Toronto General Hospital Research Institute, University Health Network (UHN), Toronto ON, M5G 1L7, Canada.
Toronto General Hospital Research Institute, University Health Network (UHN), Toronto ON, M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto ON, M5S 1A1, Canada.
Immunity. 2017 Nov 21;47(5):974-989.e8. doi: 10.1016/j.immuni.2017.10.011.
Innate and adaptive immune cells modulate heart failure pathogenesis during viral myocarditis, yet their identities and functions remain poorly defined. We utilized a combination of genetic fate mapping, parabiotic, transcriptional, and functional analyses and demonstrated that the heart contained two major conventional dendritic cell (cDC) subsets, CD103 and CD11b, which differentially relied on local proliferation and precursor recruitment to maintain their tissue residency. Following viral infection of the myocardium, cDCs accumulated in the heart coincident with monocyte infiltration and loss of resident reparative embryonic-derived cardiac macrophages. cDC depletion abrogated antigen-specific CD8 T cell proliferative expansion, transforming subclinical cardiac injury to overt heart failure. These effects were mediated by CD103 cDCs, which are dependent on the transcription factor BATF3 for their development. Collectively, our findings identified resident cardiac cDC subsets, defined their origins, and revealed an essential role for CD103 cDCs in antigen-specific T cell responses during subclinical viral myocarditis.
固有免疫和适应性免疫细胞在病毒性心肌炎期间调节心力衰竭的发病机制，但它们的身份和功能仍未得到明确界定。我们利用遗传谱系追踪、联体共生、转录组和功能分析相结合的方法，证明心脏包含两个主要的经典树突状细胞（cDC）亚群，CD103 和 CD11b，它们通过局部增殖和前体细胞募集来维持组织驻留的方式不同。心肌病毒感染后，cDC 与单核细胞浸润和常驻修复性胚胎来源的心脏巨噬细胞的丢失同时在心脏中积累。cDC 耗竭消除了抗原特异性 CD8 T 细胞的增殖扩张，将亚临床心脏损伤转化为显性心力衰竭。这些作用是由 CD103 cDC 介导的，其发育依赖于转录因子 BATF3。总之，我们的研究结果确定了驻留心脏 cDC 亚群，定义了它们的起源，并揭示了 CD103 cDC 在亚临床病毒性心肌炎期间抗原特异性 T 细胞反应中的重要作用。
