Pleiotropic, immunomodulatory effects of type I IFN on T cell responses are emerging. We used vaccine-induced, antiviral CD8+ T cell responses in IFN-β (IFN-β−/−)-or type I IFN receptor (IFNAR−/−)-deficient mice to study immunomodulating effects of type I IFN that are not complicated by the interference of a concomitant virus infection. Compared with normal B6 mice, IFNAR−/− or IFN-β−/− mice have normal numbers of CD4+ and CD8+ T cells, and CD25+ FoxP3+ T regulatory (T R) cells in liver and spleen. Twice as many CD8+ T cells specific for different class I-restricted epitopes develop in IFNAR−/− or IFN-β−/− mice than in normal animals after peptide-or DNA-based vaccination. IFN-γ and TNF-α production and clonal expansion of specific CD8+ T cells from normal and knockout mice are similar. CD25+ FoxP3+ T R cells down-modulate vaccine-primed CD8+ T cell responses in normal, IFNAR−/−, or IFN-β−/− mice to a comparable extent. Low IFN-α or IFN-β doses (500–10 3 U/mouse) down-modulate CD8+ T cells priming in vivo. IFNAR-and IFN-β-deficient mice generate 2-to 3-fold lower numbers of IL-10-producing CD4+ T cells after polyclonal or specific stimulation in vitro or in vivo. CD8+ T cell responses are thus subjected to negative control by both CD25+ FoxP3+ T R cells and CD4+ IL-10+ T R1 cells, but only development of the latter T R cells depends on type I IFN.