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

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 1

Noncognate memory CD8+ T cells and NK cells are sufficient to mediate early IFN-γ–dependent control of Mtb infection.

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Noncognate memory CD8+ T cells and NK cells are sufficient to mediate ea...
(A–F) Naive B6, Ifngr–/–, Rag1–/–, Rag2–/– Il2rg–/– mice, as well as Rag2–/– Il2rg–/– (A), Ifngr–/– (B), and B6 (C–F) mice that had received either OT-ITg cells (A–E), P14Tg cells (A), NK cells, or Ifng–/– NK cells (A) were infected with 200 CFU Mtb H37Rv via the aerosol route, and survival (A and B), OT-ITg cell numbers among CD8+ T cells (C and D), and CFU (E and F) were assessed over time. For neutralization of IFN-γ (A), mice received weekly i.p. injections of 200 μg anti–IFN-γ mAb. Results are presented as individual data points (D–F), pooled data means (A and B), or representative FACS plots (C) of 7 to 22 (A), 7 (B), and 8 to 11 (C–F) mice per group from 2 (B–F) or 5 (A) pooled, independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001, by log-rank (Mantel-Cox) test (A and B) or unpaired, 2-tailed Student’s t test per time point (E and F).