Journal Article

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

Christensen, Dennis, Wirtz, Stefan, Agger, Else Marie, Jozefowski, Katrin, Wenzel, Jens, Schleicher, Ulrike, da Costa, Clarissa Prazeres, Desel, Christiane, Kirschning, Carsten, Lang, Roland, Russkamp, Norman, Ritter, Manuel, Werninghaus, Kerstin

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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