Cross-Priming Dendritic Cells Exacerbate Immunopathology After Ischemic Tissue Damage in the Heart

Abstract

Background: 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 HF. 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-MI myocardial impairment through presentation of self-antigen from necrotic cardiomyocytes to cytotoxic CD8 + T cells. Methods: We induced type-2 myocardial infarction (MI)-like ischemic injury in the heart by treatment with a single high dose of the beta-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 Clec9a -depleted mice lacking DC cross-priming function. Results: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a -/- mice deficient in DC cross-priming are protected from long-term immune-mediated myocardial damage and decline of cardiac function, likely due to dampened activation of cytotoxic CD8 + T cells. Conclusions: Activation of cytotoxic CD8 + T cells by cross-priming DC contributes to exacerbation of post-ischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent immune-mediated worsening of post-ischemic HF.

Leukocyte-Mediated Cardiac Repair after Myocardial Infarction in Non-Regenerative vs. Regenerative Systems

“…Although DC numbers decline at day 14 with permanent ligation and at day 7 with reperfusion, these cells are still significantly elevated in comparison to sham controls [57,133]. Further, all DC subsets mobilized, permeated, and matured within the infarcted murine myocardium [95,137].…”

“…Moreover, patients with acute MI had both CD4+ helper cells and Foxp3+ Treg cells within the infarcted region [108]. Patient biopsies also demonstrated an enrichment of CD4+ Th1 and CD8+ T cells in failing hearts, as well as their potential activation with co-localization of T cells and APCs such as macrophages and dendritic cells [95,96]. In adult murine MI models, CD4+, CD8+, and γδ T cells mobilized to the injured myocardium from day 1, peaking at day 7 with permanent occlusion and at day 3 with reperfusion.…”

“…Timing: Accumulate from day 1 post-injury, peak at day 7, and lowered at day 14 with permanent ligation; peaked day 3 with reperfusion and lowered by day 7 [57,133]. Detrimental: Mature DCs worsen ventricular remodeling [134]; prevention of DC mobilization from bone marrow improved cardiac function [135]; depletion of cDCs limited inflammatory response with lowered neutrophil, macrophage, and T-cell infiltration and reduced adverse remodeling [136]; cross-priming cytotoxic T cells for perpetuation of myocardial damage [95,137]; pDCs release IFN-γ and further damaging inflammatory responses [138].…”

Regulatory T Cells in Chronic Heart Failure

“…Cross-priming DCs have the ability to activate both CD4 + T cells and CD8 + cytotoxic T cells. Recently, using Clec9a-depleted mice that were deficient in DC cross-priming, Forte E. et al (68) found that in ischemic HF, cross-priming DCs accumulated in hearts and contributed to the exacerbation of post-ischemic inflammatory damage. These results may remind us of the different roles of DCs in the process of heart injury.…”

Lymphatic Clearance of Immune Cells in Cardiovascular Disease

“…A recent study also shows that a cross-priming DC population is present and activated in the heart following MI. This population activates cytotoxic CD8 + T cells and their deletion reduces myocardial immunopathology and functional decline [58]. DCs can be classified into two major subpopulations: conventional DC (cDC) and plasmacytoid DC (pDC).…”