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Mitochondrial oxidative stress drives IL-12/IL-18-induced IFN-gamma production by CD4+ T cells and is controlled by Fas
bioRxiv - Immunology Pub Date : 2021-01-19 , DOI: 10.1101/2021.01.19.427239
Gorjana Rackov , Parinaz Tavakoli Zaniani , Sara Colomo del Pino , Rahman Shokri , Melchor Alvarez-Mon , Carlos Martinez-A , Dimitrios Balomenos

Mitochondrial activation and mROS production are crucial for CD4+ T cell responses and have a role in naive cell signaling after TCR activation. However, little is known about their role in recall responses driven by cytokine signaling. Here, we found that mROS are required for IL-12 plus IL-18-driven production of IFN-gamma, an essential cytokine in inflammatory and autoimmune disease development. In particular, memory-like cells obtained after activation-induced differentiation showed faster and augmented mROS accumulation and increased IFN-gamma production in response to IL-12 plus IL-18 compared to naive T cells. In contrast, mROS induction was similar in naive and memory-like cells after TCR-dependent signaling. Taken together these results suggested that memory-like CD4+ T cells treated by IL-12 plus IL-18 attained conditions for an extraordinary mROS-producing potential. mROS inhibition significantly downregulated the production of IFN-gamma and the expression of CD44 activation marker, suggesting a direct mROS effect on the activation of memory-like T cells. Mechanistically, mROS was required for optimal activation of key signaling pathways that drive IFN-gamma production after IL-12 plus IL-18 T cell stimulation, such as PKC-theta, AKT and STAT4 phosphorylation, and NF-kappaB activation. Notably, we identified increased mROS as key promoters of hyperactivation and IFN-gamma overproduction in Fas-deficient lpr memory-like CD4+ T cells compared to WT cells, following IL-12 plus IL-18 stimulation. mROS inhibition significantly reduced the population of disease-associated CD44hiCD62Llo lpr CD4+ T cells and their IFN-gamma production. These findings uncover a previously unidentified role for Fas in regulating mitochondrial ROS production by memory-like T cells. This apoptosis-independent Fas activity might contribute to the accumulation of CD44hiCD62Llo CD4+ T cells that produce increased IFN-gamma levels in lpr mice. Overall, our findings pinpoint mROS as central regulators of TCR-independent signaling, and support mROS pharmacological targeting to control aberrant immune responses in autoimmune-like disease.

中文翻译:

线粒体氧化应激通过CD4 + T细胞驱动IL-12 / IL-18诱导的IFN-γ产生,并受Fas控制

线粒体激活和mROS产生对于CD4 + T细胞反应至关重要,并在TCR激活后在幼稚细胞信号传导中发挥作用。然而,关于它们在细胞因子信号驱动的召回反应中的作用了解甚少。在这里,我们发现IL-12加上IL-18驱动的IFN-γ产生需要mROS,IFN-γ是炎性和自身免疫性疾病发展中必不可少的细胞因子。特别地,与天然T细胞相比,活化诱导的分化后获得的记忆样细胞显示出更快和增加的mROS积累,并响应IL-12加IL-18而增加了IFN-γ产生。相反,TCR依赖性信号转导后,在幼稚和类似记忆的细胞中,mROS的诱导作用相似。综上所述,这些结果表明,经IL-12加IL-18处理的记忆样CD4 + T细胞达到了产生非凡mROS潜力的条件。mROS抑制显着下调了IFN-γ的产生和CD44激活标记的表达,表明mROS对记忆样T细胞的激活具有直接作用。从机制上讲,需要mROS来激活IL-12加IL-18 T细胞刺激后驱动IFN-γ产生的关键信号通路的最佳激活,例如PKC-θ,AKT和STAT4磷酸化以及NF-κB激活。值得注意的是,在IL-12加IL-18刺激后,与WT细胞相比,我们发现FaROS缺失的lpr记忆样CD4 + T细胞中mROS是过度激活和IFN-γ过度生产的关键启动子。mROS抑制显着减少了疾病相关的CD44hiCD62Llo lpr CD4 + T细胞及其IFN-γ的产生。这些发现揭示了Fas在调节记忆样T细胞调节线粒体ROS产生中的作用。这种不依赖凋亡的Fas活性可能有助于CD44hiCD62Llo CD4 + T细胞的积累,从而在lpr小鼠中产生增加的IFN-γ水平。总体而言,我们的发现将mROS定位为TCR非依赖性信号传导的中央调节剂,并支持mROS药理学靶向控制自身免疫样疾病中异常的免疫反应。这种不依赖凋亡的Fas活性可能有助于CD44hiCD62Llo CD4 + T细胞的积累,从而在lpr小鼠中产生增加的IFN-γ水平。总体而言,我们的发现将mROS定位为TCR依赖性信号独立的中心调节剂,并支持mROS药理学靶向控制自身免疫性疾病中异常的免疫反应。这种不依赖凋亡的Fas活性可能有助于CD44hiCD62Llo CD4 + T细胞的积累,从而在lpr小鼠中产生增加的IFN-γ水平。总体而言,我们的发现将mROS定位为TCR依赖性信号独立的中心调节剂,并支持mROS药理学靶向控制自身免疫性疾病中异常的免疫反应。
更新日期:2021-01-20
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