The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival
The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival
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DOI：
10.4049/jimmunol.180.5.3007
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发表时间：
2008-03-01
影响因子：
4.4
通讯作者：
Berg, Leslie J.
中科院分区：
文献类型：
--
作者：
Felices, Martin;Berg, Leslie J.
胸腺中常规的CD4(+)和CD8(+)T细胞的有效阳性选择需要Tec激酶ITK和RLK。相反，最近的研究表明，这些Tec激酶对于具有先天T细胞特征的CD8(+)T细胞的发育是必不可少的。这些发现提出了关于ITK和RLK在NKT细胞发育中的潜在作用的问题，因为NKT细胞代表着天然T细胞的一个子集。为了解决这个问题，我们研究了ITK(-/-)和ITK/RLK(-/-)小鼠的不变NKT细胞。我们发现，正如之前报道的那样，ITK(-/-)小鼠的NKT细胞数量减少，主要是未成熟表型。我们进一步表明，在同时缺乏ITK和RLK的情况下，这种缺陷会大大加剧，导致ITK/RLK(-/-)小鼠胸腺中不变的NKT细胞数量减少7倍，并更严重地阻碍NKT细胞的成熟。脾ITK(-/-)和ITK/RLK(-/-)NKT细胞也有功能缺陷，因为它们在体内激活后几乎不产生细胞因子。缺乏Tec激酶的NKT细胞也表现出增强的脾细胞死亡。这些缺陷与IL-2R/IL-15Rβ链CD122的表达显著降低以及T-box转录因子T-bet的表达受损有关。这些数据表明，Tec激酶ITK和RLK为NKT细胞的终末成熟、有效的细胞因子产生和外周生存提供了重要的信号。
The Tec kinases Itk and Rlk are required for efficient positive selection of conventional CD4(+) and CD8(+) T cells in the thymus. In contrast, recent studies have shown that these Tec kinases are dispensable for the development of CD8(+) T cells with characteristics of innate T cells. These findings raise questions about the potential role of Itk and Rlk in NKT cell development, because NKT cells represent a subset of innate T cells. To address this issue, we examined invariant NKT cells in Itk(-/-) and Itk/Rlk(-/-) mice. We find, as has been reported previously, that Itk(-/-) mice have reduced numbers of NKT cells with a predominantly immature phenotype. We further show that this defect is greatly exacerbated in the absence of both Itk and Rlk, leading to a 7-fold reduction in invariant NKT cell numbers in the thymus of Itk/Rlk(-/-) mice and a more severe block in NKT cell maturation. Splenic Itk(-/-) and Itk/Rlk(-/-) NKT cells are also functionally defective, because they produce little to no cytokine following in vivo activation. Tec kinase-deficient NKT cells also show enhanced cell death in the spleen. These defects correlate with greatly diminished expression of CD122, the IL-2R/IL-15R beta-chain, and impaired expression of the T-box transcription factor, T-bet. These data indicate that the Tec kinases Itk and Rlk provide important signals for terminal maturation, efficient cytokine production, and peripheral survival of NKT cells.