Natural regulatory T cells inhibit production of cytotoxic molecules in CD8+T cells during low-level Friend retrovirus infection
© Zelinskyy et al.; licensee BioMed Central Ltd. 2013
Received: 5 June 2013
Accepted: 10 October 2013
Published: 24 October 2013
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.
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.
Expanded natural Tregs determined the cytotoxic pathways of virus-specific effector CD8+ T cells during the acute phase of retroviral infection.
KeywordsFriend retrovirus Treg Foxp3 Granzyme CTL
CD8+ cytotoxic T cells (CTL) can eliminate target cells by at least two independent cytolytic pathways, the granule exocytosis pathway and the Fas-FasL pathway . Previously, we compared the CTL response against low-and high-level Friend retrovirus (FV) infection of mice . Low-level infection induced moderate activation of CD8+ T cells expressing only FasL, whereas high-level infection resulted in extensive expansion of CD8+ effector T cells secreting molecules of the exocytosis pathway. In an in vitro model of HBV infection  it was also described that virus antigen levels were critical for regulating the quality of antigen-specific CD8+ T cells. It was concluded that stronger antigen stimulation is needed for the production of granzymes compared to FasL . Along these lines, a certain density of antigen presented on DC was necessary for the differentiation of cytotoxic CD8+ T cells . These publications acknowledge the significance of antigen levels for CD8+ T cell cytotoxicity, whereas the mechanisms that suppress the production of cytotoxic molecules in low-level virus infections were unknown. In addition, most of our basic concepts on the regulation of acute anti-viral immune responses are derived from model infections with high viral loads (e.g. LCMV), whereas the immune responses to low-level asymptomatic infections are poorly defined. A more detailed understanding of such infection courses is very important especially in chronic viral infections as acute viral loads have been shown to correlate significantly with chronic viral set points and onset of chronic disease in infections like HCV or HIV [6, 7]. In HCV infected patients, an acute low-level asymptomatic infection even results significantly more often in chronicity and thus is a negative prognostic factor .
The work was supported by the DFG Transregio 60, project B4.
We thank Tim Sparwasser (Institute for Infection Immunology, TWINCORE, Hannover, Germany) for providing DEREG mice, and Markus Simon (Max-Plank-Institut für Immunbiology, Freiburg, Germany) for providing the anti-granzyme A antibodies. We thank the NIH tetramer facility for providing MHC class II tetramers.
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