mediated T-cell spreading on ICAM-1 and ICAM-1-expressing DCs that is observed in normal lymphocytes. Kindlin-3 was also essential for cytoskeletal anchorage of the LFA-1 heterodimer and for microclustering of LFA-1 within ventral focal dots of TCR-stimulated lymphocytes spread on ICAM-1. Surprisingly, LFA-1 on Kindlin-3-null lymphocytes migrating over CCL21 acquired normal expression of an epitope associated with the conformational activation of the key headpiece domain, β I. This activated LFA-1 was highly responsive to TCR-triggered ICAM-1-driven stop signals in normal T cells locomoting on CCL21, but not in their Kindlin-3-null T-cell counterparts. We suggest that Kindlin-3 selectively contributes to a final TCR-triggered outside-in stabilization of bonds generated between chemokine-primed LFA-1 molecules and cell-surface ICAM-1.
authors.affiliation: Department of Immunology, the Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sara W
authors.initials: SW
authors.lastname: Feigelson
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Eugenia
authors.initials: E
authors.lastname: Manevich-Mendelson
authors.forename: Ronit
authors.initials: R
authors.lastname: Pasvolsky
authors.forename: Ziv
authors.initials: Z
authors.lastname: Shulman
authors.forename: Vera
authors.initials: V
authors.lastname: Shinder
authors.forename: Eugenia
authors.initials: E
authors.lastname: Klein
authors.forename: Amos
authors.initials: A
authors.lastname: Etzioni
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
mesh_terms: D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement; D048430:Cell Shape; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D021962:Membrane Microdomains / Q000276:immunology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008871:Microvilli / Q000378:metabolism / Q000648:ultrastructure; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: C515478:CCL21 protein, human; D054421:Chemokine CCL21; C477322:FERMT3 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1