The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717319253 |
| _version_ | 1828175643645313024 |
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| author | Raïssa Houmadi Delphine Guipouy Javier Rey-Barroso Zilton Vasconcelos Julie Cornet Manoel Manghi Nicolas Destainville Salvatore Valitutti Sophie Allart Loïc Dupré |
| author_facet | Raïssa Houmadi Delphine Guipouy Javier Rey-Barroso Zilton Vasconcelos Julie Cornet Manoel Manghi Nicolas Destainville Salvatore Valitutti Sophie Allart Loïc Dupré |
| author_sort | Raïssa Houmadi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T04:30:37Z |
| format | Article |
| id | doaj.art-cd38f10fffe247009f7e1be99ba9f8e6 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T04:30:37Z |
| publishDate | 2018-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-cd38f10fffe247009f7e1be99ba9f8e62022-12-22T03:47:57ZengElsevierCell Reports2211-12472018-01-0122497999110.1016/j.celrep.2017.12.088The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic SynapseRaïssa Houmadi0Delphine Guipouy1Javier Rey-Barroso2Zilton Vasconcelos3Julie Cornet4Manoel Manghi5Nicolas Destainville6Salvatore Valitutti7Sophie Allart8Loïc Dupré9INSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, FranceINSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, FranceINSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, FranceFernandes Figueira Institute, Fiocruz, Rio de Janeiro, BrazilUniversité Toulouse III Paul Sabatier, Toulouse, FranceUniversité Toulouse III Paul Sabatier, Toulouse, FranceUniversité Toulouse III Paul Sabatier, Toulouse, FranceINSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, FranceINSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, FranceINSERM, UMR 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, FranceT 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.http://www.sciencedirect.com/science/article/pii/S2211124717319253Wiskott-Aldrich syndrome proteincytotoxic T lymphocytesimmunological synapseactin cytoskeletonLFA-1lytic granulessuper-resolution microscopy |
| spellingShingle | Raïssa Houmadi Delphine Guipouy Javier Rey-Barroso Zilton Vasconcelos Julie Cornet Manoel Manghi Nicolas Destainville Salvatore Valitutti Sophie Allart Loïc Dupré The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse Cell Reports Wiskott-Aldrich syndrome protein cytotoxic T lymphocytes immunological synapse actin cytoskeleton LFA-1 lytic granules super-resolution microscopy |
| title | The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse |
| title_full | The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse |
| title_fullStr | The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse |
| title_full_unstemmed | The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse |
| title_short | The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse |
| title_sort | wiskott aldrich syndrome protein contributes to the assembly of the lfa 1 nanocluster belt at the lytic synapse |
| topic | Wiskott-Aldrich syndrome protein cytotoxic T lymphocytes immunological synapse actin cytoskeleton LFA-1 lytic granules super-resolution microscopy |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717319253 |
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