The Mincle-activating adjuvant TDB induces MyD88-dependent Th1 and Th17 responses through IL-1R signaling.

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.

• Authors: Christiane Desel, Kerstin Werninghaus, Manuel Ritter, Katrin Jozefowski, Jens Wenzel, Norman Russkamp, Ulrike Schleicher, Dennis Christensen, Stefan Wirtz, Carsten Kirschning, Else Marie Agger, Clarissa Prazeres da Costa, Roland Lang
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e53531 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23308247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Antigens, Bacterial
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Clecsf8 protein, mouse
• Cord Factors
• Cytoskeletal Proteins
• Interleukin-17
• Lectins, C-Type
• Membrane Proteins
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Pycard protein, mouse
• Receptors, Interleukin-1
• Tuberculosis Vaccines
• Vaccines, Subunit
• Interferon-gamma

Topics

• Adaptive Immunity
• Adjuvants, Immunologic (administration & dosage, chemistry)
• Animals
• Antigens, Bacterial (chemistry, immunology)
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Cord Factors (chemistry, immunology)
• Cytoskeletal Proteins (deficiency, genetics, immunology)
• Gene Expression Regulation
• Immunization
• Interferon-gamma (genetics, immunology)
• Interleukin-17 (genetics, immunology)
• Lectins, C-Type (deficiency, genetics, immunology)
• Membrane Proteins (deficiency, genetics, immunology)
• Mice
• Mice, Knockout
• Molecular Mimicry
• Myeloid Differentiation Factor 88 (genetics, immunology)
• Receptors, Interleukin-1 (genetics, immunology)
• Signal Transduction
• Th1 Cells (immunology)
• Th17 Cells (immunology)
• Tuberculosis (immunology, prevention & control)
• Tuberculosis Vaccines (administration & dosage, chemistry, immunology)
• Vaccines, Subunit