An interferon gamma response signature links myocardial aging and immunosenescence

Aging entails profound immunological transformations that can negatively impact the myocardial biology and predispose to myocardial diseases. However, preclinical research in the immune-cardiology field is mostly conducted in young healthy animals, which potentially weakens its translational relevance. Herein, we sought to investigate how the aging T-cell compartment impacts myocardial cell biology in elderly. By investigating the paired-wised age-related shifts in the heart and its draining lymph nodes, our study provides evidence for an increased myocardial IFN-gamma signaling, which is associated with inflammatory and metabolic shifts typically seen in heart failure (HF). We phenotyped the antigen-experienced CD44high T cells purified from heart-draining lymph nodes of 2, 6, 12, and 18-months old C57BL/6 mice using single-cell RNA / T-cell receptor (TCR) sequencing (sc-seq). Simultaneously, we profiled all non-cardiomyocyte cell subsets purified from 2- and 18-months old hearts and integrated our data with publicly available cardiomyocyte sc-seq datasets. With aging, the heart-draining lymph node and myocardial T cells underwent spontaneous clonal expansion and exhibited an up-regulated pro-inflammatory transcription signature, marked by an increased interferon-g (IFN-g) production. In parallel, all major myocardial cell populations showed an increased IFN-g responsive signature with aging. In the aged cardiomyocytes, a stronger IFN-g response signature was paralleled by dampening of expression levels of transcripts related to most metabolic pathways, especially oxidative phosphorylation. Likewise, induced pluripotent stem cells-derived cardiomyocytes (iPSC-CM) exposed to chronic low grade IFN-g treatment showed a similar inhibition of metabolic activity.

衰老会引发深刻的免疫相关改变，可对心肌生物学特性产生负面影响，并增加心肌疾病的易感性。然而，免疫心脏病学领域的临床前研究大多在年轻健康动物中开展，这可能会削弱其研究成果的临床转化价值。本研究旨在探究衰老T细胞库如何影响老年个体的心肌细胞生物学特性。通过成对分析心脏及其引流淋巴结中随年龄变化的特征偏移，本研究证实心肌内γ干扰素（IFN-γ）信号通路活性升高，该现象与心力衰竭（HF）中典型的炎症与代谢改变相关。本研究利用单细胞RNA/T细胞受体（TCR）测序（sc-seq）技术，对2、6、12和18月龄C57BL/6小鼠心脏引流淋巴结中纯化得到的抗原致敏CD44高表达T细胞进行了表型分析。同时，本研究对2月龄和18月龄小鼠心脏中纯化得到的所有非心肌细胞亚群进行了转录组表征，并将本研究数据与公开可用的心肌细胞sc-seq数据集进行了整合。随着衰老进程，心脏引流淋巴结与心肌内的T细胞会发生自发性克隆扩增，并呈现促炎性转录特征上调，表现为γ干扰素产生增多。与此同时，所有主要的心肌细胞群在衰老过程中均表现出IFN-γ应答特征上调。在衰老的心肌细胞中，更强的IFN-γ应答特征与多数代谢通路（尤其是氧化磷酸化）相关转录本的表达水平下调相伴出现。同样，经慢性低剂量IFN-γ处理的诱导多能干细胞衍生心肌细胞（iPSC-CM）也表现出代谢活性受到类似抑制的现象。