Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence
| Autor: | Ameya Champhekar, Michael V. Tullius, Scott G. Kitchen, Elizabeth B. Wilson, Anjie Zhen, Marcus A. Horwitz, Laura M. Snell, David G. Brooks, Jonathan Herskovitz, Cameron R. Cunningham, Juan Carlos de la Torre, Steven J. Bensinger, Barbara Jane Dillon, Stephen T. Smale, Heidi Elsaesser, Justin Rafael de la Fuente |
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| Přispěvatelé: | Loke, P'ng |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment T-Lymphocytes Cell HIV Infections Inbred C57BL Immune tolerance Mice 0302 clinical medicine Interferon Neoplasms Lymphocytic choriomeningitis virus lcsh:QH301-705.5 Oligonucleotide Array Sequence Analysis Mice Knockout Immunosuppression Flow Cytometry 3. Good health medicine.anatomical_structure Infectious Diseases Virus Diseases Medical Microbiology 030220 oncology & carcinogenesis Infection Research Article medicine.drug lcsh:Immunologic diseases. Allergy T cell Knockout Immunology Enzyme-Linked Immunosorbent Assay Biology Lymphocytic Choriomeningitis Lymphocytic choriomeningitis Real-Time Polymerase Chain Reaction Microbiology Vaccine Related 03 medical and health sciences Biodefense Virology Genetics medicine Immune Tolerance Animals Tuberculosis Molecular Biology Animal Monocyte Prevention Inflammatory and immune system HIV Dendritic cell Dendritic Cells medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Emerging Infectious Diseases Good Health and Well Being lcsh:Biology (General) Disease Models Parasitology Interferons lcsh:RC581-607 |
| Zdroj: | PLoS pathogens, vol 12, iss 1 PLoS Pathogens, Vol 12, Iss 1, p e1005356 (2016) PLoS Pathogens |
| Popis: | 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. Author Summary Persistent virus infections induce host derived immunosuppressive factors that attenuate the immune response and prevent control of infection. Although the mechanisms of T cell exhaustion are being defined, we know surprisingly little about the underlying mechanisms that induce the immunosuppressive state and the origin and functional programming of the cells that deliver these signals to the T cells. We recently demonstrated that type I interferon (IFN-I) signaling was responsible for many of the immune dysfunctions associated with persistent virus infection and in particular the induced expression of the suppressive factors IL-10 and PDL1 by dendritic cells (DCs). Yet, mechanistically how IFN-I signaling specifically generates and programs cells to become immunosuppressive is still unknown. Herein, we define the underlying mechanisms of IFN-I mediated immunosuppression and establish that the induction of factors and the generation of the DCs that express them are separable events integrally reliant on additional inflammatory factors. Further, we demonstrate a similar derivation of the suppressive DCs that emerge in other diseases associated with prolonged inflammation and immunosuppression, specifically in HIV infection, Mycobacterium tuberculosis, and cancer, indicating a conserved origin of immunosuppression and suggesting that targeting the pathways that underlie expression of immunosuppressive cells and factors could be beneficial to treat multiple chronic diseases. |
| Databáze: | OpenAIRE |
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