Frontiers in Immunology (Jun 2023)

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

  • 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

DOI
https://doi.org/10.3389/fimmu.2023.1188099
Journal volume & issue
Vol. 14

Abstract

Read online

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.

Keywords