期刊
JOURNAL OF IMMUNOLOGY
卷 177, 期 10, 页码 7451-7461出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.177.10.7451
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资金
- Telethon [TGT06S01] Funding Source: Medline
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.
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