title: Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence.
abstract: Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Cameron R
authors.initials: CR
authors.lastname: Cunningham
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Ameya
authors.initials: A
authors.lastname: Champhekar
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Tullius
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Barbara Jane
authors.initials: BJ
authors.lastname: Dillon
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, UCLA AIDS Institute and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Anjie
authors.initials: A
authors.lastname: Zhen
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Justin Rafael
authors.initials: JR
authors.lastname: de la Fuente
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Herskovitz
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.|Princess Margaret Cancer Center, Immune Therapy Program, University Health Network, Toronto, Ontario.
authors.forename: Heidi
authors.initials: H
authors.lastname: Elsaesser
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.|Princess Margaret Cancer Center, Immune Therapy Program, University Health Network, Toronto, Ontario.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Snell
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Wilson
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de la Torre
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, UCLA AIDS Institute and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Kitchen
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Horwitz
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bensinger
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smale
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.|Princess Margaret Cancer Center, Immune Therapy Program, University Health Network, Toronto, Ontario.|Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Brooks
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006678:HIV; D015658:HIV Infections / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007372:Interferons / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D007372:Interferons