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Review
. 2005 Jun;140(3):395-407.
doi: 10.1111/j.1365-2249.2005.02801.x.

Mammalian Toll-like Receptors: To Immunity and Beyond

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Free PMC article
Review

Mammalian Toll-like Receptors: To Immunity and Beyond

P A Hopkins et al. Clin Exp Immunol. .
Free PMC article

Abstract

Toll-like receptors (TLRs) constitute an archetypal pattern recognition system. Their sophisticated biology underpins the ability of innate immunity to discriminate between highly diverse microbial pathogens and self. However, the remarkable progress made in describing this biology has also revealed new immunological systems and processes previously hidden to investigators. In particular, TLRs appear to have a fundamental role in the generation of clonal adaptive immune responses, non-infectious disease pathogenesis and even in the maintenance of normal mammalian homeostasis. Although an understanding of TLRs has answered some fundamental questions at the host-pathogen interface, further issues, particularly regarding therapeutic modulation of these receptors, have yet to be resolved.

Figures

Fig. 1
Fig. 1
Complexity and consequences of Toll-like receptor (TLR)-mediated pattern recognition. Each TLR has an extracellular domain [containing multiple leucine-rich repeats, (LRRs)], and a Toll-interleukin (IL)-1 receptor (TIR) domain. Sophisticated interactions between different TLRs can occur both at the cell surface and at common nodes within signal transduction pathways. Cross-talk between TLRs in distinct cellular locations or on distant cell types can facilitate co-ordinated innate and adaptive immune responses and the modulation of other cellular processes such as apoptosis.
Fig. 2
Fig. 2
Toll-like receptor (TLR) signalling cascade and the locations for negative regulation and microbial subversion of these pathways. Two central adapter proteins MyD88 and TRIF propagate TLR signal transduction by interacting with TLRs via their respective Toll-interleukin (IL)-1 receptor (TIR) components and recruiting down-stream enzymes (e.g. IRAK4, TRAF6) through their ‘death’ domains. Subsequent modulation of transcriptional control elements is less well defined but occurs through linker molecules such as TAB1, TAK1 and TBK1. The powerful proinflammatory properties of Gram-negative lipopolysacharide (LPS) may be explained by TLR4-mediated recruitment of both major adapter proteins. Abbreviations are explained in Table 1 [–,–132].
Fig. 3
Fig. 3
Summary of mammalian Toll-like receptor (TLR)-mediated biology. TLRs are now known to be pivotal in both immunological responses and more general cellular homeostasis. Their role in the pathogenesis of diverse disease processes may offer the prospect of new adjuvant immunological therapies in addition to improved vaccine design.

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