Abstract
Autoimmune myocarditis often leads to dilated cardiomyopathy (DCM). Although T cell reactivity to cardiac self-antigen is common in the disease, it is unknown which antigen presenting cell (APC) triggers autoimmunity. Experimental autoimmune myocarditis (EAM) was induced by immunizing mice with α-myosin loaded bone marrow APCs cultured in GM-CSF. APCs found in such cultures include conventional type 2 CD11b+ cDCs (GM-cDC2s) and monocyte-derived cells (GM-MCs). However, only α-myosin loaded GM-cDC2s could induce EAM. We also studied antigen presenting capacity of endogenous type 1 CD24+ cDCs (cDC1s), cDC2s, and MCs for α-myosin-specific TCR-transgenic TCR-M CD4+ T cells. After EAM induction, all cardiac APCs significantly increased and cDCs migrated to the heart-draining mediastinal lymph node (LN). Primarily cDC2s presented α-myosin to TCR-M cells and induced Th1/Th17 differentiation. Loss of IRF4 in Irf4fl/fl.Cd11cCre mice reduced MHCII expression on GM-cDC2s in vitro and cDC2 migration in vivo. However, partly defective cDC2 functions in Irf4fl/fl.Cd11cCre mice did not suppress EAM. MCs were the largest APC subset in the inflamed heart and produced pro-inflammatory cytokines. Targeting APC populations could be exploited in the design of new therapies for cardiac autoimmunity.
Highlights
In acute myocarditis immune and inflammatory cells infiltrate the heart, causing damage to cardiomyocytes, transient heart failure and life threatening arrhythmias [1]
Experimental autoimmune myocarditis (EAM) was initiated in wild type (WT) Balb/c mice by immunization with in vitro GM-CSF-derived bulk bone marrow derived DCs (BMDC) loaded with cardiac αMyHC614−629 peptide according to a published protocol (Figure 1A) [19]
It was observed that CD11c+MHCII+ BMDCs grown in GM-CSF are not a uniform population but consist of conventional dendritic cells (DCs) (GM-cDCs) and monocyte-derived cells (GM-MCs) with a macrophage-like phenotype in C57Bl/6 mice [34]
Summary
In acute myocarditis immune and inflammatory cells infiltrate the heart, causing damage to cardiomyocytes, transient heart failure and life threatening arrhythmias [1]. Whereas cardiac inflammation often disappears spontaneously, a subset of patients progresses to dilated cardiomyopathy (DCM) and chronic heart failure with high mortality [2, 3]. Acute myocarditis is traditionally triggered by coxsackie B3 (CVB3) infection that directly destroys cardiomyocytes as part of their replicative lytic cycle [4]. As adaptive immunity can be triggered by infection or release of danger associated molecular patterns (DAMPs) from dying cells, there is inherent risk of autoimmunity following acute myocarditis. Organ-directed autoimmunity perpetuates inflammation and is a risk factor for DCM development as a result of continuing myocardial injury [5].
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