This document summarizes Toll-like receptors (TLRs), which are a family of pattern recognition receptors involved in the innate immune system. TLRs recognize molecular patterns from bacteria, viruses and other microbes. They are type I transmembrane proteins containing leucine-rich repeats in their extracellular domain and a Toll/interleukin-1 receptor domain in their cytoplasmic tail. Different TLRs recognize distinct pathogen-associated molecular patterns, such as TLR4 which recognizes lipopolysaccharide, TLR3 which recognizes double-stranded RNA, and TLR9 which recognizes unmethylated CpG motifs in bacterial DNA. TLR signaling activates immune response pathways to defend against infection.

1. Sukhbir Kaur

2.  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.

3.  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.

5.  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 .

8.  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)

9.  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)

10.  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.

11.  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.

12.  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.

13.  TLR9
• Receptor for CpGDNA
• Bacterial DNA has unmethylated CpG motifs.
 TLR11
• Active in mouse.
• Expressed in urinary bladdedr epithelial cells.
• Recognizes uropathogenic bacteria.