Fig. 1: Molecular targets of adjuvants.
a | Toll-like receptors (TLRs) TLR1, TLR2, TLR4, TLR5 and TLR6 are expressed on the cell surface, whereas TLR3, TLR7, TLR8 and TLR9 are expressed in endosomes. TLR1 and TLR6 heterodimerize with TLR2 and signal through the myeloid differentiation primary response 88 (MyD88) pathway to activate NF-κB and MAP kinases, leading to secretion of pro-inflammatory and anti-inflammatory cytokines. TLR4 and TLR5 function as homodimers and signal through the MyD88 pathway. TLR7 and TLR9 also use the MyD88 pathway, but rapidly activate IRF7 to induce type I interferons. TLR3 uses TIR domain-containing adapter-inducing IFNβ (TRIF) signalling to induce type I interferons through IRF3. b | Cytosolic pattern recognition receptors (PRRs) are sensors of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) present inside the cytoplasm of the cell. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are cytosolic sensors of bacterial PAMPs but also recognize multiple cellular products including ATP, uric acid and K+ to activate the NF-κB pathway and induce cytokines driving T helper 2 (TH2) cell differentiation. Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) are intracellular viral sensors that drive type I interferon response through IRF3 and IRF7. The cGAS–stimulator of interferon genes (STING) pathway recognized double-stranded DNA (dsDNA) to induce the NF-κB pathway. c | C-type lectin receptors (CLRs) are cell surface molecules expressed on multiple myeloid cell subsets. Dectins 1 and 2 and MINCLE recruit SYK1 and activate NF-κB through the CARD9–BCL-10–MALT1 complex. Furthermore, dectin 1 has been shown to induce the NFAT and AP1 pathways in macrophages and dendritic cells (DCs) and in in vitro experimental models, respectively. Dectins are also specialized in inducing antifungal immunity. Dendritic cell-specific ICAM3-grabbing non-integrin 1 (DC-SIGN) activates NF-κB via acetylation of p65; however, the resulting gene expression is poorly understood although IL-10 expression has been shown to be induced. DEC205 and DNGR1 are known to induce cross-presentation but the signalling pathways are unknown. ASC, apoptosis-associated speck-like protein containing a CARD; CpG, cytosine phosphoguanosine; dsRNA, double-stranded RNA; LPS, lipopolysaccharide; ssRNA, single-stranded RNA; TDM, trehalose-6,6-dimycolate; Treg cell, regulatory T cell.
