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Type I IFN Negatively Regulates CD8⁺ T Cell Responses through IL-10-Producing CD4⁺ T Regulatory 1 Cells¹

Nektarios Dikopoulos^2,*, Antonio Bertoletti, Andrea Kröger, Hansjörg Hauser, Reinhold Schirmbeck^* and Jörg Reimann^*

^* Department of Medical Microbiology and Immunology, University of Ulm, Ulm, Germany; Institute of Hepatology, University College of London, London, United Kingdom; and German Research Centre for Biotechnology, Braunschweig, Germany

Pleiotropic, immunomodulatory effects of type I IFN on T cell responses are emerging. We used vaccine-induced, antiviral CD8⁺ T cell responses in IFN- (IFN-^–/–)- 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-^–/– 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-^–/– mice than in normal animals after peptide- or DNA-based vaccination. IFN- and TNF- 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-^–/– mice to a comparable extent. Low IFN- or IFN- doses (500–10³ U/mouse) down-modulate CD8⁺ T cells priming in vivo. IFNAR- and IFN--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.

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