Innate Signalling Promotes Formation of Regulatory Nitric Oxide-Producing Dendritic Cells Limiting T Cell Expansion in Experimental Autoimmune Myocarditis
Background—Activation of innate pattern recognition receptors promotes CD4+ T cell-mediated autoimmune myocarditis and subsequent inflammatory cardiomyopathy. Mechanisms, which counter-regulate exaggerated heart-specific autoimmunity are poorly understood.
Methods and Results—Experimental Autoimmune Myocarditis (EAM) was induced in BALB/c mice by immunization with alpha-myosin heavy chain peptide (αMyHC) and complete Freund's adjuvant (CFA). Together with IFN-γ, heat-killed M. tuberculosis (Mtbhk), an essential component of CFA, converted CD11bhiCD11c- monocytes into TNFα- and nitric oxide synthase 2 (NOS2)-producing dendritic cells (TipDCs). Mtbhk stimulated NOS2 production via Toll-like receptor (TLR)2-mediated NF-κB activation. TipDCs limited antigen-specific T cell expansion through NOS2-dependent nitric oxide production. Moreover, TipDCs promoted NOS2 production in hematopoietic and stromal cells in a paracrine manner. Consequently, NOS2 production by both, radiosensitive hematopoietic and radioresistant stromal cells prevented exacerbation of autoimmune myocarditis in vivo.
Conclusions—Innate TLR2 stimulation promotes formation of regulatory TipDCs, which confine autoreactive T cell responses in EAM via nitric oxide. Therefore, activation of innate pattern recognition receptors is not only critical for disease induction, but also for counter-regulatory mechanisms, protecting the heart from exaggerated autoimmunity.
- Received December 5, 2012.
- Revision received April 8, 2013.
- Accepted April 17, 2013.