A CD103+ Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis

Abstract

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.

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions

“…High numbers of mast cells are found in mice susceptible to autoimmune heart disease after CVB3 infection 86 . Viral infection also leads to the recruitment of natural killer cells 87,88 and dendritic cells 89 , which prevent the development of myocarditis. In mice with enterovirus-induced myocarditis, signalling mediated by the activating receptor NKG2D in natural killer cells was found to protect against progression to inflammatory cardiomyopathy, leading to effective clearance of CVB3 from the heart 87 .…”

“…In mice with enterovirus-induced myocarditis, signalling mediated by the activating receptor NKG2D in natural killer cells was found to protect against progression to inflammatory cardiomyopathy, leading to effective clearance of CVB3 from the heart 87 . Dendritic cells have been reported to accumulate in the mouse heart after viral infection of the myocardium, coincident with monocyte infiltration and loss of resident reparative, embryonic cardiac macrophages 89 . After ingesting dead and damaged cardiomyocytes, dendritic cells migrate to regional lymph nodes and the spleen to present antigens to naive B cells and T cells, which initiates the activation of the adaptive immune response.…”

“…After ingesting dead and damaged cardiomyocytes, dendritic cells migrate to regional lymph nodes and the spleen to present antigens to naive B cells and T cells, which initiates the activation of the adaptive immune response. The relevance of dendritic cells as antigen-presenting cells has been demonstrated in mouse studies showing that cardiac dendritic cell depletion abrogated the generation of antigen-specific CD8 + T cells, promoting the progression of subclinical cardiac injury into overt HF 89 . Dendritic cells can also process endogenous antigens and, therefore, might also trigger autoimmune myocarditis.…”

Leukocyte-Dependent Regulation of Cardiac Fibrosis

“…These cDCs have been shown to mediate tolerance to self-antigens (Van der Borght et al, 2017). DCs become of even greater relevance as the heart experiences injury (Clemente-Casares et al, 2017;Van der Borght et al, 2017;Wang et al, 2017). Their specific roles in pathology, especially in relation to cardiac fibrosis, is distinct; we consider them below.…”

“…For instance, patients with DCM have decreased DCs compared to controls, and experience enhanced fibrosis and worsened cardiac function (Pistulli et al, 2013). There are also additional studies, focused on myocarditis, which suggest protective DC roles following injury (Clemente-Casares et al, 2017). A specific deletion of cardiac CD103 + DCs results in significantly enhanced fibrosis following viral myocarditis, which suggests the role of DCs in blunting the transition to HF following injury (Clemente-Casares et al, 2017).…”