Journal
JOURNAL OF IMMUNOLOGY
Volume 193, Issue 7, Pages 3600-3612Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1401088
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Funding
- Medical Research Council, U.K. [U117565642]
- European Research Council [294682-TB-PATH]
- Fundacao para a Ciencia e Tecnologia, Portugal
- Fundacao para a Ciencia e Tecnologia, Portugal [SFRH/BPD/77399/2011]
- MRC [MC_U117565642] Funding Source: UKRI
- Medical Research Council [MC_U117565642] Funding Source: researchfish
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Tuberculosis, caused by the intracellular bacterium Mycobacterium tuberculosis, currently causes similar to 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-alpha, IL-12, and IL-1 beta 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-gamma, including M. tuberculosis killing. These findings describe important mechanisms by which type I IFN inhibits the immune response during tuberculosis.
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