TLR signal transduction is initiated usually by the recruitment of one or more adaptor proteins [18–20], which include myeloid differentiation primary response protein 88 (MyD88), MyD88-adaptor-like [Mal, also referred to as Toll/IL-1 receptor (TIR) domain-containing adaptor protein Sunitinib chemical structure (TIRAP)], TIR domain-containing adaptor protein inducing interferon (IFN)-β (TRIF, also known as TICAM1) and TRIF-related adaptor molecule (TRAM; also known as TICAM2) [21,22]. These adaptors associate with the cytoplasmic
domains of TLRs through homophilic interactions between TIR domains present in each TLR. All TLR family members use the MyD88 adaptor, except TLR-3, which recruits TRIF . TLR-4 is the only family member that activates both MyD88-dependent and TRIF-dependent signal transduction pathways . The structural or conformational changes that facilitate adaptor binding remain poorly Sorafenib defined, although it seems likely that increased proximity between the cytoplasmic domains of
TLRs creates a binding interface for the relevant TIR domain-containing adaptors. Although the signalling events downstream of MyD88 and TRIF differ, the outcome of each pathway is conceptually similar: nuclear factor-κB, interferon-regulatory factors (IRFs) and other more general transcription factors are activated [16,22,25]. In certain cases differential activation of IRF family members leads to distinct transcriptional responses. Efficient
Interleukin-3 receptor immune responses depend upon a close interaction between the innate and adaptive immune systems. The innate immune system not only reacts promptly to microbial infection or environmental insult, but also instructs APCs to activate and secrete cytokines in order to polarize T cells towards an appropriate effector phenotype . Only mature DCs will be able, through appropriate antigen presentation, to stimulate naive T cells such that they differentiate into effector T cells. The types of effector T cells that evolve from the naive cells are influenced greatly by the pattern of cytokines induced by the TLR engagement. Apparently, in addition to presenting antigens to naive T cells in an appropriate major histocompatibility complex (MHC) context, the range of co-stimulatory signals delivered to T cells by APCs is determined, if not all, at least partially, by TLR ligation. TLRs serve as an important link between the innate and adaptive immune responses . Different types of DCs selectively express cytokines, co-receptors and several other polarizing signals that promote the development of Th1, Th2, CD4+CD25+ Treg cells or the recently defined Th17 lineage, respectively [28,29]. In this context, selected TLR ligands can be used alone or in combination as potential vaccine adjuvants to elicit the most appropriate immune response in humans or mice.