The Jackson Laboratory, Bar Harbor, ME (E.F., B.P., T.M.D., D.A.S., J.B., M.B.F., M.G.H., N.R.).
National Heart and Lung Institute, Imperial College London, UK (A.S., H.S.K., A.P., C.J., M.A., R.A.C., M.B., M.D.S., S.E.H., F.S.N., N.R., S.S.).
Circulation. 2021 Feb 23;143(8):821-836. doi: 10.1161/CIRCULATIONAHA.120.044581. Epub 2020 Dec 10.
Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of heart failure. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells, and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4 helper and CD8 cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross-priming DC in post-myocardial infarction immunopathology through presentation of self-antigen from necrotic cardiac cells to cytotoxic CD8 T cells.
We induced type 2 myocardial infarction-like ischemic injury in the heart by treatment with a single high dose of the β-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long-term cardiac immunopathology and functional decline in wild type and -depleted mice lacking DC cross-priming function.
A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. mice deficient in DC cross-priming are protected from persistent immune-mediated myocardial damage and decline of cardiac function, likely because of dampened activation of cytotoxic CD8 T cells.
Activation of cytotoxic CD8 T cells by cross-priming DC contributes to exacerbation of postischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent postischemic immunopathology and heart failure.
缺血性心脏病是心力衰竭的主要原因，尽管有先进的治疗选择，发病率和死亡率仍然很高。尽管已经广泛研究了心肌细胞死亡引起的急性炎症，但随后的适应性免疫活性和抗心脏自身免疫也可能导致心力衰竭的发展。在心肌缺血损伤后，树突状细胞（DC）对心肌细胞坏死作出反应，将心脏抗原呈递给 T 细胞，并可能引发针对心脏的持续性自身免疫反应。交叉呈递 DC 具有在响应坏死细胞时激活 CD4 辅助和 CD8 细胞毒性 T 细胞的能力，因此可能是加剧针对心脏的自身免疫的关键因素。本研究通过将坏死的心脏细胞的自身抗原呈递给细胞毒性 CD8 T 细胞，研究了交叉呈递 DC 在心肌梗死后免疫病理学中的作用。
我们通过单次给予高剂量β-肾上腺素能激动剂异丙肾上腺素诱导类似于 2 型心肌梗死的缺血性损伤。我们对心脏和纵隔淋巴结中的 DC 群体进行了特征描述，并分析了野生型和缺乏 DC 交叉呈递功能的耗尽型小鼠的长期心脏免疫病理学和功能下降。
在缺血性损伤后，心脏和激活的心脏中存在多种 DC 群体，包括交叉呈递 DC。缺乏 DC 交叉呈递功能的小鼠可免受持续的免疫介导的心肌损伤和心功能下降的影响，这可能是由于细胞毒性 CD8 T 细胞的激活受到抑制。
交叉呈递 DC 激活细胞毒性 CD8 T 细胞有助于加重缺血后心肌炎症损伤和相应的心功能下降。重要的是，这为预防缺血后免疫病理学和心力衰竭提供了新的治疗靶点。
