title: Type I IFN induces IL-10 production in an IL-27-independent manner and blocks responsiveness to IFN-γ for production of IL-12 and bacterial killing in Mycobacterium tuberculosis-infected macrophages.
abstract: Tuberculosis, caused by the intracellular bacterium Mycobacterium tuberculosis, currently causes ∼1.4 million deaths per year, and it therefore remains a leading global health problem. The immune response during tuberculosis remains incompletely understood, particularly regarding immune factors that are harmful rather than protective to the host. Overproduction of the type I IFN family of cytokines is associated with exacerbated tuberculosis in both mouse models and in humans, although the mechanisms by which type I IFN promotes disease are not well understood. We have investigated the effect of type I IFN on M. tuberculosis-infected macrophages and found that production of host-protective cytokines such as TNF-α, IL-12, and IL-1β is inhibited by exogenous type I IFN, whereas production of immunosuppressive IL-10 is promoted in an IL-27-independent manner. Furthermore, much of the ability of type I IFN to inhibit cytokine production was mediated by IL-10. Additionally, type I IFN compromised macrophage activation by the lymphoid immune response through severely disrupting responsiveness to IFN-γ, including M. tuberculosis killing. These findings describe important mechanisms by which type I IFN inhibits the immune response during tuberculosis.
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom; finlay.x.mcnab@gsk.com.
authors.forename: Finlay W
authors.initials: FW
authors.lastname: McNab
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: John
authors.initials: J
authors.lastname: Ewbank
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Howes
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom; Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; Life and Health Sciences Research Institute and Biomaterials, Biodegradables and Biomimetics Research Group, Portugal Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal; and.
authors.forename: Lucia
authors.initials: L
authors.lastname: Moreira-Teixeira
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: Anna
authors.initials: A
authors.lastname: Martirosyan
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.affiliation: Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; Life and Health Sciences Research Institute and Biomaterials, Biodegradables and Biomimetics Research Group, Portugal Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal; and.
authors.forename: Margarida
authors.initials: M
authors.lastname: Saraiva
authors.affiliation: Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
mesh_terms: D000818:Animals; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: C556062:IL10 protein, mouse; C587672:IL1B protein, mouse; C486767:Il27 protein, mouse; D007370:Interferon Type I; D053583:Interleukin-1beta; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma