SIRT3 negatively regulates TFH cell differentiation in cancer

IF 8.1 1区 医学 Q1 IMMUNOLOGY Cancer immunology research Pub Date : 2024-04-17 DOI:10.1158/2326-6066.cir-23-0786
Yueru Hou, Yejin Cao, Ying He, Lin Dong, Longhao Zhao, Yingjie Dong, Ruiying Niu, Yujing Bi, Guangwei Liu
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Abstract

Follicular helper T (TFH) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity in tumors, but the mechanisms underlying TFH cell differentiation remain unclear. Here, we found that the metabolism sensor sirtuin 3 (SIRT3) is critical for TFH cell differentiation and GC formation during tumor and viral infection. SIRT3 deficiency in CD4+ T cells intrinsically enhanced TFH cell differentiation and GC reactions during tumor and virus infection. Mechanistically, damaged oxidative phosphorylation (OXPHOS) compensatively triggered the NAD+-glycolysis pathway to provide a cellular energy supply, which was necessary for SIRT3 deficiency-induced TFH cell differentiation. Blocking NAD+ synthesis–glycolysis signaling or recovering OXPHOS activities reversed the TFH cell differentiation induced by SIRT3 deficiency. Moreover, the mTOR and HIF1α signaling axis was found to be responsible for TFH cell differentiation induced by SIRT3 deficiency. HIF1α directly interacted with and regulated the activity of the transcription factor Bcl-6. Thus, our findings identify a cellular energy compensatory mechanism, regulated by the mitochondrial sensor SIRT3, that triggers NAD+-dependent glycolysis during mitochondrial OXPHOS injuries and a mTOR–HIF1α–Bcl-6 pathway to reprogram TFH cell differentiation. These data have implications for future cancer immunotherapy research targeting SIRT3 in T cells.
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SIRT3 负向调控癌症中的 TFH 细胞分化
滤泡辅助T(TFH)细胞对于诱导生殖中心(GC)反应以介导肿瘤中的体液适应性免疫至关重要,但TFH细胞分化的机制仍不清楚。在这里,我们发现代谢传感器sirtuin 3(SIRT3)对肿瘤和病毒感染过程中TFH细胞的分化和GC的形成至关重要。在肿瘤和病毒感染过程中,CD4+ T 细胞缺乏 SIRT3 会增强 TFH 细胞分化和 GC 反应。从机制上讲,受损的氧化磷酸化(OXPHOS)代偿性地触发了NAD+-糖酵解途径以提供细胞能量供应,这是SIRT3缺乏诱导的TFH细胞分化所必需的。阻断 NAD+ 合成-糖酵解信号或恢复 OXPHOS 活性可逆转 SIRT3 缺乏诱导的 TFH 细胞分化。此外,研究还发现mTOR和HIF1α信号轴是SIRT3缺乏诱导TFH细胞分化的原因。HIF1α直接与转录因子Bcl-6相互作用并调节其活性。因此,我们的研究结果确定了一种由线粒体传感器 SIRT3 调节的细胞能量补偿机制,该机制在线粒体 OXPHOS 损伤期间触发 NAD+ 依赖性糖酵解,并通过 mTOR-HIF1α-Bcl-6 途径重新规划 TFH 细胞分化。这些数据对未来针对 T 细胞中 SIRT3 的癌症免疫疗法研究具有重要意义。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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