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The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation

The Wiskott–Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for...

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Autores principales: Pille, Melissa, Avila, John, Sanchez, Guillem Sanchez, Goetgeluk, Glenn, De Munter, Stijn, Jansen, Hanne, Billiet, Lore, Weening, Karin, Xue, Haipeng, Bonte, Sarah, Ingels, Joline, De Cock, Laurenz, Pascal, Eva, Deseins, Lucas, Kerre, Tessa, Taghon, Tom, Leclercq, Georges, Vermijlen, David, Davis, Brian, Vandekerckhove, Bart
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10282776/
https://www.ncbi.nlm.nih.gov/pubmed/37350958
http://dx.doi.org/10.3389/fimmu.2023.1188099
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author Pille, Melissa
Avila, John
Sanchez, Guillem Sanchez
Goetgeluk, Glenn
De Munter, Stijn
Jansen, Hanne
Billiet, Lore
Weening, Karin
Xue, Haipeng
Bonte, Sarah
Ingels, Joline
De Cock, Laurenz
Pascal, Eva
Deseins, Lucas
Kerre, Tessa
Taghon, Tom
Leclercq, Georges
Vermijlen, David
Davis, Brian
Vandekerckhove, Bart
author_facet Pille, Melissa
Avila, John
Sanchez, Guillem Sanchez
Goetgeluk, Glenn
De Munter, Stijn
Jansen, Hanne
Billiet, Lore
Weening, Karin
Xue, Haipeng
Bonte, Sarah
Ingels, Joline
De Cock, Laurenz
Pascal, Eva
Deseins, Lucas
Kerre, Tessa
Taghon, Tom
Leclercq, Georges
Vermijlen, David
Davis, Brian
Vandekerckhove, Bart
author_sort Pille, Melissa
collection PubMed
description The Wiskott–Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. In vitro, their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR)(+) CD4(+) CD8(+) double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8(+) SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation.
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spelling pubmed-102827762023-06-22 The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation Pille, Melissa Avila, John Sanchez, Guillem Sanchez Goetgeluk, Glenn De Munter, Stijn Jansen, Hanne Billiet, Lore Weening, Karin Xue, Haipeng Bonte, Sarah Ingels, Joline De Cock, Laurenz Pascal, Eva Deseins, Lucas Kerre, Tessa Taghon, Tom Leclercq, Georges Vermijlen, David Davis, Brian Vandekerckhove, Bart Front Immunol Immunology The Wiskott–Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. In vitro, their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR)(+) CD4(+) CD8(+) double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8(+) SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation. Frontiers Media S.A. 2023-06-07 /pmc/articles/PMC10282776/ /pubmed/37350958 http://dx.doi.org/10.3389/fimmu.2023.1188099 Text en Copyright © 2023 Pille, Avila, Sanchez, Goetgeluk, De Munter, Jansen, Billiet, Weening, Xue, Bonte, Ingels, De Cock, Pascal, Deseins, Kerre, Taghon, Leclercq, Vermijlen, Davis and Vandekerckhove https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Pille, Melissa
Avila, John
Sanchez, Guillem Sanchez
Goetgeluk, Glenn
De Munter, Stijn
Jansen, Hanne
Billiet, Lore
Weening, Karin
Xue, Haipeng
Bonte, Sarah
Ingels, Joline
De Cock, Laurenz
Pascal, Eva
Deseins, Lucas
Kerre, Tessa
Taghon, Tom
Leclercq, Georges
Vermijlen, David
Davis, Brian
Vandekerckhove, Bart
The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation
title The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation
title_full The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation
title_fullStr The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation
title_full_unstemmed The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation
title_short The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation
title_sort wiskott–aldrich syndrome protein is required for positive selection during t-cell lineage differentiation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10282776/
https://www.ncbi.nlm.nih.gov/pubmed/37350958
http://dx.doi.org/10.3389/fimmu.2023.1188099
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