Department of Immunology, Tufts University, Boston, MA (A.L.B., S.S., N.N., A.H.-M., K.K., K.S., M.A., S.S., P.A.).
Department of Medicine, Washington University School of Medicine, Saint Louis, MO (J.A., K.L.).
Circ Res. 2023 Aug 18;133(5):412-429. doi: 10.1161/CIRCRESAHA.123.323030. Epub 2023 Jul 26.
Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown.
We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled wild type versus mouse T cells at the transcript and protein level and performed several functional assays.
Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated T cells had increased proinflammatory signaling at the transcript and protein level compared with wild type, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling.
Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress.
心力衰竭中心脏炎症的特征是存在损伤相关分子模式、髓样细胞和 T 细胞。心脏损伤相关分子模式通过 TLR（ toll 样受体）向髓样细胞提供持续的促炎信号，这些 TLR 汇聚到衔接蛋白 MyD88（髓样分化反应 88）上。这些信号诱导髓样细胞有效激活成为抗原呈递细胞，通过其 TCR（T 细胞受体）激活 T 细胞。T 细胞的激活导致心脏向心性、心脏成纤维细胞转化和适应性心脏重构。T 细胞依赖 TCR 信号传导发挥效应功能和存活，尽管它们表达 MyD88 和损伤相关分子模式受体，但它们在 T 细胞激活和心脏炎症中的作用尚不清楚。
我们在 T 细胞中缺乏 MyD88 的小鼠中进行了横主动脉缩窄，并分析了重构、收缩功能、存活和 T 细胞激活。我们对野生型和 型小鼠 T 细胞进行了转录组和蛋白质组水平的分析，并进行了几项功能测定。
单细胞 RNA 测序数据集的分析表明，MyD88 在小鼠和人类心脏 T 细胞中表达。T 细胞中 MyD88 的缺失导致横主动脉缩窄后心脏 T 细胞浸润和纤维化增加。我们发现，与野生型相比，TCR 激活的 T 细胞在转录组和蛋白质水平上具有更高的促炎信号，导致 T 细胞效应功能增加，如粘附、穿过内皮细胞迁移和激活心脏成纤维细胞。从机制上讲，我们发现 MyD88 通过 TCR 依赖性而不是 TLR 依赖性信号来调节 T 细胞的激活和存活。
我们的研究结果概述了 MyD88 在限制 T 细胞激活中的新的内在作用，这对于在心脏适应压力的过程中调节心脏炎症至关重要。
