Astrakhan Alexander, Ochs Hans D, Rawlings David J
Department of Immunology, University of Washington School of Medicine and Seattle Children's Research Institute, Seattle, WA 98101, USA.
J Immunol. 2009 Jun 15;182(12):7370-80. doi: 10.4049/jimmunol.0804256.
NKT cells comprise a separate T lineage expressing semi-invariant T cell receptors. Canonical invariant NKT (iNKT) cells specifically recognize lipid Ags presented by CD1d, a MHC class I-like molecule. iNKT cells function, in part, as initial responders to bacterial infection and play a role in immune surveillance and tumor rejection. The Wiskott-Aldrich Syndrome protein (WASp) serves as a crucial link between cellular stimuli and cytoskeletal rearrangements. Although we and others have identified a key role for WASp in homeostasis of T-regulatory and marginal zone B cells, little data exist regarding the role for WASp within the iNKT lineage. Analysis of WASp-expressing cell populations in heterozygous female WASp mice revealed a substantial selective advantage for WASp(+) vs WASp(-) iNKT cells. Although adult WASp-deficient (WASp(-/-)) mice had normal thymic and bone marrow iNKT numbers, we observed 2- to 3-fold reduction in the numbers of iNKT cells in the spleen and liver. This peripheral iNKT deficit is manifested, in part, due to defective iNKT homeostasis. WASp(-/-) iNKT cells exhibited reduced levels of integrin surface expression and decreased homing and/or retention within peripheral tissues in a competitive repopulation model. In addition, analysis of young mice showed that WASp is important for both maturation and egress of thymic iNKT cells. WASp(-/-) iNKT cells also exhibited a marked reduction in Ag-induced proliferation and cytokine production. Our findings highlight the crucial role for WASp in iNKT development, homeostasis, and activation, and identify iNKT dysfunction as an additional factor likely to contribute to the clinical features observed in WAS patients.
自然杀伤T细胞（NKT细胞）构成了一个表达半不变T细胞受体的独立T细胞谱系。典型的不变自然杀伤T细胞（iNKT细胞）特异性识别由CD1d（一种I类主要组织相容性复合体样分子）呈递的脂质抗原。iNKT细胞部分作为细菌感染的初始应答者发挥作用，并在免疫监视和肿瘤排斥中发挥作用。威斯科特-奥尔德里奇综合征蛋白（WASp）是细胞刺激与细胞骨架重排之间的关键纽带。尽管我们和其他人已经确定WASp在调节性T细胞和边缘区B细胞的稳态中起关键作用，但关于WASp在iNKT细胞谱系中的作用的数据很少。对杂合雌性WASp小鼠中表达WASp的细胞群体的分析显示，WASp(+) iNKT细胞相对于WASp(-) iNKT细胞具有显著的选择性优势。尽管成年WASp缺陷（WASp(-/-)）小鼠的胸腺和骨髓iNKT细胞数量正常，但我们观察到脾脏和肝脏中iNKT细胞数量减少了2至3倍。这种外周iNKT细胞缺陷部分是由于iNKT细胞稳态缺陷所致。在竞争再增殖模型中，WASp(-/-) iNKT细胞表现出整合素表面表达水平降低，在外周组织中的归巢和/或滞留减少。此外，对幼鼠的分析表明，WASp对胸腺iNKT细胞的成熟和迁出都很重要。WASp(-/-) iNKT细胞在抗原诱导的增殖和细胞因子产生方面也显著减少。我们的研究结果突出了WASp在iNKT细胞发育、稳态和激活中的关键作用，并确定iNKT细胞功能障碍是可能导致WAS患者临床特征的另一个因素。
