Differential Effect of Human Herpesvirus 6A on Cell Division and Apoptosis among Naïve and Central and Effector Memory CD4 + and CD8 + T-Cell Subsets

Abstract

The immune responses of naive and different memory subsets of CD4(+) and CD8(+) T cells to human herpesvirus 6 (HHV-6) have not been previously investigated. We show that HHV-6A induces cell division, as measured by 5,6-carboxyfluorescein succinimidyl ester dye and flow cytometry, predominantly in two populations of effector memory CD4(+) and CD8(+) T cells (T(EM) and T(EMRA)); naïve (T(N)) and central memory (T(CM)) CD4(+) and CD8(+) T cells showed almost no cell division. In contrast, HHV-6A induced apoptosis primarily in T(N) and T(CM) CD4(+) and CD8(+) T cells, whereas T(EM) and T(EMRA) CD4(+) and CD8(+) T cells were resistant to HHV-6A-induced apoptosis. HHV-6A-induced apoptosis was associated with activation of caspase-8, caspase-9, and caspase-3, suggesting the involvement of death receptor and mitochondrial signaling pathways. In addition, HHV-6A induced secretion of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), IL-8, and gamma interferon by peripheral blood mononuclear cells; TNF-alpha secretion was observed exclusively from CCR7(+) (T(N) plus T(CM)) CD4(+) T cells. These data show that HHV-6 differentially influences the functions of naïve T cells and different subsets of memory CD4(+) and CD8(+) T cells, which in part may be due to differential susceptibility to HHV-6A-induced apoptosis.