γδ+ T cells regulate major histocompatibility complex class II (IA and IE)-dependent susceptibility to coxsackievirus B3-induced autoimmune myocarditis

Coxsackievirus B3 (CVB3) infection induces myocardial inflammation and myocyte necrosis in some, but not all, strains of mice. C57BL/6 mice, which inherently lack major histocompatibility complex (MHC) class II LE antigen, develop minimal cardiac lesions despite high levels of virus in the heart. The present experiments evaluate the relative roles of class II IA and IE expression on myocarditis susceptibility in four transgenic C57BL/6 mouse strains differing in MHC class LI antigen expression. Animals lacking MHC class II IE antigen (C57BL/6 [IA(+) IE-] and AB degrees [IA(-) IE-]) developed minimal cardiac lesions subsequent to infection despite high concentrations of virus in the heart. In contrast, strains expressing IE (AB degrees E alpha [IA(-) IE+] and Bl.Tg.E alpha [IA(+) IE+]) had substantial cardiac injury. Myocarditis susceptibility correlated to a Th1 (gamma interferon-positive) cell response in the spleen, while disease resistance correlated to a preferential Th2 (interleukin-4-positive) phenotype, V gamma/V delta analysis indicates that distinct subpopulations of gamma delta(+) T cells are activated after CVB3 infection of C57BL/6 and BI.Tg.E alpha mice. Depletion of gamma delta(+) T cells abrogated myocarditis susceptibility in IE+ animals and resulted in a Th1-->Th2 phenotype shift. These studies indicate that the MWC class II. antigen haplotype controls myocarditis susceptibility, that this control is most likely mediated through the type of gamma delta T cells activated during CVB3 infection, and finally that different subpopulations of gamma delta(+) T cells may either promote or inhibit Th1 cell responses.