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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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1188099/full |
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| author | Melissa Pille John Avila Guillem Sanchez Sanchez Guillem Sanchez Sanchez Guillem Sanchez Sanchez Guillem Sanchez Sanchez Glenn Goetgeluk Glenn Goetgeluk Stijn De Munter Stijn De Munter Hanne Jansen Lore Billiet Karin Weening Haipeng Xue Sarah Bonte Sarah Bonte Joline Ingels Joline Ingels Laurenz De Cock Laurenz De Cock Eva Pascal Eva Pascal Lucas Deseins Lucas Deseins Tessa Kerre Tessa Kerre Tom Taghon Tom Taghon Georges Leclercq Georges Leclercq David Vermijlen David Vermijlen David Vermijlen David Vermijlen Brian Davis Bart Vandekerckhove Bart Vandekerckhove |
| author_facet | Melissa Pille John Avila Guillem Sanchez Sanchez Guillem Sanchez Sanchez Guillem Sanchez Sanchez Guillem Sanchez Sanchez Glenn Goetgeluk Glenn Goetgeluk Stijn De Munter Stijn De Munter Hanne Jansen Lore Billiet Karin Weening Haipeng Xue Sarah Bonte Sarah Bonte Joline Ingels Joline Ingels Laurenz De Cock Laurenz De Cock Eva Pascal Eva Pascal Lucas Deseins Lucas Deseins Tessa Kerre Tessa Kerre Tom Taghon Tom Taghon Georges Leclercq Georges Leclercq David Vermijlen David Vermijlen David Vermijlen David Vermijlen Brian Davis Bart Vandekerckhove Bart Vandekerckhove |
| author_sort | Melissa Pille |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-13T06:58:05Z |
| format | Article |
| id | doaj.art-8e328ea3407848819b605b95f452cf7f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-13T06:58:05Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-8e328ea3407848819b605b95f452cf7f2023-06-07T05:16:04ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-06-011410.3389/fimmu.2023.11880991188099The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiationMelissa Pille0John Avila1Guillem Sanchez Sanchez2Guillem Sanchez Sanchez3Guillem Sanchez Sanchez4Guillem Sanchez Sanchez5Glenn Goetgeluk6Glenn Goetgeluk7Stijn De Munter8Stijn De Munter9Hanne Jansen10Lore Billiet11Karin Weening12Haipeng Xue13Sarah Bonte14Sarah Bonte15Joline Ingels16Joline Ingels17Laurenz De Cock18Laurenz De Cock19Eva Pascal20Eva Pascal21Lucas Deseins22Lucas Deseins23Tessa Kerre24Tessa Kerre25Tom Taghon26Tom Taghon27Georges Leclercq28Georges Leclercq29David Vermijlen30David Vermijlen31David Vermijlen32David Vermijlen33Brian Davis34Bart Vandekerckhove35Bart Vandekerckhove36Laboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumBrown Foundation Institute of Molecular Medicine, Mc Govern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United StatesDepartment of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles (ULB), Brussels, BelgiumInstitute for Medical Immunology, Université Libre de Bruxelles (ULB), Brussels, BelgiumULB Center for Research in Immunology (U-CRI), Université Libre de Bruxelles (ULB), Brussels, BelgiumWELBIO Department, WEL Research Institute, Wavre, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumCancer Research Institute Ghent (CRIG), Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumCancer Research Institute Ghent (CRIG), Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumBrown Foundation Institute of Molecular Medicine, Mc Govern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United StatesCancer Research Institute Ghent (CRIG), Ghent, BelgiumDepartment of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumCancer Research Institute Ghent (CRIG), Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumCancer Research Institute Ghent (CRIG), Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumCancer Research Institute Ghent (CRIG), Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumCancer Research Institute Ghent (CRIG), Ghent, BelgiumDepartment of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium0Department of Hematology, Ghent University Hospital, Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumCancer Research Institute Ghent (CRIG), Ghent, BelgiumLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumCancer Research Institute Ghent (CRIG), Ghent, BelgiumDepartment of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles (ULB), Brussels, BelgiumInstitute for Medical Immunology, Université Libre de Bruxelles (ULB), Brussels, BelgiumULB Center for Research in Immunology (U-CRI), Université Libre de Bruxelles (ULB), Brussels, BelgiumWELBIO Department, WEL Research Institute, Wavre, BelgiumBrown Foundation Institute of Molecular Medicine, Mc Govern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United StatesLaboratory of Experimental Immunology, Department of Diagnostic Sciences, Ghent University, Ghent, BelgiumCancer Research Institute Ghent (CRIG), Ghent, BelgiumThe 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1188099/fullT-cell developmentWiskott Aldrich syndromeT-cell repertoireATOCRISPR/Cas9INDEL |
| spellingShingle | Melissa Pille John Avila Guillem Sanchez Sanchez Guillem Sanchez Sanchez Guillem Sanchez Sanchez Guillem Sanchez Sanchez Glenn Goetgeluk Glenn Goetgeluk Stijn De Munter Stijn De Munter Hanne Jansen Lore Billiet Karin Weening Haipeng Xue Sarah Bonte Sarah Bonte Joline Ingels Joline Ingels Laurenz De Cock Laurenz De Cock Eva Pascal Eva Pascal Lucas Deseins Lucas Deseins Tessa Kerre Tessa Kerre Tom Taghon Tom Taghon Georges Leclercq Georges Leclercq David Vermijlen David Vermijlen David Vermijlen David Vermijlen Brian Davis Bart Vandekerckhove Bart Vandekerckhove The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation Frontiers in Immunology T-cell development Wiskott Aldrich syndrome T-cell repertoire ATO CRISPR/Cas9 INDEL |
| 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 | T-cell development Wiskott Aldrich syndrome T-cell repertoire ATO CRISPR/Cas9 INDEL |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1188099/full |
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