Intracellular homodimers (TLR3, TLR7, TLR8 and TLR9) are indicated in gray. All TLRs except TLR3 require MyD88 recruitment to the TIR website for signaling activity [27]. signaling. In B cells, TLR signaling induces up-regulation of surface markers involved in antigen up-take (MHC I and MHC II) and in cross-talk with T cells (CD40, CD80, CD86), ultimately enhancing antigen-specific antibody production when TLR ligands are used combined with antigens in the context of vaccination. In addition, TLR signaling also plays Rabbit Polyclonal to Keratin 19 a role in induction of B- and T-cell memory space. In APCs, including B cell, DCs and macrophages, TLR signaling also results in enhanced secretion of both pro- and anti-inflammatory mediators that travel development of T helper cell subsets into Th1-, Th2- or Th17-type, depending on the type of APC involved [18]. Generally, signaling via TLR3, TLR4, TLR7, TLR8 and TLR9 promotes Th1-type immune reactions while signaling via TLR2 (along with TLR1 or TLR6) and TLR5 favors Th2-type immune reactions [19,20]. TLR ligands also influence Treg development [21]. A direct influence of TLR signaling on Treg development has been shown, due to manifestation of practical TLRs on these cells, as well as an indirect effect, due to Treg connection with TLR-activated APCs [22]. TLR signaling can lead to either Tregs practical activation or suppression, depending on the TLR ligand type and effect on antagonistic induction of Th17 cells [21]. This element is particularly relevant for malignancy, autoimmunity and chronic inflammation, due to the effects of Th17-type cytokines (IL-17A, IL-17F and IL-22) [21,23]. This review discusses the mechanisms of action of TLR agonists with vaccine adjuvant properties and shows their potential use to improve vaccination against infectious diseases and malignancy. 2. TLR Signaling Mechanism and Pathways Toll-like receptors (TLRs) comprise users of a family of related trans-membrane proteins that identify microbial and viral products. TLRs have been classified as pattern acknowledgement receptors (PRRs) that identify ligands from pathogenic microorganisms (the pathogen-associated molecular patterns (PAMPs) [24]), from commensal organisms (the commensal-associated molecular patterns (CAMPs) [25]) and endogenous ligands deriving from damaged cells (the danger-associated molecular patterns (DAMPs)) [26]. The structure of TLRs is definitely that of horse-shoe formed proteins composed of three domains: an extracellular or cytoplasmic leucine-rich replicate (LRR) domain which mediates ligand acknowledgement, a single trans-membrane domain, and an intra-cytoplasmic domain, the TIR domain, homologous to the related intracellular domain of the IL-1 receptor (IL-1R) Toll/IL-1R [17]. In humans, 10 TLRs have been identified so far. TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are surface-expressed and identify extracellular ligands and microorganisms, while TLR3, TLR7, TLR8 Flumatinib mesylate and TLR9 are situated on endosomal membranes within the cell and are engaged by intracellular ligands and microrganisms [17]. Ligand binding and TLR homo- or heterodimerization brings the TIR domains of adjacent TLRs collectively, providing a conformational switch necessary to result in signaling. Binding of additional adaptor proteins is also essential for intracellular cascades. Adaptor proteins include the myeloid differentiation element 88 (MyD88) [27], the MyD88 adaptor-like protein (Mal/TIRAP), the TIR domain-containing adaptor protein inducing interferon- (TRIF/TICAM) and the TRIF-related adaptor molecule (TRAM) [28,29] (Number 1). Bad Flumatinib mesylate regulators of TLR function have also been identified and include the Toll-interacting protein (Tollip), IRAK-M, the – and HEAT-Armadillo-motif-containing protein (SARM) and the B cell adaptor for PI3K (BCAP) [30]. Open in a separate window Number 1 Schematic cartoon of Flumatinib mesylate Toll-like receptor (TLR) signaling [17,24,27,28,29,30]. Extracellular TLR homodimers (TLR4 and TLR5) are displayed in black; heterodimers of TLR2 and TLR1, TLR6 or TLR10 are indicated in black/green. Intracellular homodimers (TLR3, TLR7, TLR8 and TLR9) are indicated in gray. All TLRs except TLR3 require MyD88 recruitment to the TIR website for signaling activity [27]. TLR2 and TLR4 also require the assistance of the adaptor protein Mal/TIRAP. In the MyD88-dependent signaling pathway,.