Table_1_Single-Cell Analysis Revealed the Role of CD8+ Effector T Cells in Preventing Cardioprotective Macrophage Differentiation in the Early Phase of Heart Failure.xlsx

Heart failure is a complex clinical syndrome characterized by insufficient cardiac function. Heart-resident and infiltrated macrophages have been shown to play important roles in the cardiac remodeling that occurs in response to cardiac pressure overload. However, the possible roles of T cells in this process, have not been well characterized. Here we show that T cell depletion conferred late-stage heart protection but induced cardioprotective hypertrophy at an early stage of heart failure caused by cardiac pressure overload. Single-cell RNA sequencing analysis revealed that CD8+T cell depletion induced cardioprotective hypertrophy characterized with the expression of mitochondrial genes and growth factor receptor genes. CD8+T cells regulated the conversion of both cardiac-resident macrophages and infiltrated macrophages into cardioprotective macrophages expressing growth factor genes such as Areg, Osm, and Igf1, which have been shown to be essential for the myocardial adaptive response after cardiac pressure overload. Our results demonstrate a dynamic interplay between cardiac CD8+T cells and macrophages that is necessary for adaptation to cardiac stress, highlighting the homeostatic functions of resident and infiltrated macrophages in the heart.

心力衰竭是一种以心功能不全为特征的复杂临床综合征。已有研究证实，心脏驻留巨噬细胞与浸润巨噬细胞在心脏压力负荷诱导的心肌重构过程中发挥关键作用，但T细胞在该进程中的潜在功能尚未得到充分阐释。本研究表明，T细胞耗竭可在心脏压力负荷诱导的心力衰竭晚期提供心脏保护，而在疾病早期则诱导产生心脏保护性肥大。单细胞RNA测序（single-cell RNA sequencing）分析显示，CD8+T细胞耗竭所介导的心脏保护性肥大以线粒体基因与生长因子受体基因的表达为典型特征。CD8+T细胞可调控心脏驻留巨噬细胞与浸润巨噬细胞向表达Areg、Osm及Igf1等生长因子基因的心脏保护性巨噬细胞转化，而上述生长因子基因已被证实对心脏压力负荷后的心肌适应性反应不可或缺。本研究结果揭示了心脏CD8+T细胞与巨噬细胞间的动态互作是心脏应激适应的必要条件，同时凸显了心脏驻留与浸润巨噬细胞的稳态调控功能。