Inducible T Cell Kinase Regulates the Acquisition of Cytolytic Capacity and Degranulation in CD8(+) CTLs.
Inducible T Cell Kinase Regulates the Acquisition of Cytolytic Capacity and Degranulation in CD8(+) CTLs.
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DOI：
10.4049/jimmunol.1601202
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发表时间：
2017-04-01
期刊：
影响因子：
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通讯作者：
Schwartzberg PL
中科院分区：
文献类型：
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作者：
Kapnick SM;Stinchcombe JC;Griffiths GM;Schwartzberg PL
ITK突变的患者易受病毒感染，特别是Epstein巴尔病毒，表明这些患者具有CD 8+细胞溶解性T淋巴细胞（CTL）功能缺陷。在这里，我们评估了ITK缺陷对ITK缺陷的鼠CTL以及用ITK抑制剂处理的人和鼠细胞中的细胞溶解的影响。我们发现ITK缺陷导致多个靶点的细胞溶解中的全局缺陷。ITK的缺乏既影响了CTL的扩增，又延迟了激活过程中溶细胞效应物的表达。此外，ITK的缺乏导致了先前未被认识到的内在缺陷脱粒。尽管如此，这些缺陷可以通过早期或长期暴露于IL-2或通过向培养物中添加IL-12来克服，这表明细胞因子信号传导可以恢复ITK缺陷型CD 8 + T细胞中效应子功能的获得。我们的研究结果为ITK和次优TCR信号对CD 8 + T细胞功能的影响提供了新的见解，以及这些信号如何有助于与ITK缺陷相关的表型。
Patients with mutations in ITK are susceptible to viral infections, particularly Epstein Barr Virus, suggesting that these patients have defective function of CD8+ cytolytic T lymphocytes (CTLs). Here, we evaluated the effects of ITK-deficiency on cytolysis in murine CTLs deficient in ITK, and both human and murine cells treated with an ITK inhibitor. We find that ITK-deficiency leads to a global defect in the cytolysis of multiple targets. The absence of ITK both affected CTL expansion and delayed the expression of cytolytic effectors during activation. Furthermore, absence of ITK led to a previously unappreciated intrinsic defect in degranulation. Nonetheless, these defects could be overcome by early or prolonged exposure to IL-2, or by addition of IL-12 to cultures, revealing that cytokine signaling could restore the acquisition of effector function in ITK-deficient CD8+ T cells. Our results provide new insight into the effect of ITK and suboptimal TCR signaling on CD8+ T cell function, and how these may contribute to phenotypes associated with ITK-deficiency.