TLRs

Toll-like receptors (TLRs)

Membrane-bound pattern recognition receptors that detect microbial components and activate innate immune responses

Main function of TLRs

Detect pathogen-associated molecular patterns and activate inflammatory signaling pathways

Location of TLRs

Plasma membrane or endosomal membranes

Extracellular TLRs

TLR1, TLR2, TLR4, TLR5, TLR6

Endosomal TLRs

TLR3, TLR7, TLR8, TLR9

Why some TLRs are endosomal

To detect nucleic acids from viruses and degraded pathogens

TLR1 ligand

Triacyl lipopeptides from bacteria

TLR2 ligand

Bacterial lipoproteins, lipoteichoic acid, peptidoglycan, zymosan

TLR1/2 heterodimer ligand

Triacyl lipopeptides

TLR2/6 heterodimer ligand

Diacyl lipopeptides

TLR3 ligand

Double-stranded RNA from viruses

TLR4 ligand

Lipopolysaccharide (LPS) from Gram-negative bacteria

TLR4 accessory protein

MD-2 assists TLR4 in recognizing LPS

TLR5 ligand

Flagellin from bacterial flagella

TLR7 ligand

Single-stranded viral RNA

TLR8 ligand

Single-stranded viral RNA

TLR9 ligand

Unmethylated CpG DNA commonly found in bacterial and viral DNA

Major adaptor protein for most TLRs

MyD88

Exception to MyD88 usage

TLR3 uses TRIF instead

TLR4 adaptor proteins

MyD88 and TRIF

First step in TLR signaling

Ligand binding causes receptor dimerization

Role of TIR domain

Recruits adaptor proteins to start signaling cascade

Function of MyD88

Initiates signaling leading to activation of NF-κB

NF-κB

Transcription factor that activates inflammatory gene expression

Genes activated by NF-κB

Cytokines, chemokines, adhesion molecules

Cytokines produced after TLR activation

IL-1β, IL-6, TNF-α

Role of cytokines produced by TLR signaling

Promote inflammation and recruit immune cells

TRIF signaling pathway

Activates interferon regulatory factors and type I interferons

Type I interferons

Antiviral cytokines such as IFN-α and IFN-β

Outcome of TLR activation

Inflammation, antiviral response, activation of adaptive immunity

TLR signaling importance

Links innate immune detection to adaptive immune activation

Why TLRs detect conserved molecules

Microbial survival depends on these structures so they mutate less frequently

Why TLRs have limited diversity

They are germline encoded receptors

Difference between PRRs and adaptive receptors

PRRs detect general patterns while BCR/TCR detect specific antigens