Data from SIRT3 Negatively Regulates T_FH-Cell Differentiation in Cancer

• DOI: 10.1158/2326-6066.c.7311395.v1
• Publication Date: 2024-07-02T08:30:55Z
• Authors: Yueru Hou; Yejin Cao; Ying He; Lin Dong; Longhao Zhao; Yingjie Dong; Ruiying Niu; Yujing Bi; Guangwei Liu

<div>Abstract<p>Follicular helper T (T_FH) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity in tumors; however, the mechanisms underlying T_FH-cell differentiation remain unclear. In this study, we found that the metabolism sensor sirtuin 3 (SIRT3) is critical for T_FH-cell differentiation and GC formation during tumor development and viral infection. SIRT3 deficiency in CD4⁺ T cells intrinsically enhanced T_FH-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 T_FH-cell differentiation. Blocking NAD⁺ synthesis–glycolysis signaling or recovering OXPHOS activities reversed the T_FH-cell differentiation induced by SIRT3 deficiency. Moreover, the mTOR and hypoxia-inducible factor 1α (HIF1α) signaling axis was found to be responsible for T_FH-cell differentiation induced by SIRT3 deficiency. HIF1α directly interacted with and regulated the activity of the transcription factor <i>Bcl6</i>. 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 T_FH-cell differentiation. These data have implications for future cancer immunotherapy research targeting SIRT3 in T cells.</p></div>