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
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.
Funder
Fonds Wetenschappelijk Onderzoek
Walloon excellence in life sciences and biotechnology
Fonds De La Recherche Scientifique - FNRS
Subject
Immunology,Immunology and Allergy
Cited by
2 articles.
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