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.

Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α

“…In contrast, we and others observed intact in vitro activation of macrophages or granulocytes by TDM or TDB in the absence of MYD88, arguing against a role for TLR (7,11,12). In vivo, glycolipid adjuvant activity depends on MYD88 signaling (3,6), which is at least partially due to IL-1R signaling but independent of TLR2/3/4/7/9 (13).…”

“…TLRindependent functions of the MYD88 adapter protein can also contribute to TDB/TDM responses in vivo, as the adjuvant effect of TDB is independent of TLR2/3/4/7 but requires MYD88 (6). We recently tested the role of the MYD88-utilizing cytokines IL-1, IL-18, and IL-33 for adjuvanticity of TDB, and identified an important contribution of IL-1R signaling (13). Similar findings of TLR-independent, but IL-1R-Myd88-dependent, in vivo adjuvanticity have been reported by Sher's group (56) for CFA.…”

Liposomes as vaccine delivery systems: a review of the recent advances

“…TDB induces strong T H 1 and T H 17 immune responses and the C-type lectin Mincle is the receptor for APC activation. The adjuvant effect also requires MyD88 and Schweneker and colleagues identified the Nlrp3 inflammasome as mediator for TDB-triggered induction of immune response [Werninghaus et al 2009;Desel et al 2013;Schweneker et al 2013]. Properties of cationic liposome-forming lipids were studied with rigid DDA or fluid dimethyldioleoylammonium (DODA) liposomes.…”

A case-study investigating the physicochemical characteristics that dictate the function of a liposomal adjuvant

“…Molecular mechanisms of TDB/TDM adjuvanticity were identified to be strictly Mincle-dependent and strong IL-17 production post immunization controls the generation of cellular immunity. 31,32 Desel et al 32 showed that adjuvanticity of TDM/TDB not only depends on Mincle, but also necessitates MyD88. Whereas in vitro studies identified MyD88 independence, in vivo adjuvanticity was strongly dependent on MyD88 signaling.…”