Defective Th1 cytokine gene transcription in CD4+ and CD8 + T cells from Wiskott-Aldrich syndrome patients

Sara Trifari, Giovanni Sitia, Alessandro Aiuti, Samantha Scaramuzza, Francesco Marangoni, Luca G. Guidotti, Silvana Martino, Paola Saracco, Luigi D. Notarangelo, Maria Grazia Roncarolo, Loïc Dupré

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Wiskott-Aldrich syndrome (WAS) protein (WASP) plays a key role in TCR-mediated activation and immunological synapse formation. However, the effects of WASP deficiency on effector functions of human CD4+ and CD8+ T cells remain to be determined. In this study, we report that TCR/CD28-driven proliferation and secretion of IL-2, IFN-γ, and TNF-α are strongly reduced in CD8+ T cells from WAS patients, compared with healthy donor CD8+ T cells. Furthermore, WAS CD4 + T cells secrete low levels of IL-2 and fail to produce IFN-γ and TNF-α, while the production of IL-4, IL-5, and IL-10 is only minimally affected. Defective IL-2 and IFN-γ production persists after culture of naive WAS CD4+ T cells in Th1-polarizing conditions. The defect in Th1 cytokine production by WAS CD4+ and CD8+ T cells is also present at the transcriptional level, as shown by reduced IL-2 and IFN-γ mRNA transcripts after TCR/CD28 triggering. The reduced transcription of Th1 cytokine genes in WAS CD4+ T cells is associated with a defective induction of T-bet mRNA and a reduction in the early nuclear recruitment of NFAT-1, while the defective activation of WAS CD8+ T cells correlates with reduced nuclear recruitment of both NFAT-1 and NFAT-2. Together, our data indicate that WASP regulates the transcriptional activation of T cells and is required specifically for Th1 cytokine production.

Original languageEnglish
Pages (from-to)7451-7461
Number of pages11
JournalJournal of Immunology
Issue number10
Publication statusPublished - Nov 15 2006


ASJC Scopus subject areas

  • Immunology

Cite this

Trifari, S., Sitia, G., Aiuti, A., Scaramuzza, S., Marangoni, F., Guidotti, L. G., Martino, S., Saracco, P., Notarangelo, L. D., Roncarolo, M. G., & Dupré, L. (2006). Defective Th1 cytokine gene transcription in CD4+ and CD8 + T cells from Wiskott-Aldrich syndrome patients. Journal of Immunology, 177(10), 7451-7461.