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

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

doi:10.1172/jci84978

Cited by 67Tuberculosis Research and EpidemiologyImmune responses and vaccinationsImmune Response and Inflammation

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

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Kupz, Andreas, Zedler, Ulrike, Stäber, Manuela, Perdomo, Carolina, Dorhoi, Anca, Brosch, Roland, Kaufmann, Stefan H.E.·2016·Journal of Clinical Investigation

DOI 10.1172/jci84978PMC PMC4887189

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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.

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Due to the absence of ESX-1, BCG does not gain access to the host cell cytosol and thus lacks the induction of certain immune signaling pathways.
“Due to the absence of ESX-1, BCG does not gain access to the host cell cytosol and thus lacks the induction of certain immune signaling pathways (74,86).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [74]

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Authors: Kupz, A., Zedler, U., Stäber, M., Perdomo, C., Dorhoi, A., Brosch, R., & Kaufmann, S. H. E.
Affiliations: Australian Institute of Tropical Health and Medicine (AU)
Max Planck Institute for Infection Biology (DE)
Institut Pasteur (FR)
Corresponding author: Kupz, Andreas
Kaufmann, Stefan H.E.
ORCID: Kupz, Andreas
Perdomo, Carolina
Dorhoi, Anca
Brosch, Roland
Kaufmann, Stefan H.E.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2016-04-25
Volume: 126
Issue: 6
Pages: 2109-2122
ISSN: 0021-9738 (ISSN-L)
1558-8238
DOI: 10.1172/jci84978
PMC: PMC4887189
OpenAlex: W2343808808
Cited by: 67
References: 86
Citations by year: 2026: 5 · 2025: 3 · 2024: 3 · 2022: 4 · 2021: 4 · 2020: 8 · 2019: 11 · 2018: 10 · 2017: 11 · 2016: 7
FWCI: 11.99
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
ResearchOnline - JCU (James Cook University) (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Max Planck Digital Library (submittedVersion)
Funders: University of Washington
European Commission (EU-FP7)
Max-Planck-Gesellschaft
Université de Lausanne
Rheinische Friedrich-Wilhelms-Universität Bonn
Genentech
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: tuberculosis, Mycobacterium tuberculosis, ESAT-6, CD8+ T cells, natural killer cells, IL-18, NLRP3 inflammasome, pattern recognition, CD11c+ cells, BCG vaccine, host defense
MeSH terms: Animals, Antigens, Bacterial, Bacterial Proteins, BCG Vaccine, Cytosol, Dendritic Cells, Disease Models, Animal, Female, Humans, Immunity, Innate, Immunologic Memory, Interferon-gamma, Male, Mice, Inbred C57BL, Mycobacterium tuberculosis, Tuberculosis, Pulmonary, Virulence, CD4-Positive T-Lymphocytes, Mice, Knockout, CD8-Positive T-Lymphocytes, Interleukin-18, Mice

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

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