The history of Toll-like receptors — redefining innate immunity

Abstract

The discovery of Toll--like receptors (TLRs) was an important event for immunology research and was recognized as such with the awarding of the 2011 Nobel Prize in Physiology or Medicine to Jules Hoffmann and Bruce Beutler, who, together with Ralph Steinman, the third winner of the 2011 Nobel Prize and the person who discovered the dendritic cell, were pioneers in the field of innate immunity. TLRs have a central role in immunity -in this Timeline article, we describe the landmark findings that gave rise to this important field of research.

RIP kinases: key decision makers in cell death and innate immunity

“…PRRs include transmembrane Toll-like receptors (TLRs), 1 cytosolic NOD-like receptors (NLRs), 2 RIG-I-like receptors 3 and DNA sensors. 4 When engaged by relevant PAMPs, PRRs trigger signal transduction cascades resulting in activation of transcription factors such as NFkB and induction of a plethora of pro-inflammatory genes.…”

Innate immune activation of NFκB and its antagonism by poxviruses

“…TLRs are prototypical PRRs for PAMPs and DAMPs and are conserved across the animal kingdom, having retained a key role in immunity in diverse species [38]. Contexts whereby TLRs could sense the presence of poxviruses include when cells come into contact with extracellular virus particles, within the endosomes of phagocytotic macrophages and dendritic cells at sites of infection or after endocytosis and uncoating of virus during infection of multiple cell types.…”

“…TLR3 recognizes viral double stranded RNA (dsRNA) in endosomes and signals via homotypic interactions between Toll-IL-1R (TIR) domains through the adapter TIR-domain-containing adapter-inducing interferon-b (TRIF), leading to recruitment and activation of receptor-interacting protein 1 (RIP1) and TNF receptor associated factor 6 (TRAF6), both of which are involved in transducing a signal to the IKK complex via activation the transforming growth factor beta-activated kinase 1 (TAK1) [38] (Fig. 2).…”

“…Apart from TLR3, other endosomal TLRs have been linked to poxviral responses (Table 2): TLR9, the first DNA-sensing PRR to be discovered [46], senses unmethylated CpG DNA, whilst TLR7 and TLR8 sense ssRNA [38]. These endosomal TLRs activate NFkB via myeloid differentiation primary response gene 88 (MyD88) and TRAF6 [38] (Fig.…”

“…These endosomal TLRs activate NFkB via myeloid differentiation primary response gene 88 (MyD88) and TRAF6 [38] (Fig. 2).…”