ESAT-6-dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo.
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.
Andreas
A
Kupz
Ulrike
U
Zedler
Manuela
M
Stäber
Carolina
C
Perdomo
Anca
A
Dorhoi
Roland
R
Brosch
Stefan H E
SH
Kaufmann
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001500:BCG Vaccine / Q000494:pharmacology; D001426:Bacterial Proteins / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003600:Cytosol / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D014774:Virulence / Q000276:immunology
D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D020382:Interleukin-18; D007371:Interferon-gamma