title: 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: Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Erlangen, Germany. christiane.desel@uk-erlangen.de
authors: Christiane
authors: C
authors: Desel
authors: Kerstin
authors: K
authors: Werninghaus
authors: Manuel
authors: M
authors: Ritter
authors: Katrin
authors: K
authors: Jozefowski
authors: Jens
authors: J
authors: Wenzel
authors: Norman
authors: N
authors: Russkamp
authors: Ulrike
authors: U
authors: Schleicher
authors: Dennis
authors: D
authors: Christensen
authors: Stefan
authors: S
authors: Wirtz
authors: Carsten
authors: C
authors: Kirschning
authors: Else Marie
authors: EM
authors: Agger
authors: Clarissa
authors: C
authors: Prazeres da Costa
authors: Roland
authors: R
authors: Lang
mesh_terms: D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003311:Cord Factors / Q000737:chemistry / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D007114:Immunization; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018716:Molecular Mimicry; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D022223:Vaccines, Subunit
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C113583:Clecsf8 protein, mouse; D003311:Cord Factors; D003598:Cytoskeletal Proteins; D020381:Interleukin-17; D037181:Lectins, C-Type; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C498534:Pycard protein, mouse; D017472:Receptors, Interleukin-1; D032581:Tuberculosis Vaccines; D022223:Vaccines, Subunit; D007371:Interferon-gamma