The Wiskott-Aldrich syndrome protein in dendritic cells is required for polarization of the microtubules cytoskeleton, synapse formation and activation of T cells

The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency characterized by recurrent infections, thrombocytopenia and a predisposition to develop autoimmune phenomena and lymphoreticular malignancies. The disease arises form mutations in the gene that codes for the WAS protein (WASp), a key regulator of actin dynamics in hematopoietic cells. Extensive analysis of WASp activation, regulation and function in T lymphocytes, have contributed to the understanding of the molecular basis of the immunodeficiency in WAS patients. However, it is increasingly evident that a general impairment of hematopoietic cell functions contributes to the pathogenesis of the disease Dendritic cells (DCs) are professional antigen-presenting cells (APCs) pivotal in the initiation of primary immune responses against pathogens and in the maintenance of peripheral T-cell tolerance against self-antigens. Despite clear indications of a role of WASp in the cytoarchitecture and migration of immature DCs, little is known about the effect of WASp deficiency on the ability of DCs to handle antigens and to interact with and activate na\uefve T-cells The aim of this project was to extend the present knowledge on the biology of DCs by studying the role of WASp in several aspects of their activity and to increase our understanding of the role of DCs in WAS pathogenesis. Using a murine model of WASp deficiency (WASp-) we focused on four main topics in DCs. First, we evaluated the ability of WASp- DCs to internalize and process physiologically relevant forms of antigens. Second, we measured the ability to migrate and encounter na\uefve T cells in vivo and in vitro. Third, we studied the ability to physically interact, present antigens and form stable synapses with T cells. Finally, we evaluated the efficacy of WASp- DCs to support T-cell activation in vivo and in vitro. In this work we demonstrate that WASp is a key protein in DCs, required to properly activate T cells. We also reveal a new mechanism of polarization in DCs that supports the synaptic delivery of cytokines and enhances T-cell activation