In a recent paper in Science, Lund et al.[1] investigated the effect of regulatory T cells (Tregs) on the antiviral immune response to an acute herpes virus infection. Previous studies on the role of Tregs in different viral infections suggested that this T cell population suppresses antiviral effector T cell responses or local immune activation at the sites of viral replication [2, 3], which might subsequently facilitate viral immune evasion and the establishment of chronic infections [4, 5, 6]. Thus, it was quite surprising that ablation of Tregs in HSV-2-infected mice resulted in an accelerated fatal infection with increased viral loads instead of enhanced immunity to the virus [1]. In their fascinating paper, the authors showed that depletion of Tregs amplified the immune responses in draining lymph nodes at the site of infection, but at the same time delayed the entry of the immune cells into the HSV-2-infected tissue. As a general concept, Lund et al. postulated that Tregs promote immune responses in acute infections in which the pathogen replicates in non-lymphoid tissues. However, a number of viruses that induce severe human diseases, like HIV or the measles virus, replicate in primary or secondary lymphoid organs. Therefore, the question arises whether Tregs have a suppressive or promoting effect on antiviral immune responses in infections with viruses that are lymphotropic. We have used the Friend retrovirus (FV) mouse model to address this question. FV is a lymphotropic retroviral complex that replicates efficiently in the spleen of infected mice and can induce a lethal erythroleukemia [7]. It was demonstrated in previous studies that the virus induces a significant expansion of Tregs during acute infection [8]. Similar to Lund et al.[1], we used a transgenic mouse expressing the diphtheria toxin (DT) receptor and GFP under the control of the Foxp3 promoter [9] to selectively deplete Tregs by DT injection during acute FV infection. DT injection into FV-infected mice at days 0, 2, 4, 6, and 8 postinfection depleted all GFP-expressing CD4+ Foxp3+ T cells in the spleen (Figure S1A), which resulted in a slight reduction of the overall CD4+ T cell counts (Figure S1B). However, a small population of cells positive for CD4 and Foxp3 but negative for GFP remained detectable. The DT injection did not significantly influence the overall numbers of CD8+ T cells and CD19+ B cells in the spleen of infected mice, indicating that the general lymphocyte population was not affected. In addition, a recent study clearly indicates that a DT injection into mice expressing a DT receptor/GFP cassette under the control of the Foxp3 promoter leads to a specific ablation of Tregs [10], but not to the depletion of epithelial cells as previously suggested by Liu et al.[11]. Since virus-specific CD8+ T cells are the most important immune cells that control acute FV replication [12], we determined the quantity and quality of these cells in the spleen of mice experimentally ablated of Tregs. At 10 days postinfection, significantly more CD8+ T cells expressing markers of effector T cells (CD43+) were found in the spleen of Treg-depleted mice compared to non-depleted controls (Figure 1A). Treg ablation also enhanced the number of FV-specific CD8+ T cells in the spleen of infected mice, which were stained with a FVgag MHC class I tetramer [4](Figure 1B). In addition to the magnitude of the CD8+ T cell response, we analyzed the functional properties of these T cells. After Treg ablation, the expression of the cytotoxic molecules granzyme A and B in splenic CD8+ T cells was significantly enhanced during acute FV infection (Figure 1C and 1D), suggesting an improved cytotoxic potential of these cells. To verify that the …