MyD88 signaling controls autoimmune myocarditis induction

Abstract

Background - Experimental autoimmune myocarditis (EAM) is a CD4+ T-cell-mediated mouse model of postviral cardiomyopathy. Activation of interleukin-1 type 1 and Toll-like receptors that share the common downstream adaptor molecule MyD88 is required for disease induction. The specific role of MyD88 in myocarditis, however, is not known. Methods and Results - In contrast to control littermates, MyD88-/- mice were protected from myocarditis after immunization with α-myosin heavy chain-derived peptide (MyHC-α) and complete Freund's adjuvant. Disease resistance of MyD88 -/- mice resulted from impaired expansion of heart-specific CD4 + T cells after immunization. Intrinsic defects of MyD88 -/- CD4+ T cells were excluded. In contrast, MyD88 -/- but not MyD88+/+ primary antigen presenting dendritic cells (DCs) were defective in their capacity to prime CD4+ T cells. This defect mainly resulted from the inability of MyD88-/- DCs to release tumor necrosis factor-α. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-α-loaded MyD88+/+ DCs that fully restored T-cell expansion and myocarditis in MyD88-/- mice. Conclusions - Autoimmune myocarditis induction depends on MyD88 signaling in self-antigen presenting cells in the peripheral compartments. We conclude that MyD88 might become a target for prevention of heart-specific autoimmunity and cardiomyopathy. © 2006 American Heart Association, Inc.