Activation of Dendritic Cells through the Interleukin 1 Receptor 1 Is Critical for the Induction of Autoimmune Myocarditis

Abstract

Dilated cardiomyopathy, resulting from myocarditis, is the most common cause of heart failure in young patients. We here show that interleukin (IL)-1 receptor type 1–deficient (IL-1R1^−/−) mice are protected from development of autoimmune myocarditis after immunization with α-myosin-peptide(614–629). CD4⁺ T cells from immunized IL-1R1^−/− mice proliferated poorly and failed to transfer disease after injection into naive severe combined immunodeficiency (SCID) mice. In vitro stimulation experiments suggested that the function of IL-1R1^−/−CD4⁺ T cells was not intrinsically defect, but their activation by dendritic cells was impaired in IL-1R1^−/− mice. Accordingly, production of tumor necrosis factor (TNF)-α, IL-1, IL-6, and IL-12p70 was reduced in dendritic cells lacking the IL-1 receptor type 1. In fact, injection of immature, antigen-loaded IL-1R1^+/+ but not IL-1R1^−/− dendritic cells into IL-1R1^−/− mice fully restored disease susceptibility by rendering IL-1R1^−/− CD4⁺ T cells pathogenic. Thus, IL-1R1 triggering is required for efficient activation of dendritic cells, which is in turn a prerequisite for induction of autoreactive CD4⁺ T cells and autoimmunity.