In FY2016 we have made progress in the following areas: 1) Following infection with many viral pathogens, the virus first encounters components of the innate immune system that generate inflammatory signals that can initially control the infection, but the adaptive immune response is critical in determining whether the infection is ultimately cleared or becomes chronic. Signaling through the Type I IFN receptor (IFN/R or IFNAR) expressed on CD8+ and CD4+ T cells is required for Teff expansion and survival. During infection with (LCMV Type I IFNs are produced in large quantities immediately following viral infection. To examine the role of IFNAR signaling in Tregs in chronic viral infection, we infected mice with a Treg-specific deletion of the IFNAR with LCMV clone 13. Both CD4+ and CD8+ Teff cells of mice with a Treg-specific deletion of the IFNAR exhibited enhanced exhaustion. The number of LCMV antigen-specific memory CD8+ T cells was decreased and the remaining virus-specific T cells produced less IFN-gamma and TNF-alpha than CD8+ T cells from infected wild type (WT) mice. At day 46 post-infection, higher viral titers were found in spleen, liver and kidney of the mice with a Treg-specific IFNAR deletion. Similar results were observed after acute infection with LCMV Armstrong. These results are consistent with the view that type I IFNs inhibit Treg function during the course of both acute and chronic viral infection. 2.Previous studies have shown that IFNAR KO mice, following immunization with MOG, developed exacerbated clinical EAE with enhanced lethality. Mice with a deletion of the IFNAR in T, B, or neuroectodermal cells exhibited a normal disease course, while mice with a deletion of the IFNAR on myeloid cells developed severe disease. The authors of this study concluded that monocytes and macrophages and microglia, are the IFNAR-dependent myeloid cells critical in shaping CNS autoimmunity. One difficulty with interpretation of this study is that the authors used IFNARfl/fl X CD4Cre mice and thereby deleted the IFNAR from both Tconv cells and Tregs. When we induced EAE in IFNARfl/fl X Foxp3Cre mice, they developed more severe EAE than WT mice. While the number of total Teff cells in the spinal cord is higher in the IFNARfl/fl X Foxp3Cre mice compared to WT, the percentages of CD4+ Teff cells (secreting IFN-gamma or IL-17 or both) is not different. One other cell type that has been shown to play an immnmodulatory role in EAE is the granulocytic-myeloid-derived suppressor cell (Gr-MDSC) . Draining LNs of WT mice contained a significant number of Gr-MDSC, while they were barely detectable in the LNs of the IFNARfl/fl X Foxp3Cre animals. In contrast, the percentage of monocytic-derived MDSC was comparable in the WT and KO mice. These results suggest a complex cross-talk between Type I IFNs, Tregs, and Gr-MDSC resulting in suppression of autoimmune disease.
