Figure 4

Casitas-B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, negatively regulates T cell responses, and plays a crucial in T cell tolerance. Cbl-b polymorphisms have been shown to be associated with several autoimmune diseases including type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Indeed, Cblb–/– mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) which are believed to be mediated by Th17, a newly identified CD4+ subset. We and others have shown that experimental autoimmune myocarditis (EAM), an animal model of human autoimmune myocarditis which occurs in a small subset of patients after acute cardiotropic viral infection and can lead to dilated cardiomyopathy (DCM), is also mediated by Th17 cells. However, although mice lacking Cbl-b develop severe myocarditis, surprisingly, Cbl-b deficiency in T cells is not the primary driving force for severe disease. Further analysis indicates that Cbl-b does not seem to inhibit Th17 cell differentiation. These data suggest that the severe myocarditis observed in Cblb–/– mice may not be due to the loss of Cbl-b in T cells but rather in antigen presenting cells (APCs). In support of this notion, Dectin-1, -2 and -3 degradation is compromised in macrophages lacking Cbl-b upon triggering with their ligands. As Dectin family of CLRs are major receptors for the potent mycobacterial adjuvants, and are crucial for the development of Th17 responses, we hypothesize that the Cbl-b targets Dectin CLR for ubiquitination and degradation in the lysosome in macrophages, which then suppresses Th17 responses and susceptibility to EAM. In this proposal, we will investigate whether Cbl-b deficiency in macrophages results in severe myocarditis and heightened Th17 responses; and whether and how Cbl-b regulates Th17 responses and myocarditis via targeting Dectin family of CLR for ubiquitination in macrophages. A better understanding of the cellular and molecular mechanisms involved in aberrant Th17 responses in EAM and possibly in subset of human myocarditis may provide a useful approach to develop novel strategies against a devastating heart disease.