Abstract
Successful vaccination against intracellular pathogens requires the generation of cellular immune responses. Trehalose-6,6-dibehenate (TDB), the synthetic analog of the mycobacterial cord factor trehalose-6,6-dimycolate (TDM), is a potent adjuvant inducing strong Th1 and Th17 immune responses. We previously identified the C-type lectin Mincle as receptor for these glycolipids that triggers the FcRγ-Syk-Card9 pathway for APC activation and adjuvanticity. Interestingly, in vivo data revealed that the adjuvant effect was not solely Mincle-dependent but also required MyD88. Therefore, we dissected which MyD88-dependent pathways are essential for successful immunization with a tuberculosis subunit vaccine. We show here that antigen-specific Th1/Th17 immune responses required IL-1 receptor-mediated signals independent of IL-18 and IL-33-signaling. ASC-deficient mice had impaired IL-17 but intact IFNγ responses, indicating partial independence of TDB adjuvanticity from inflammasome activation. Our data suggest that the glycolipid adjuvant TDB triggers Mincle-dependent IL-1 production to induce MyD88-dependent Th1/Th17 responses in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptive Immunity
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Adjuvants, Immunologic / administration & dosage*
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Adjuvants, Immunologic / chemistry
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Animals
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Antigens, Bacterial / chemistry
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Antigens, Bacterial / immunology
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Cord Factors / chemistry
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Cord Factors / immunology
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Cytoskeletal Proteins / deficiency
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / immunology
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Gene Expression Regulation
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Immunization
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-17 / genetics
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Interleukin-17 / immunology
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Lectins, C-Type / deficiency
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology*
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / immunology*
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Mice
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Mice, Knockout
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Molecular Mimicry
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / immunology*
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-1 / immunology*
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Signal Transduction
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Th1 Cells / immunology*
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Th17 Cells / immunology*
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Tuberculosis / immunology
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Tuberculosis / prevention & control*
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Tuberculosis Vaccines / administration & dosage
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Tuberculosis Vaccines / chemistry
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Tuberculosis Vaccines / immunology*
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Vaccines, Subunit
Substances
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Adjuvants, Immunologic
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Antigens, Bacterial
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Clecsf8 protein, mouse
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Cord Factors
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Cytoskeletal Proteins
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Interleukin-17
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Lectins, C-Type
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Membrane Proteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Pycard protein, mouse
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Receptors, Interleukin-1
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Tuberculosis Vaccines
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Vaccines, Subunit
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Interferon-gamma
Grants and funding
This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB796 to RL and SFB/TR22 to CPdP) and the European Union (FP6 NEWTBVAC to EMA, DC and RL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.