Toll Like Receptors(TLRs)

Sukhbir Kaur

First line of defense – innate immunity. Ability to discriminate between self and

foreign pathogen relies on TLRs. Discovered in Drosophila melanogaster as

a receptor for establishing dorsoventral polarity during embryogenesis and component of innate immunity in adult flies.

TLRs : first PRR to be identified . Recognize different features (PAMPs) of

bacteria, viruses and other microbes.

Toll Like Receptors

TLRs are type I transmembrane proteins having:• Ectodomain :amino terminal domain composed of

repeated motifs rich in leucine and known as lecine rich repeats(LRRs).

• Transmembrane region• Cytosolic domain: called as Toll/Interleukin I

receptor (TIR) domain. TIR domain has 3 regions, highly conserved

among all family members, called boxes 1,2 in and 3. these serve as binding site for intra cellular proteins that participate in signalling pathway.

Structure of TLRs

Structure of TLR

TLRs are expressed on cell surface and within intracellular vesicles( ER, endosomes, lysosomes etc.)

TLRs on cell surface recognize components of microbial membrane while those expressed within intracellular vesicles recognize foreign nucleic acids.

Protein PRAT4A regulates exit of TLR1, TLR2,TLR4, TLR7 and TLR9 from ER to respective places.

Gp96 – ER resident heat shock protein 90 family acts as chaperone for most TLRs .

Localisation of TLRs

Localization of TLRs

TLR1, TLR2 and TLR6 Structurally related. TLR2 recognizes: Lipoproteins from various pathogens• Peptidoglycan and techoic acid (Gram + ve

bacteria)• Lipoarabinomanan (mycobacterium)• Glycophosphatidyl inositol (Trypanosoma cruzi).• Zymosan (fungi)• Glycolipids (Treponema)

Recognition of PAMPs by various TLRs

TLR1, TLR2 and TLR6 Heterodimer of TLR2 and TLR6 recognize

diacyl lipopeptides from mycoplasma. Heterodimer of TLR2 and TLR1 recognize

triacyl lipopeptides from Gram –ve bacteria. TLR2 and Dectin1( lectin family receptor)

recognize β-glucan (component of fungal cell wall)

Contd..

TLR3 Recognizes: Genomic RNA from dsRNA virus (reovirus). dsRNA (Influenza A, West Nile virus) dsDNA (Herpes Simplex Virus) TLR4 Essential for LPS recognition LPS binds to soluble LPS binding protein

(LBP), then LPS transferred to CD14 and finally TLR4 is activated.

Contd..

TLR4 Also recognizes endogenous ligands such

as: Heat shock protein ( HSP 60 and 70) Extra domain A of fibronectin, heparan

sulfate and fibrinogen. Heterodimer of TLR4 and TLR6 enhances

the activity of TLR4 while its dimerisation with TLR1 inhibits its activity.

Contd….

TLR5 Recognize flagellin Expressed where? Mucosal surface of intestinal epithelial cells Epithelial cells of lungs. TLR7 and TLR8 Recognize imidazoquinoline (anti-viral compound). TLR8 active in humans not in mouse. Also recognize nucleoside guanosine or uridine rich

ssRNA from viruses such as HIV and Influenza virus.

Contd…

TLR9• Receptor for CpGDNA• Bacterial DNA has unmethylated CpG

motifs. TLR11• Active in mouse.• Expressed in urinary bladdedr epithelial

cells.• Recognizes uropathogenic bacteria.

Contd..