1. Kindlin-3 is required for the stabilization of TCR-stimulated LFA-1:ICAM-1 bonds critical for lymphocyte arrest and spreading on dendritic cells
- Author
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Ronit Pasvolsky, Amos Etzioni, Sara W. Feigelson, Eugenia Manevich-Mendelson, Memet Aker, Ziv Shulman, Ronen Alon, Valentin Grabovsky, Eugenia Klein, and Vera Shinder
- Subjects
Chemokine ,Immunological Synapses ,Lymphocyte ,T-Lymphocytes ,Immunology ,Leukocyte-Adhesion Deficiency Syndrome ,Receptors, Antigen, T-Cell ,Motility ,chemical and pharmacologic phenomena ,Cell Communication ,Biology ,Lymphocyte Activation ,Biochemistry ,Epitope ,Membrane Microdomains ,Cell Movement ,Coactivator ,medicine ,Cell Adhesion ,Humans ,Cell Shape ,Cells, Cultured ,Cytoskeleton ,ICAM-1 ,Chemokine CCL21 ,Microvilli ,T-cell receptor ,Membrane Proteins ,hemic and immune systems ,Cell Biology ,Hematology ,Dendritic Cells ,Intercellular Adhesion Molecule-1 ,Lymphocyte Function-Associated Antigen-1 ,Cell biology ,Neoplasm Proteins ,Protein Transport ,medicine.anatomical_structure ,biology.protein ,Protein Multimerization ,CCL21 ,Signal Transduction - 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.
- Published
- 2011