Effective chemokine secretion by dendritic cells and expansion of cross-presenting CD4-/CD8+ dendritic cells define a protective phenotype in the mouse model of coxsackievirus myocarditis

Enteroviruses such as coxsackievirus B3 (CVB3) are able to induce lethal acute and chronic myocarditis. In resistant C57BL/6 mice, CVB3 myocarditis is abrogated by T-cell-dependent mechanisms, whereas major histocompatibility complex (MHC)-matched permissive A.BY/Snj mice develop chronic myocarditis based on virus persistence. To define the role of T-cell-priming dendritic cells (DCs) in the outcome of CVB3 myocarditis, DCs were analyzed in this animal model in the course of CVB3 infection. In both mouse strains, DCs were found to be infectible with CVB3; however, formation of infectious virions was impaired. In DCs derived from C57BL/6 mice, significantly higher quantities of interleukin-10 (IL-10) and the proinflammatory cytokines IL-6 and tumor necrosis factor alpha were measured compared to those from A.BY/SnJ mice. Additionally, the chemokines interferon-inducible protein 10 (IP-10) and RANTES were secreted by DCs from resistant C57BL/6 mice earlier in infection and at significantly higher levels. The protective role of IP-10 in CVB3 myocarditis was confirmed in IP-10(-/-) mice, which had increased myocardial injury compared to the immunocompetent control animals. Also, major differences in resistant and permissive mice were found in DC subsets, with C57BL/6 mice harboring more cross-priming CD4(-) CD8(+) DCs. As CD4(-) CD8(+) DCs are known to express 10 times more Toll-like receptor 3 (TLR3) than other DC subsets, we followed the course of CVB3 infection in TLR3(-/-) mice. These mice developed a fulminant acute myocarditis and secreted sustained low amounts of type I interferons; secretion of IP-10 and RANTES was nearly abrogated in DCs. We conclude that MHC-independent genetic factors involving DC-related IP-10 secretion and TLR3 expression are beneficial in the prevention of chronic coxsackievirus myocarditis.