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. 2020 Oct 21;8(4):621. doi: 10.3390/vaccines8040621

Figure 2.

Figure 2

Mechanisms of action of novel adjuvants under investigation in experimental aP vaccines. Activation of signaling pathways in APC by various adjuvants can be harnessed to generate Th1/Th17 polarizing conditions following immunization. These include the TLR2 agonist LP1569 and the TLR4 agonists MPL, LpxL1 and LpxL2 which are synthetic analogues of LPS. SMIP7.10 and CpG ligate the endosomal TLRs, TLR7 and TLR 9 respectively. TLR 2, 4, 7 and 9 signal through the adaptor molecule MyD88, with TLR2 and TLR4 requiring the bridging adaptor Mal to activate MyD88-mediated signaling. MyD88 signaling results in downstream activation of NFκB and MAPKs. MAPKs activate transcription factors such as AP-1. NFκB and AP-1 translocate to the nucleus leading to the transcription of pro-inflammatory and T cell-polarizing cytokines, chemokines, MHC class II and costimulatory molecules. The CLR, Mincle, is ligated by the TDB component (shown in red) of liposomes, which signals via SYK, and subsequently activates CARD9-Bcl10-Malt signalosome and NFκB. c-di-GMP activates the intracellular DNA sensor, STING, located at the ER, and complexed with TBK1 translocates to perinuclear regions, activating NFκB and IRF3. LP-GMP, which combines LP1569 and c-di-GMP adjuvants, signals through TLR2 and STING respectively, resulting in synergistic induction of Th1/Th17 responses. Block arrows denote activation and dashed arrows denote translocation of transcription factors to the nucleus. Images from Servier Medical Art (www.smart.servier.com). APC: antigen presenting cell, TLR: Toll-like receptor, Th: T helper cell, MPL: Monophosphoryl lipid A, LPS: Lipopolysaccharide, MyD88: Myeloid differentiation primary response gene 88, Mal: MyD88 adaptor-like, NF-κB: Nuclear Factor kappa B, MAPK: Mitogen-activated tyrosine kinase, TDB: α,α trehalose 6,6’-dibehenate, SYK: Spleen tyrosine kinase, CARD9: Caspase recruitment domain family member 9, Bcl10: B-cell lymphoma 10, Malt1: Mucosa-associated lymphoid tissue 1, AP1: Activator protein 1, IRF3: Interferon response factor 3, STING: Stimulator of interferon genes, TBK1: TANK-binding kinase 1, MHC Class II: Major histocompatibility complex class II, Costim: costimulatory molecules.