The Mincle-Activating Adjuvant TDB Induces MyD88-Dependent Th1 and Th17 Responses through IL-1R Signaling

• Published in: PloS one Vol. 8; no. 1; p. e53531
• Main Authors: Desel, Christiane, Werninghaus, Kerstin, Ritter, Manuel, Jozefowski, Katrin, Wenzel, Jens, Russkamp, Norman, Schleicher, Ulrike, Christensen, Dennis, Wirtz, Stefan, Kirschning, Carsten, Agger, Else Marie, da Costa, Clarissa Prazeres, Lang, Roland
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.01.2013; Public Library of Science (PLoS)
• Subjects: Activation; Adaptive Immunity; Adjuvanticity; Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - chemistry; Animals; Antigen-presenting cells; Antigens; Antigens, Bacterial - chemistry; Antigens, Bacterial - immunology; Apoptosis Regulatory Proteins; Biology; CARD Signaling Adaptor Proteins; Cord factor; Cord Factors - chemistry; Cord Factors - immunology; Cytokines; Cytoskeletal Proteins - deficiency; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - immunology; Experiments; Gene Expression Regulation; Glycolipids; Helper cells; Hospitals; Hygiene; Immune response; Immune response (cell-mediated); Immunization; Immunoglobulins; Immunology; Infectious diseases; Inflammasomes; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin 1; Interleukin 1 receptors; Interleukin 17; Interleukin 18; Interleukin-17 - genetics; Interleukin-17 - immunology; Intracellular signalling; Lectins; Lectins, C-Type - deficiency; Lectins, C-Type - genetics; Lectins, C-Type - immunology; Lymphocytes; Lymphocytes T; Medicine; Membrane lipids; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Knockout; Molecular Mimicry; Mycobacterium tuberculosis; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Neutrophils; Plant lipids; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - immunology; Signal Transduction; Syk protein; Th1 Cells - immunology; Th17 Cells - immunology; Trehalose; Tuberculosis; Tuberculosis - immunology; Tuberculosis - prevention & control; Tuberculosis vaccines; Tuberculosis Vaccines - administration & dosage; Tuberculosis Vaccines - chemistry; Tuberculosis Vaccines - immunology; Vaccination; Vaccines; Vaccines, Subunit; γ-Interferon; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0053531

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.