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THE WISKOTT-ALDRICH SYNDROME PROTEIN CONTRIBUTES TO THE ASSEMBLY OF THE LFA-1 NANOCLUSTER BELT AT THE LYTIC SYNAPSE
Houmadi, Raïssa et al. | Date Issued: 2018
Author
Houmadi, Raïssa
Guipouy, Delphine
Rey-Barroso, Javier
Vasconcelos, Zilton
Cornet, Julie
Manghi, Manoel
Destainville, Nicolas
Valitutti, Salvatore
Allart, Sophie
Dupré, Loïc
Affilliation
INSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France / Université Toulouse III Paul Sabatier, Toulouse, France / CNRS, UMR 5282, Toulouse, France.
INSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France / Université Toulouse III Paul Sabatier, Toulouse, France / CNRS, UMR 5282, Toulouse, France / TxCell, Allée de la Nertière, Valbonne, Sophia-Antipolis, France.
INSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France / Université Toulouse III Paul Sabatier, Toulouse, France / CNRS, UMR 5282, Toulouse, France.
Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Rio de Janeiro, RJ, Brasil.
Université Toulouse III Paul Sabatier, Toulouse, France / CNRS, UMR 5152, Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes, Laboratoire de Physique Théorique, Toulouse, France.
Université Toulouse III Paul Sabatier, Toulouse, France / CNRS, UMR 5152, Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes, Laboratoire de Physique Théorique, Toulouse, France.
Université Toulouse III Paul Sabatier, Toulouse, France / CNRS, UMR 5152, Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes, Laboratoire de Physique Théorique, Toulouse, France.
INSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France / Université Toulouse III Paul Sabatier, Toulouse, France / CNRS, UMR 5282, Toulouse, France / Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France.
INSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France / Université Toulouse III Paul Sabatier, Toulouse, France / CNRS, UMR 5282, Toulouse, France.
INSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France / Université Toulouse III Paul Sabatier, Toulouse, France / CNRS, UMR 5282, Toulouse, France.
Abstract
T lymphocyte cytotoxicity relies on a synaptic ring of lymphocyte function-associated antigen 1 (LFA-1), which permits polarized delivery of lytic granules. How LFA-1 organization is controlled by underlying actin cytoskeleton dynamics is poorly understood. Here, we explored the contribution of the actin cytoskeleton regulator WASP to the topography of LFA-1 using a combination of microscopy modalities. We uncover that the reduced cytotoxicity of Wiskott-Aldrich syndrome patient-derived CD8+ T lymphocytes lacking WASP is associated with reduced LFA-1 activation, unstable synapse, and delayed lethal hit. At the nanometric scale, WASP constrains high-affinity LFA-1 into dense nanoclusters located in actin meshwork interstices. At the cellular scale, WASP is required for the assembly of a radial belt composed of hundreds of LFA-1 nanoclusters and for lytic granule docking within this belt. Our study unravels the nanoscale topography of LFA-1 at the lytic synapse and identifies WASP as a molecule controlling individual LFA-1 cluster density and LFA-1 nanocluster belt integrity.
Keywords
LFA-1
Wiskott-Aldrich syndrome protein
Actin cytoskeleton
Cytotoxic T lymphocytes
Immunological synapse
Lytic granules
Super-resolution microscopy
 
Publisher
Cell Press
Citation
HOUMADI, Raïssa et al. The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse. Cell Reports, v. 22, n. 4, p. 979-991, Jan. 2018.
DOI
10.1016/j.celrep.2017.12.088
ISSN
2211-1247