Coxsackievirus B3 (CVB3) induces myocarditis in male BALB/c mice. Female mice are resistant to viral myocarditis, except in the third trimester of pregnancy and postpartum. Cardiac damage is mediated by T lymphocytes activated during virus infection. Th1 (interferon-gamma+) cell responses promote cardiac injury, while disease resistance correlates to preferential activation of Th2 (interleukin-4+) cell responses. CVB3-specific Th1 and Th2 cell clones were established, treated with between 0 and 100 ng/ml 17beta estradiol and 4-androsten-17beta-ol-one (testosterone) for two days, 51Cr-labeled and cultured on FasL-transfected 3T3 cells to determine susceptibility to Fas-dependent apoptosis. Testosterone treatment enhanced Th2 cell lysis while estradiol treatment was protective. Staining of Th2 cells for Bcl 2, an anti-apoptotic factor, indicates that Bcl 2 expression increased in these cells with estradiol but decreased with testosterone exposure. Hormone-induced changes in Bcl 2 expression likely explain the selective survival of Th2 cells in females and prevention of viral myocarditis.

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.

It is demonstrated that methotrexate/cisplatin-sensitive L1210 cells express low levels of major histocompatibility complex (MHC) class II relative to the high levels expressed on methotrexate (MTX)/cisplatin-resistant L1210/DDP cells. L1210 cells express cell-surface Fas, while the L1210/DDP cells express no cell-surface Fas. Expression of costimulatory molecules B7-1/B7-2 and Fas is increased on L1210 cells, but not L1210/DDP, in the presence of methotrexate or trimetrexate (TMTX). Therefore, a component of the mechanism of action of some anti-cancer agents may be to facilitate immune recognition and T cell-directed, Fas-induced cell death. Loss of cell-surface Fas expression and failure of Fas (CD95)-dependent apoptotic death has been observed when cells develop drug resistance. The defect in apoptosis can be overcome by anti-cancer agents or experimental manipulation that induce Fas expression on the drug-resistant cells.

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 IE 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 II antigen expression. Animals lacking MHC class II IE antigen (C57BL/6 [IA+ IE−] and ABo [IA− IE−]) developed minimal cardiac lesions subsequent to infection despite high concentrations of virus in the heart. In contrast, strains expressing IE (ABo Eα [IA− IE+] and Bl.Tg.Eα [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. Vγ/Vδ analysis indicates that distinct subpopulations of γδ+ T cells are activated after CVB3 infection of C57BL/6 and Bl.Tg.Eα mice. Depletion of γδ+ T cells abrogated myocarditis susceptibility in IE+ animals and resulted in a Th1→Th2 phenotype shift. These studies indicate that the MHC class II antigen haplotype controls myocarditis susceptibility, that this control is most likely mediated through the type of γδ T cells activated during CVB3 infection, and finally that different subpopulations of γδ+ T cells may either promote or inhibit Th1 cell responses.

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