Figure 1

CVB3 up-regulates CD1d on dendritic cells and non-hemopoietic cells such as cardiac myocytes. CD1d-glycolipid complexes on dendritic cells activate NKT and Vγ4+ T cells which kill virus infected cells limit virus infections, while the activated NKT/Vγ4+ cells also alter dendritic cells. CTLR4 expression by NKT cells either blocks or down-regulates B7 co-stimulatory molecules inhibiting antigen presentation to antigen-specific CD4+ and CD8+ T cells, and promoting inducible Tregulatory cell activation through release of TGFβ, IL-10 and IL-2. TNFα and IFNγ secretion by Vγ4+ T cells enhances maturation and antigen presentation by dendritic cells but suppresses activation of the inducible Tregulatory cell. CVB3 infection up-regulates CD1d expression on a subpopulation of CD4+CD25+FoxP3+ Tregulatory cells. The CD1d+Tregulatory cells are substantially more immunosuppressive than CD1d- Tregulatory cells and are primarily responsible for preventing autoimmunity to cardiac antigens and myocarditis during CVB3 infection. Vγ4+ T cells selectively kill CD1d+ T regulatory cells through caspase-dependent apoptosis which then results in autoimmunity induction. Thus, pathogenesis in CVB3 infection depends upon the balance in NKT and Vγ4+ T cell activation.