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.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL-12, IL-1 and TNF-α, as well as IFN-γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL-10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease.