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

Kupz, Andreas, Zedler, Ulrike, Stäber, Manuela, Perdomo, Carolina, Dorhoi, Anca, Brosch, Roland, and Kaufmann, Stefan H.E. (2016) ESAT-6-dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo. Journal of Clinical Investigation, 126 (6). pp. 2109-2122.

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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.

Item ID: 43960
Item Type: Article (Research - C1)
ISSN: 1558-8238
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Funders: Max Planck Society (MPS), European Union Seventh Framework Programme (EU FP7), European Union Horizon 2020 (EU H2020), European Union (EU), Fondation pour la Recherche Médicale (FRM), National Health and Medical Research Council of Australia (NHMRC), CJ Martin Biomedical Early Career Fellowship (CJMBECF)
Projects and Grants: EU FP7 "ADITEC" project (HEALTH-F4-2011-280873), EU H2020 "TBVAC 2020" project (grant 643381), EU grant 643381, FRM DEQ20130326471, NHMRC/CJMBECF APP1052764
Date Deposited: 12 Aug 2016 02:28
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320211 Infectious diseases @ 40%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320407 Innate immunity @ 20%
31 BIOLOGICAL SCIENCES > 3107 Microbiology > 310702 Infectious agents @ 40%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 35%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 65%
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