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Defective Th1 cytokine gene transcription in CD4(+) and CD8(+) T cells from Wiskott-Aldrich syndrome patients
Defective Th1 cytokine gene transcription in CD4(+) and CD8(+) T cells from Wiskott-Aldrich syndrome patients JOURNAL OF IMMUNOLOGY Trifari, S., Sitia, G., Aiuti, A., Scaramuzza, S., Marangoni, F., Guidotti, L. G., Martino, S., Saracco, P., Notarangelo, L. D., Roncarolo, M., Dupre, L. 2006; 177 (10): 7451-7461Abstract
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-gamma, and TNF-alpha 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-gamma and TNF-alpha, while the production of IL-4, IL-5, and IL-10 is only minimally affected. Defective IL-2 and IFN-gamma 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-gamma 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.
View details for Web of Science ID 000242009700100
View details for PubMedID 17082665