SIRT3 Negatively Regulates TFH-Cell Differentiation in Cancer

SIRT3 锡尔图因 细胞生物学 生物 氧化磷酸化 细胞分化 线粒体 生发中心 NAD+激酶 PI3K/AKT/mTOR通路 细胞 转录因子 癌细胞 癌症研究 信号转导 癌症 免疫学 B细胞 生物化学 抗体 遗传学 基因
作者
Yueru Hou,Yejin Cao,Ying He,Lin Dong,Longhao Zhao,Yingjie Dong,Ruiying Niu,Yujing Bi,Guangwei Liu
出处
期刊:Cancer immunology research [American Association for Cancer Research]
卷期号:12 (7): 891-904 被引量:1
标识
DOI:10.1158/2326-6066.cir-23-0786
摘要

Follicular helper T (TFH) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity in tumors; however, the mechanisms underlying TFH-cell differentiation remain unclear. In this study, we found that the metabolism sensor sirtuin 3 (SIRT3) is critical for TFH-cell differentiation and GC formation during tumor development and viral infection. SIRT3 deficiency in CD4+ T cells intrinsically enhanced TFH-cell differentiation and GC reactions during tumor development and viral 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 hypoxia-inducible factor 1α (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 Bcl6. 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 an mTOR-HIF1α-Bcl6 pathway to reprogram TFH-cell differentiation. These data have implications for future cancer immunotherapy research targeting SIRT3 in T cells.
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