gamma delta(+) 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 myoc yte necrosis in some, but not all, strains of mice. C57BL/6 mice, which inh erently lack major histocompatibility complex (MHC) class II LE antigen, de velop minimal cardiac lesions despite high levels of virus in the heart. Th e present experiments evaluate the relative roles of class II IA and IE exp ression on myocarditis susceptibility in four transgenic C57BL/6 mouse stra ins differing in MHC class LI antigen expression. Animals lacking MHC class II IE antigen (C57BL/6 [IA(+) IE-] and AB degrees [IA(-) IE-]) developed m inimal cardiac lesions subsequent to infection despite high concentrations of virus in the heart. In contrast, strains expressing IE (AB degrees E alp ha [IA(-) IE+] and Bl.Tg.E alpha [IA(+) IE+]) had substantial cardiac injur y. Myocarditis susceptibility correlated to a Th1 (gamma interferon-positiv e) cell response in the spleen, while disease resistance correlated to a pr eferential Th2 (interleukin-4-positive) phenotype, V gamma/V delta analysis indicates that distinct subpopulations of gamma delta(+) T cells are activ ated after CVB3 infection of C57BL/6 and BI.Tg.E alpha mice. Depletion of g amma delta(+) T cells abrogated myocarditis susceptibility in IE+ animals a nd 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 cell s activated during CVB3 infection, and finally that different subpopulation s of gamma delta(+) T cells may either promote or inhibit Th1 cell response s.