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.
Highlights
Recombinant subunit vaccines are cheap and safe, but only weakly immunogenic unless adjuvants are used
We identified here IL-1/IL-1R1 as the TLR-independent MyD88 pathway significantly contributing to induction of Th1 and Th17 cellular immune responses upon vaccination with DDA/TDB
IL-1 has been linked to induction of pathogenic Th17 cells in an EAE model [22] but was shown to induce protective Th17 immune responses using Escherichia coli heat-labile enterotoxin as adjuvant [23]
Summary
Recombinant subunit vaccines are cheap and safe, but only weakly immunogenic unless adjuvants are used. A prerequisite for an efficient adjuvant is the activation of antigen presenting cells (APCs) by ligands for pattern recognition receptors. The choice of adjuvant(s) critically determines the type of memory response elicited, depending on the receptors and pathways triggered in APC via generation of cytokine milieus directing Th cell differentiation. DDA/TDB ( known as CAF01) is a generation adjuvant and has entered clinical studies for vaccination with the recombinant Mycobacterium tuberculosis fusion protein Ag85B-ESAT-6 (H1) [3,4]. TDB-immunized MyD882/2 mice failed to mount antigen-specific Th1 immune responses [7] Since this was unexpected and contradictory to our in vitro results, we investigated in vivo requirements of known MyD88utilizing signaling events in immunization experiments using DDA/TDB and H1. Inflammasome activation via ASC only partially accounted for CMI induction upon immunization with the glycolipid-containing adjuvant DDA/ TDB
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