Innate Signaling Promotes Formation of Regulatory Nitric Oxide–Producing Dendritic Cells Limiting T-Cell Expansion in Experimental Autoimmune Myocarditis
Abstract
Background—Activation of innate pattern-recognition receptors promotes CD4+ T-cell–mediated autoimmune myocarditis and subsequent inflammatory cardiomyopathy. Mechanisms that counterregulate exaggerated heart-specific autoimmunity are poorly understood.
Methods and Results—Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with α-myosin heavy chain peptide and complete Freund’s adjuvant. Together with interferon-γ, heat-killedMycobacterium tuberculosis, an essential component of complete Freund’s adjuvant, converted CD11bhiCD11c− monocytes into tumor necrosis factor-α– and nitric oxide synthase 2–producing dendritic cells (TipDCs). Heat-killed M. tuberculosis stimulated production of nitric oxide synthase 2 via Toll-like receptor 2–mediated nuclear factor-κB activation. TipDCs limited antigen-specific T-cell expansion through nitric oxide synthase 2–dependent nitric oxide production. Moreover, they promoted nitric oxide synthase 2 production in hematopoietic and stromal cells in a paracrine manner. Consequently, nitric oxide synthase 2 production by both radiosensitive hematopoietic and radioresistant stromal cells prevented exacerbation of autoimmune myocarditis in vivo.
Conclusions—Innate Toll-like receptor 2 stimulation promotes formation of regulatory TipDCs, which confine autoreactive T-cell responses in experimental autoimmune myocarditis via nitric oxide. Therefore, activation of innate pattern-recognition receptors is critical not only for disease induction but also for counterregulatory mechanisms, protecting the heart from exaggerated autoimmunity.