TLR AGONISTS: Are They Good Adjuvants?

TLR 1,-2,-4, -5 and -6 are expressed in the plasma membrane where TLR2 associates with either TLR1 or TLR6. TLR3, -7, -8 and -9 traffic from the endoplasmic reticulum to the endosome where they encounter their ligands. MYD88 (myeloid differentiation primary response protein 88) and TRIF (TIR domain-containing adaptor protein inducing IFN) are signalling adaptors that link Toll-like receptors (TLRs) are to downstream kinases that define a given signalling pathway. All TLRs use MyD88, except for TLR3 which uses TRIF. The sorting adaptor TIRAP (TIR domain-containing adaptor protein) is used by TLR1, TLR2, TLR4 and TLR6 and links the TIR domain to MyD88, whereas TRIF is recruited by both TLR4 and TLR3. An additional adaptor TRAM, links the TIR domain of TLR4 with TRIF. TLRs which use the MyD88 dependent pathway recruit the IRAK family of proteins and TRAF6 resulting in the activation of TAK1. This in turn leads to the activation of NFKB and the MAPK pathway and results in the induction of pro-inflammatory cyokines and upregulation of phenotypic markers of activation (CD80, CD86). TLR4 (which relies on additional accessory molecules MD2 and CD14) and TLR3 both trigger the TRIF-dependent pathway, which also leads to activation of inflammatory cytokines via NFKB and MAP Kinase. In addition, TRIF recruits TRAF, leading to the activation of TBK1/IKKi, IRF3 and IRF7 and transcription of type I IFN. MyD88 also associates with the IRAK family of proteins. A complex of proteins (TRAF3, IRAK1 and Ikkα) subsequently activates IRF7. Examples of ligands binding the TLRs are shown. (Adapted from Kumar et al.,()).Abbreviations: LPS, lipopolysaccharide; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphospate; TRAF3, TNFR-associated factor 3.

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TLR AGONISTS: Are They Good Adjuvants?. () Nina Bhardwaj, et al. Cancer J. ;16(4):382-391. Figure: F1. All organisms Homo sapiens Mus musculus Drosophila melanogaster Danio rerio

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