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
酶
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]
日期:2024-04-17
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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