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Toll-like receptors and innate immunity

Key Points

  • Pattern-recognition receptors of the innate immune system recognize conserved pathogen-associated molecular patterns.

  • Drosophila has two main pathways of microbial recognition. The Toll pathway is involved in recognition of fungal and Gram-positive bacterial pathogens. The Imd pathway is essential for recognition and response to Gram-negative bacterial infection.

  • Mammalian Toll-like receptors (TLRs) recognize a variety of microbial products: TLR2 is specific for peptidoglycan and lipoproteins; TLR3 is specific for double-stranded RNA; TLR4 is specific for lipopolysaccharide and lipoteichoic acids; TLR5 is specific for bacterial flagellin; and TLR9 is specific for CpG DNA.

  • TLR2 cooperates with TLR1 and TLR6 for recognition of distinct sets of ligands.

  • TLRs signal through MyD88, IL-1R-associated kinase (IRAK) and TNF-receptor-associated factor 6 (TRAF6). In addition to MyD88-dependent signalling, TLR4 signals through an additional adaptor protein, TIRAP (TIR domain-containing adaptor protein).

  • TLR-mediated recognition and signalling have a crucial role in the initiation of adaptive immune responses and in the induction of T-cell differentiation into T helper (TH)1 effectors.

Abstract

Toll-like receptors have a crucial role in the detection of microbial infection in mammals and insects. In mammals, these receptors have evolved to recognize conserved products unique to microbial metabolism. This specificity allows the Toll proteins to detect the presence of infection and to induce activation of inflammatory and antimicrobial innate immune responses. Recognition of microbial products by Toll-like receptors expressed on dendritic cells triggers functional maturation of dendritic cells and leads to initiation of antigen-specific adaptive immune responses.

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Figure 1: TIR domain in host-defence pathways.
Figure 2: Drosophila Toll and Imd pathways.
Figure 3: Ligand specificities of TLRs.
Figure 4: Toll signalling pathways.
Figure 5: Role of TLRs in the control of adaptive immunity.

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Authors and Affiliations

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DATABASES

Flybase

18 Wheeler

Cactus

Dif

Diptericin

Dorsal

Dredd

Drosomycin

dIKK-β

dIKK-γ

imd

necrotic

Pelle

Relish

Spätzle

dTAK1

Toll

Toll-5

Tube

LocusLink

CD14

CD80

CD86

HSP60

IFN-γ

IL-1β

IL-1R

IL-6

IL-10

IL-13

IL-18R

IRAK

LBP

LYN

MD-1

MD-2

MKK6

MyD88

p38 MAP kinase

p50

p58

p65

p100

p105

PACT

PKR

RAC1

RP105

TAK1

TGF-β

TIRAP

TLR1

TLR2

TLR3

TLR4

TLR5

TLR6

TLR9

TNF-α

TOLLIP

TRAF6

Glossary

TYPE III SECRETION SYSTEM

A specialized multisubunit secretion apparatus found in many Gram-negative bacterial pathogens. It allows the bacteria to secrete various effector proteins directly into the cytosol of the host cells, where they have several functions, such as induction of apoptosis and stimulation of phagocytosis.

DEATH DOMAIN

A protein–protein interaction domain found in many proteins that are involved in signalling and apoptosis.

ENDOTOXIC SHOCK

A clinical condition induced by hyper-reaction of the innate immune system to bacterial LPS. It is mediated by the inflammatory cytokines IL-1 and TNF-α, which are produced in high amounts due to sustained stimulation of TLR4 by LPS.

COMPLETE FREUND'S ADJUVANT

(CFA). A mixture of mycobacterial lysate with mineral oil. When animals are immunized with antigen mixed with CFA, they induce strong immune responses to the antigen.

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Medzhitov, R. Toll-like receptors and innate immunity. Nat Rev Immunol 1, 135–145 (2001). https://doi.org/10.1038/35100529

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