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Cell Rep. 2018 Jan 23;22(4):979-991. doi: 10.1016/j.celrep.2017.12.088. Epub 2018 Jan 28.

The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse.

Author information

1
INSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France; CNRS, UMR 5282, Toulouse, France.
2
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.
3
Fernandes Figueira Institute, Fiocruz, Rio de Janeiro, Brazil.
4
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.
5
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.
6
INSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France; CNRS, UMR 5282, Toulouse, France. Electronic address: loic.dupre@inserm.fr.

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

PMID:
29386139
DOI:
10.1016/j.celrep.2017.12.088
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