Journal
INFECTION AND IMMUNITY
Volume 83, Issue 6, Pages 2242-2254Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00135-15
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Funding
- National Institutes of Health [T32 GM007250, T32 AI089474, R21 AI103443, R01 AI027243, R01 AI069085, R01 AI034343]
- Case Western Reserve University/University Hospitals Center for AIDS Research (NIH) [P30 AI036219]
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Mycobacterium tuberculosis survives within macrophages and employs immune evasion mechanisms to persist in the host. Protective T helper type 1 (Th1) responses are induced, and the immune response in most individuals is sufficient to restrict Mycobacterium tuberculosis to latent infection, but most infections are not completely resolved. As T cells and macrophages respond, a balance is established between protective Th1-associated and other proinflammatory cytokines, such as interleukin-12 (IL-12), interferon gamma (IFN-gamma), and tumor necrosis factor alpha, and anti-inflammatory cytokines, such as IL-10. The mechanisms by which Mycobacterium tuberculosis modulates host responses to promote its survival remain unclear. In these studies, we demonstrate that Mycobacterium tuberculosis induction of IL-10, suppression of IL-12, and inhibition of class II major histocompatibility complex (MHC-II) molecules in infected macrophages are all driven by Toll-like receptor 2 (TLR2)-dependent activation of the extracellular signal-regulated kinases (ERK). Elimination of ERK signaling downstream of TLR2 by pharmacologic inhibition with U0126 or genetic deletion of Tpl2 blocks IL-10 secretion and enhances IL-12 p70 secretion. We demonstrate that Mycobacterium tuberculosis regulation of these pathways in macrophages affects T cell responses to infected macrophages. Thus, genetic blockade of the ERK pathway in Tpl2(-/-) macrophages enhances Th1 polarization and IFN-gamma production by antigen-specific CD4(+) T cells responding to Mycobacterium tuberculosis infection. These data indicate that Mycobacterium tuberculosis and its potent TLR2 ligands activate ERK signaling in macrophages to promote anti-inflammatory macrophage responses and blunt Th1 responses against the pathogen.
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