Abstract
Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches. Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system. In this review, we highlight the research that has focused over the last 20 years on T lymphocytes from Wiskott–Aldrich syndrome (WAS) patients. WAS T lymphocytes are defective for the WAS protein (WASP), a regulator of actin cytoskeleton remodeling. Therefore, study of WAS T lymphocytes has helped to grasp that many steps of T lymphocyte activation and function depend on the crosstalk between membrane receptors and the actin cytoskeleton. These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions. The recent concept that WASP also works as a regulator of transcription within the nucleus is an illustration of the complexity of signal integration in T lymphocytes. Finally, this review will discuss how further study of WAS may contribute to solve novel challenges of T lymphocyte biology.
Highlights
GENERAL PRESENTATION OF THE WISKOTT–ALDRICH SYNDROME The Wiskott–Aldrich syndrome (WAS) is an X-linked primary immunodeficiency (PID) characterized by the association of multiple clinical manifestations
We will focus on the role played by WAS protein (WASP) in T lymphocytes and will highlight how this line of research has contributed to our current understanding of signal integration during T lymphocyte activation and function
In the periphery, T regulatory (Treg) cell suppressive function is impaired and can be partially rescued in vitro by treatment with IL-2 [78, 80]. These data argue in favor of defective antigen-driven expansion and function. This is corroborated by the observation, in a case of spontaneous revertant mutation, that WASP-expressing Treg cells possess an in vivo selective advantage over WASP-defective Treg cells [79]
Summary
GENERAL PRESENTATION OF THE WISKOTT–ALDRICH SYNDROME The Wiskott–Aldrich syndrome (WAS) is an X-linked primary immunodeficiency (PID) characterized by the association of multiple clinical manifestations. Over the last two decades, hundreds of studies have provided insights into how WASP regulates the activation and function of the different subsets of hematopoietic cells in which it is normally expressed [6]. The GTPase binding domain (GBD), in a non-activated state of the WASP molecule, is found in an intramolecular hydrophobic link with the C-terminal VCA (composed by the verprolin-homology, central hydrophobic, and acidic regions) domain. The intramolecular GBD-VCA binding is regarded as a critical allosteric control of WASP activity, since mutations in GBD produce a constitutively active molecule that seems to directly affect myeloid and lymphoid cells, including lymphocyte number and proliferation, and increased T cell death and genomic instability, as found in X-linked neutropenia patients and in a mouse model [15,16,17]
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