Au-Yeung Byron B, Fowell Deborah J
Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
J Immunol. 2007 Jul 1;179(1):111-9. doi: 10.4049/jimmunol.179.1.111.
NKT cells rapidly secrete cytokines upon TCR stimulation and thus may modulate the acquired immune response. Recent studies suggest that signaling for development and effector function in NKT cells may differ from conventional T cells. The tyrosine kinase Itk is activated downstream of the TCR, and its absence in CD4(+) T cells results in impaired Th2, but not Th1 responses. In this study, we investigated NKT cell function in the absence of Itk as impaired type 2 responses in vivo could be manifest through IL-4 defects in a number of cell types. We show that Itk-deficient NKT cells up-regulate IL-4 mRNA in the thymus and express constitutive IL-4 and IFN-gamma transcripts in peripheral organs. Thus, Itk is not required for the developmental activation of cytokine loci in NKT cells. Nevertheless, Itk-deficient NKT cells are severely impaired in IL-4 protein production. Strikingly, unlike conventional CD4(+) T cells, Itk-deficient NKT cells also have profound defects in IFN-gamma production. Furthermore, both IL-4 and IFN-gamma production were markedly impaired following in vivo challenge with alpha-galactosyl ceramide. Function can be restored in Itk-deficient NKT cells by provision of calcium signals using ionomycin. These results suggest that NKT cells are highly dependent on Itk for IL-4- and IFN-gamma-mediated effector function. Thus, the pattern of cytokine genes that are affected by Itk deficiency appears to be cell lineage-specific, likely reflecting differences in activation threshold between immune effectors. The severe defect in NKT cell function may underlie a number of the Th1 and Th2 immune defects in Itk-deficient mice.
NKT细胞在TCR刺激后迅速分泌细胞因子，因此可能调节获得性免疫反应。最近的研究表明，NKT细胞发育和效应功能的信号传导可能与传统T细胞不同。酪氨酸激酶Itk在TCR下游被激活，CD4(+) T细胞中缺乏Itk会导致Th2反应受损，但Th1反应不受影响。在本研究中，我们研究了缺乏Itk时NKT细胞的功能，因为体内2型反应受损可能通过多种细胞类型中的IL-4缺陷表现出来。我们发现，缺乏Itk的NKT细胞在胸腺中上调IL-4 mRNA，并在外周器官中表达组成性的IL-4和IFN-γ转录本。因此，Itk不是NKT细胞中细胞因子基因发育激活所必需的。然而，缺乏Itk的NKT细胞在IL-4蛋白产生方面严重受损。令人惊讶的是，与传统的CD4(+) T细胞不同，缺乏Itk的NKT细胞在IFN-γ产生方面也有严重缺陷。此外，用α-半乳糖神经酰胺进行体内攻击后，IL-4和IFN-γ的产生均明显受损。通过使用离子霉素提供钙信号，可以恢复缺乏Itk的NKT细胞的功能。这些结果表明，NKT细胞在IL-4和IFN-γ介导的效应功能方面高度依赖于Itk。因此，受Itk缺乏影响的细胞因子基因模式似乎是细胞谱系特异性的，可能反映了免疫效应器之间激活阈值的差异。NKT细胞功能的严重缺陷可能是Itk缺陷小鼠中许多Th1和Th2免疫缺陷的基础。
