Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
Immunology Unit, Universidad Autónoma de Madrid, Hospital Universitario la Princesa, Madrid, Spain.
J Clin Invest. 2021 May 3;131(9). doi: 10.1172/JCI146136.
Restriction of HIV-1 replication in elite controllers (ECs) is frequently attributed to T cell-mediated immune responses, while the specific contribution of innate immune cells is less clear. Here, we demonstrate an upregulation of the host long noncoding RNA (lncRNA) MIR4435-2HG in primary myeloid dendritic cells (mDCs) from ECs. Elevated expression of this lncRNA in mDCs was associated with a distinct immunometabolic profile, characterized by increased oxidative phosphorylation and glycolysis activities in response to TLR3 stimulation. Using functional assays, we show that MIR4435-2HG directly influenced the metabolic state of mDCs, likely through epigenetic mechanisms involving H3K27ac enrichment at an intronic enhancer in the RPTOR gene locus, the main component of the mammalian target of rapamycin complex 1 (mTORC1). Together, these results suggest a role of MIR4435-2HG for enhancing immunometabolic activities of mDCs in ECs through targeted epigenetic modifications of a member of the mTOR signaling pathway.
在精英控制者 (ECs) 中，HIV-1 复制受到 T 细胞介导的免疫反应的限制，而先天免疫细胞的具体贡献尚不清楚。在这里，我们证明了宿主长非编码 RNA (lncRNA) MIR4435-2HG 在 EC 中的原代髓样树突状细胞 (mDCs) 中上调。该 lncRNA 在 mDCs 中的高表达与独特的免疫代谢特征相关，其特征是在 TLR3 刺激下氧化磷酸化和糖酵解活性增加。通过功能测定，我们表明 MIR4435-2HG 通过涉及在 RPTOR 基因座内含子增强子处 H3K27ac 富集的表观遗传机制，直接影响 mDC 的代谢状态，RPTOR 基因座是雷帕霉素靶蛋白复合物 1 (mTORC1) 的主要组成部分。总之，这些结果表明 MIR4435-2HG 通过靶向 mTOR 信号通路成员的表观遗传修饰，增强 ECs 中 mDC 的免疫代谢活性。
