title: CD28 Deficiency Enhances Type I IFN Production by Murine Plasmacytoid Dendritic Cells.
abstract: Type I IFNs (IFN-I) are key innate mediators that create a profound antiviral state and orchestrate the activation of almost all immune cells. Plasmacytoid dendritic cells (pDCs) are the most powerful IFN-I-producing cells and play important roles during viral infections, cancer, and autoimmune diseases. By comparing gene expression profiles of murine pDCs and conventional DCs, we found that CD28, a prototypic T cell stimulatory receptor, was highly expressed in pDCs. Strikingly, CD28 acted as a negative regulator of pDC IFN-I production upon TLR stimulation but did not affect pDC survival or maturation. Importantly, cell-intrinsic CD28 expression restrained pDC (and systemic) IFN-I production during in vivo RNA and DNA viral infections, limiting antiviral responses and enhancing viral growth early after exposure. Finally, CD28 also downregulated IFN-I response upon skin injury. Our study identified a new pDC regulatory mechanism by which the same CD28 molecule that promotes stimulation in most cells that express it is co-opted to negatively regulate pDC IFN-I production and limit innate responses.
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093; and.
authors.forename: Monica
authors.initials: M
authors.lastname: Macal
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093; and.
authors.forename: Miguel A
authors.identifier: http://orcid.org/0000-0001-8094-7090
authors.initials: MA
authors.lastname: Tam
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093; and.
authors.forename: Charles
authors.identifier: http://orcid.org/0000-0002-6690-3283
authors.initials: C
authors.lastname: Hesser
authors.affiliation: Service de Dermatologie et vénéréologie, Centre Hospitalier Universitaire Vaudois, University Hospital of Lausanne, Lausanne CH-1011, Switzerland.
authors.forename: Jeremy
authors.identifier: http://orcid.org/0000-0002-6281-3918
authors.initials: J
authors.lastname: Di Domizio
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093; and.
authors.forename: Psylvia
authors.initials: P
authors.lastname: Leger
authors.affiliation: Service de Dermatologie et vénéréologie, Centre Hospitalier Universitaire Vaudois, University Hospital of Lausanne, Lausanne CH-1011, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093; and eizuniga@ucsd.edu.
authors.forename: Elina I
authors.initials: EI
authors.lastname: Zuniga
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D018106:CD28 Antigens; D007370:Interferon Type I