Natural regulatory T cells inhibit production of cytotoxic molecules in CD8(+) T cells during low-level Friend retrovirus infection

BACKGROUND: Cytotoxic T cells (CTL) play a central role in the control of viral infections. Their antiviral activity can be mediated by at least two cytotoxic pathways, namely the granule exocytosis pathway, involving perforin and granzymes, and the Fas-FasL pathway. It was shown that the level of Friend retrovirus (FV) replication determines the cytotoxic pathway for the control of viral infection. In low-level infection only the Fas pathway is active, whereas cytotoxic molecules are not produced. In the current study, we elucidate the role of CD4(+) regulatory T cells (Tregs) in suppressing the exocytosis pathway during an asymptomatic low-level infection. FINDINGS: We show that even a low-level retrovirus infection induced a strong activation and proliferation of natural Tregs. The expanded Tregs suppressed the proliferation of virus-specific CD8(+) T cells and the production of cytotoxic molecules by these cells. Not surprisingly, the in vivo killing activity of these CD8(+) T cells was rather weak. Selective depletion of Foxp3(+) Tregs resulted in de novo granzyme production and augmented virus-specific in vivo killing, but did not affect the low-level virus replication. CONCLUSIONS: Expanded natural Tregs determined the cytotoxic pathways of virus-specific effector CD8(+) T cells during the acute phase of retroviral infection.