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

Abstract

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 (TR) 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+ TR 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 (500–103 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+ TR cells and CD4+IL-10+ TR1 cells, but only development of the latter TR cells depends on type I IFN.

Genetic susceptibility to PolyI:C-induced IFNα/β-dependent accelerated disease in lupus-prone mice

“…This effect could be due to the induction of increased levels of IFNg in IFNAR À/À mice, a phenomenon that has previously been described. 33 In agreement with this idea, we found that polyI:C-treated IFNAR À/À (B6.Nba2 Â NZW)F1 mice expressed an increased ratio of IgG2a to IgG1, a known response to IFNg. Alternatively, this difference might be owing to the diverse genetic background of the two crosses, that is, the lack of NZW-derived suppressor (Sles) genes 34 or the introduction of additional 129-derived susceptibility loci in IFNAR-targeted (B6.Nba2 Â NZW)F1 offspring.…”

Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor

“…These IL-10-producing Treg-like cells induced by DC-sTNFRI could significantly inhibit the proliferation of syngeneic CD4 ϩ T cells in response to allogeneic Ag. Although IL-10 plays a key role in the development of IL-10-producing T cells (1,46), and other studies report that IL-10 is crucial in T regulatory cell-mediated immune tolerance in vivo (47)(48)(49), the current data show that the anti-TGF-␤ Ab can reverse the inhibitory function of Treg-like cells. Consistent with other studies, although the resulting Treg-like cells produce high levels of IL-10, their high levels of expression of TGF-␤, CTLA-4, the transcription factor Foxp3, and cell contact-dependent mechanisms may lead to potent inhibitory effects on T cells (42,49).…”

IL-20 Receptor 2 Signaling Down-Regulates Antigen-Specific T Cell Responses

“…Spleen cells (1 ϫ 10 7 /ml) were incubated for 4 h in RPMI 1640 medium with 1 g/ml K b /S 190-197 VWLSVIWM or K b OVA 257-264 SIINFEKL or nonspecific control peptides, as described (25). After 1 h, brefeldin A (BFA) was added.…”

“…Cytokines in supernatants were either detected by conventional doublesandwich ELISA (IL-2, IFN-␥, IL-10) using detection and capture Abs from BD Biosciences, as described (25), or by flow cytometry (Fluorikine xMAP Technology, on workstations with Luminex IS Software v2.3). For conventional ELISAs, extinction was measured at 405/490 nm on a TECAN microplate-ELISA reader (TECAN) using the EasyWin software (TECAN).…”