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首页> 外文期刊>EBioMedicine >Diacylglycerol Kinase ζ Limits Cytokine-dependent Expansion of CD8+ T Cells with Broad Antitumor Capacity
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Diacylglycerol Kinase ζ Limits Cytokine-dependent Expansion of CD8+ T Cells with Broad Antitumor Capacity

机译：二酰基甘油激酶ζ限制具有宽抗肿瘤能力的CD8 + T细胞的细胞因子依赖性扩增

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Abstract Interleukin-2 and -15 drive expansion/differentiation of cytotoxic CD8+ T cells that eliminate targets via antigen-independent killing. This property is clinically relevant for the improvement of T cell-based antitumor therapies. Diacylglycerol kinase α and ζ (DGKα/ζ) metabolize the diacylglycerol generated following antigen recognition by T lymphocytes. Enhanced expression of these two lipid kinases in tumor-infiltrating CD8+ T cells promotes a hyporesponsive state that contributes to tumor immune escape. Inhibition of these two enzymes might thus be of interest for potentiating conventional antigen-directed tumor elimination. In this study, we sought to characterize the contribution of DGKα and ζ to antigen-independent cytotoxic functions of CD8+ T cells. Analysis of DGKζ-deficient mice showed an increase in bystander memory-like CD8+ T cell populations not observed in DGKα-deficient mice. We demonstrate that DGKζ limits cytokine responses in an antigen-independent manner. Cytokine-specific expansion of DGKζ-deficient CD8+ T cells promoted enhanced differentiation of innate-like cytotoxic cells in vitro, and correlated with the more potent in vivo anti-tumor responses of DGKζ-deficient mice engrafted with the murine {A20} lymphoma. Our studies reveal a isoform-specific function for DGKζ downstream of IL-2/IL-15-mediated expansion of innate-like cytotoxic T cells, Pharmacological manipulation of DGKζ activity is of therapeutic interest for cytokine-directed anti-tumor treatments.
机译：摘要白细胞介素2和-15驱动细胞毒性CD8 + T细胞的扩增/分化，后者通过抗原非依赖性杀伤来消除靶标。该性质在临床上与基于T细胞的抗肿瘤疗法的改善有关。二酰基甘油激酶α和ζ（DGKα/ζ）代谢由T淋巴细胞识别抗原后产生的二酰基甘油。这两种脂质激酶在肿瘤浸润性CD8 + T细胞中的增强表达促进了反应低下状态，这有助于肿瘤免疫逃逸。因此，抑制这两种酶可能是增强常规抗原指导的肿瘤消除的兴趣所在。在这项研究中，我们试图表征DGKα和ζ对CD8 + T细胞的抗原非依赖性细胞毒功能的贡献。对DGKζ缺陷小鼠的分析显示，在DGKα缺陷小鼠中未观察到旁观者记忆样CD8 + T细胞的数量增加。我们证明DGKζ以抗原独立的方式限制细胞因子的反应。缺乏DGKζ的CD8 + T细胞的细胞因子特异性扩增促进了先天性细胞毒性细胞的体外分化增强，并且与移植有鼠{A20}淋巴瘤的DGKζ缺乏小鼠的体内抗肿瘤反应更有效。我们的研究揭示了IL-2 / IL-15介导的先天性细胞毒性T细胞的扩增对DGKζ下游的异构体特异性功能。DGKζ活性的药理处理对于细胞因子定向的抗肿瘤治疗具有治疗意义。

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