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

Authors :
Melissa Pille
John Avila
Guillem Sanchez Sanchez
Glenn Goetgeluk
Stijn De Munter
Hanne Jansen
Lore Billiet
Karin Weening
Haipeng Xue
Sarah Bonte
Joline Ingels
Laurenz De Cock
Eva Pascal
Lucas Deseins
Tessa Kerre
Tom Taghon
Georges Leclercq
David Vermijlen
Brian Davis
Bart Vandekerckhove
Source :
Frontiers in Immunology, Vol 14 (2023)
Publication Year :
2023
Publisher :
Frontiers Media S.A., 2023.

Abstract

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.

Details

Language :
English
ISSN :
16643224
Volume :
14
Database :
Directory of Open Access Journals
Journal :
Frontiers in Immunology
Publication Type :
Academic Journal
Accession number :
edsdoj.8e328ea3407848819b605b95f452cf7f
Document Type :
article
Full Text :
https://doi.org/10.3389/fimmu.2023.1188099