The role of Wiskott-Aldrich Syndrome protein in activation and function of human T cells

Trifari, Sara (2006). The role of Wiskott-Aldrich Syndrome protein in activation and function of human T cells. PhD thesis The Open University.



Wiskott-Aldrich Syndrome (WAS) is a X-linked genetic disease caused by mutation in the gene encoding for the Wiskott-Aldrich Syndrome protein (WASP). WASP is specifically expressed in hematopoietic cells, where it regulates the reorganization of actin cytoskeleton in response to extracellular stimuli. WAS is characterized by micro-throm bocytopenia, eczema, immunodeficiency and high susceptibility to autoimmune disorders and haematological malignancies. Although WASP deficiency affects the function of several haematopoietic cells, T cell dysfunction plays a predominant role in WAS pathogenesis. Our study focused on the functional and molecular analysis of different effector T cell subsets from WAS patients and on a possible defect in peripheral tolerance.

We found that WASP lowers the threshold for T cell proliferation, induced by TCR/CD28 triggering. Restoration of WASP expression mediated by lentiviral vectors gene transfer fully reconstitutes TCR-driven proliferation. Furthermore, we showed that WASP regulates the levels of the ganglioside GM1 upon TCR/CD28 triggering. In addition, WASP deficiency selectively impairs the production of Th1 cytokines, after TCR/CD28 triggering in CD4+ and CD8+ T cells from WAS patients, as a consequence of reduced Th1 cytokine gene transcription. Reduced expression of IL-2 and IFN-ɣ mRNA in WAS T cells is associated with reduced nuclear levels of NFAT, and in WAS CD4+ T cells also with defective induction of T-bet transcription factor.

The function of natural regulatory T cells (nTreg) from WAS patients was also investigated, showing that WASP deficiency impairs the suppressive activity of nTreg cells.

This study clarifies the role of WASP in T cell activation and effector functions, and suggests that dysfunctions in regulatory T cells can be involved in the pathogenesis of WAS.

Viewing alternatives

Download history


Public Attention

Altmetrics from Altmetric

Number of Citations

Citations from Dimensions

Item Actions