The Journal of Immunology Type I IFN Induces IL-10 Production in an IL-27–Independent Manner and Blocks Responsiveness to IFN-g for Production of IL-12 and Bacterial Killing in Mycobacterium

Tuberculosis, caused by the intracellular bacteriumMycobacterium 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-a, IL-12, and IL-1b is inhibited by exogenous type I IFN, whereas production of immunosuppressive IL-10 is promoted in an IL-27–independent manner. Further-more, much of the ability of type I IFN to inhibit cytokine production was mediated by IL-10. Additionally, type I IFN compro-mised macrophage activation by the lymphoid immune response through severely disrupting responsiveness to IFN-g, including M. tuberculosis killing. These findings describe important mechanisms by which type I IFN inhibits the immune response durin