Hormonal Regulation of CD4 + T-Cell Responses in Coxsackievirus B3-Induced Myocarditis in Mice

Abstract

ABSTRACT Coxsackievirus B3 infection causes significant cardiac inflammation in male, but not female, B1.Tg.Eα mice. This gender difference in disease susceptibility correlates with selective induction of CD4 + Th1 (gamma interferon-positive) cell responses in animals with testosterone, whereas estradiol promotes preferential CD4 + Th2 (interleukin-4 positive [IL-4 + ]) cell responses. Differences in immune deviation of CD4 + T cells cannot be explained by variation in B7-1 or B7-2 expression. Infection significantly upregulated both molecules, but no differences were detected between estradiol- and testosterone-treated groups. Significantly increased numbers of activated (CD69 + ) T cells expressing the γδ T-cell receptor were found in male and testosterone-treated male and female mice. In vivo depletion of γδ + cells by using monoclonal antibodies inhibited myocarditis and resulted in a shift from a Th1 to Th2 response phenotype. Taken together, our results indicate that testosterone promotes a CD4 + Th1 cell response and myocarditis by promoting increased γδ + cell activation.