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ESAT-6–dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo
Andreas Kupz, … , Roland Brosch, Stefan H.E. Kaufmann
Andreas Kupz, … , Roland Brosch, Stefan H.E. Kaufmann
Published April 25, 2016
Citation Information: J Clin Invest. 2016;126(6):2109-2122. https://doi.org/10.1172/JCI84978.
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Research Article Infectious disease

ESAT-6–dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo

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Abstract

IFN-γ is a critical mediator of host defense against Mycobacterium tuberculosis (Mtb) infection. Antigen-specific CD4+ T cells have long been regarded as the main producer of IFN-γ in tuberculosis (TB), and CD4+ T cell immunity is the main target of current TB vaccine candidates. However, given the recent failures of such a TB vaccine candidate in clinical trials, strategies to harness CD4-independent mechanisms of protection should be included in future vaccine design. Here, we have reported that noncognate IFN-γ production by Mtb antigen–independent memory CD8+ T cells and NK cells is protective during Mtb infection and evaluated the mechanistic regulation of IFN-γ production by these cells in vivo. Transfer of arenavirus- or protein-specific CD8+ T cells or NK cells reduced the mortality and morbidity rates of mice highly susceptible to TB in an IFN-γ–dependent manner. Secretion of IFN-γ by these cell populations required IL-18, sensing of mycobacterial viability, Mtb protein 6-kDa early secretory antigenic target–mediated (ESAT-6–mediated) cytosolic contact, and activation of NLR family pyrin domain–containing protein 3 (NLRP3) inflammasomes in CD11c+ cell subsets. Neutralization of IL-18 abrogated protection in susceptible recipient mice that had received noncognate cells. Moreover, improved Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine–induced protection was lost in the absence of ESAT-6–dependent cytosolic contact. Our findings provide a comprehensive mechanistic framework for antigen-independent IFN-γ secretion in response to Mtb with critical implications for future intervention strategies against TB.

Authors

Andreas Kupz, Ulrike Zedler, Manuela Stäber, Carolina Perdomo, Anca Dorhoi, Roland Brosch, Stefan H.E. Kaufmann

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Figure 3

Innate IFN-γ depends on RD1 and ESAT-6–mediated cytosolic contact.

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Innate IFN-γ depends on RD1 and ESAT-6–mediated cytosolic contact.
(A–F)...
(A–F) Percentage of IFN-γ+ cells among total viable CD3–NK1.1+ (A–C) and CD3+CD8+ (D–F) lung cells and serum IL-18 concentrations (G–I) 24 hours after B6 mice were injected with different purified mycobacterial ligands (A, D, and G) or 1 × 108 CFU WT or recombinant Mtb or BCG strains (B, C, E, F, H, and I). Individual data points of 3 to 15 mice per group from at least 2 pooled, independent experiments are shown. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA. rESAT-6, recombinant ESAT-6.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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