ESAT-6–dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo
Andreas Kupz, Ulrike Zedler, Manuela Stäber, Carolina Perdomo, Anca Dorhoi, Roland Brosch, Stefan H.E. Kaufmann
Andreas Kupz, Ulrike Zedler, Manuela Stäber, Carolina Perdomo, Anca Dorhoi, Roland Brosch, Stefan H.E. Kaufmann
View: Text | PDF
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

×

Figure 1

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

Options: View larger image (or click on image) Download as PowerPoint
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).