David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, NY, USA.
Blood. 2010 Apr 29;115(17):3498-507. doi: 10.1182/blood-2009-07-235754. Epub 2009 Dec 23.
Patients with Wiskott-Aldrich syndrome (WAS) have numerous immune cell deficiencies, but it remains unclear how abnormalities in individual cell types contribute to the pathologies of WAS. In T cells, the WAS protein (WASp) regulates actin polymerization and transcription, and plays a role in the dynamics of the immunologic synapse. To examine how these events influence CD4 function, we isolated the WASp deficiency to CD4(+) T cells by adoptive transfer into wild-type mice to study T-cell priming and effector function. WAS(-/-) CD4(+) T cells mediated protective T-helper 1 (Th1) responses to Leishmania major in vivo, but were unable to support Th2 immunity to Nippostrongylus brasiliensis or L major. Mechanistically, WASp was not required for Th2 programming but was required for Th2 effector function. WAS(-/-) CD4(+) T cells up-regulated IL-4 and GATA3 mRNA and secreted IL-4 protein during Th2 differentiation. In contrast, cytokine transcription was uncoupled from protein production in WAS(-/-) Th2-primed effectors. WAS(-/-) Th2s failed to produce IL-4 protein on restimulation despite elevated IL-4/GATA3 mRNA. Moreover, dominant-negative WASp expression in WT effector T cells blocked IL-4 production, but had no effect on IFNgamma. Thus WASp plays a selective, posttranscriptional role in Th2 effector function.
Wiskott-Aldrich 综合征（WAS）患者存在多种免疫细胞缺陷，但尚不清楚单个细胞类型的异常如何导致 WAS 的病理。在 T 细胞中，WAS 蛋白（WASp）调节肌动蛋白聚合和转录，并在免疫突触的动力学中发挥作用。为了研究这些事件如何影响 CD4 功能，我们通过过继转移将 WASp 缺陷分离到野生型小鼠的 CD4(+) T 细胞中，以研究 T 细胞的初始激活和效应功能。WAS(-/-) CD4(+) T 细胞在体内介导了对利什曼原虫的保护性 T 辅助 1（Th1）反应，但无法支持对旋毛虫或利什曼原虫的 Th2 免疫。从机制上讲，WASp 不需要 Th2 编程，但需要 Th2 效应功能。WAS(-/-) CD4(+) T 细胞在 Th2 分化过程中上调了 IL-4 和 GATA3 mRNA，并分泌了 IL-4 蛋白。相比之下，细胞因子转录与 WAS(-/-) Th2 激活效应器中的蛋白产生脱偶联。尽管 IL-4/GATA3 mRNA 升高，但 WAS(-/-) Th2 细胞在再刺激时未能产生 IL-4 蛋白。此外，WT 效应 T 细胞中的显性负性 WASp 表达阻断了 IL-4 的产生，但对 IFNgamma 没有影响。因此，WASp 在 Th2 效应功能中发挥选择性的转录后作用。
