TLRs are a category of pattern recognition receptors that play an important role in innate immunity. Each TLR detects a distinct subset of pathogens. TLRs have an extracellular domain containing leucine-rich repeats for ligand binding and an intracellular TIR domain for signaling. Engagement of TLRs by microbial ligands initiates signaling cascades involving adaptor proteins like MyD88 that ultimately activate transcription factors such as NF-κB and induce inflammatory responses that promote pathogen clearance.

1. Kashmeera N.A.Kashmeera N.A.
IV Sem MSc.ZoologyIV Sem MSc.Zoology
Roll No. 37Roll No. 37
Christ collegeChrist college

3. Innate immunity uses a variety ofInnate immunity uses a variety of
receptors to detect infectionreceptors to detect infection
–– Pattern Recognition Receptors (PRRs).Pattern Recognition Receptors (PRRs).
TLRs – important category of PRRs.TLRs – important category of PRRs.
Each TLR detect distinct subset ofEach TLR detect distinct subset of
pathogens.pathogens.
Complete set of TLRs in humans canComplete set of TLRs in humans can
detect broad variety of viruses,bacteria,fungidetect broad variety of viruses,bacteria,fungi
& even some protozoa.& even some protozoa.

5. TLRs have :TLRs have :
Exterior domainExterior domain
Membrane spanning domainMembrane spanning domain
TIR domain / interior domainTIR domain / interior domain

7. EXTERIOR DOMAINEXTERIOR DOMAIN
Contains many leucine rich repeats (LRRs).Contains many leucine rich repeats (LRRs).
All TLRs contain several LRRs.All TLRs contain several LRRs.
A subset of LRRs make up the extracellularA subset of LRRs make up the extracellular
ligand-binding region of TLR.ligand-binding region of TLR.

8. INTRACELLULAR DOMAININTRACELLULAR DOMAIN
• TIR domain (Toll IL-1 Receptor).TIR domain (Toll IL-1 Receptor).
• Have 3 regions with highly conservedHave 3 regions with highly conserved
sequences of a.assequences of a.as
–– box 1,box 2 & box 3.box 1,box 2 & box 3.
• Box 1,box 2 & box 3 – Binding sitesBox 1,box 2 & box 3 – Binding sites
for intracellular proteins in signallingfor intracellular proteins in signalling
pathways.pathways.

10. • Indispensable components of pathogens.Indispensable components of pathogens.
• Cannot mutate to forms lacking theseCannot mutate to forms lacking these
components.components.
• Ex: Nucleic acids of viruses.Ex: Nucleic acids of viruses.
LPS on wall of bacteria.LPS on wall of bacteria.
Zymosan on cellwall of fungiZymosan on cellwall of fungi

13. Location of TLRLocation of TLR
Depend on nature of ligand.Depend on nature of ligand.
Extracellular ligand – surface ofExtracellular ligand – surface of
cell.cell.
Intracellular ligand - intracellularIntracellular ligand - intracellular
membranemembrane

16. PairingPairing
• TLRs 1,2,4,6 – Dimers.TLRs 1,2,4,6 – Dimers.
• TLR 4,5 – homodimers.TLR 4,5 – homodimers.
• Others heterodimers.Others heterodimers.
• TLRs 3,7,8,9 – monomers.TLRs 3,7,8,9 – monomers.

17. Pairing affects specificityPairing affects specificity
• TLR 2 - TLR 1 : Bacterial lipoproteinsTLR 2 - TLR 1 : Bacterial lipoproteins
& Some surface proteins of parasites.& Some surface proteins of parasites.
• TLR 2 - TLR 6 : Peptidoglycan ,TLR 2 - TLR 6 : Peptidoglycan ,
Zymosans,Bacterial lipopeptidesZymosans,Bacterial lipopeptides

18. Bacterial lipoproteins &
Some surface proteins of
parasites
Peptidoglycan
Zymosans
Bacterial
lipopeptides LPS Flagellin
CpG

20. TLR Signaling pathway results inTLR Signaling pathway results in
induction of many signature featuresinduction of many signature features
of innate immunity , includingof innate immunity , including
generation of inflammatory cytokinesgeneration of inflammatory cytokines
& chemokines,& chemokines,
generation of antimicrobial peptides,generation of antimicrobial peptides,
& so on.& so on.

21. Initiation by interaction ofInitiation by interaction of
signal with receptorsignal with receptor
Microbial products + ECMicrobial products + EC
portion of TLR.portion of TLR.
Cytoplasmic TIR domain –Cytoplasmic TIR domain –
binding sites for otherbinding sites for other
components of pathway.components of pathway.

22. Signal-induced assembly ofSignal-induced assembly of
pathway components/ involvementpathway components/ involvement
of an adaptor moleculeof an adaptor molecule
• Adaptor proteins containing TIRAdaptor proteins containing TIR
domains,interact with TIR domain of TLRs.domains,interact with TIR domain of TLRs.
• Common adaptor protein for TLRs isCommon adaptor protein for TLRs is
MyD88.MyD88.
• MyD88 promote association of 2 PKs, IRAK1MyD88 promote association of 2 PKs, IRAK1
& IRAK4& IRAK4

23. Protein kinase – mediatedProtein kinase – mediated
phosphorylationphosphorylation
• PK IRAK4,of IRAK1:IRAK4 complex, PO4sPK IRAK4,of IRAK1:IRAK4 complex, PO4s
IRAK1.IRAK1.
• New PO4 provides docking site on IRAK1 forNew PO4 provides docking site on IRAK1 for
TRAF6.TRAF6.
• TRAF6 binds & dissociates with IRAK1→TRAF6 binds & dissociates with IRAK1→
IRAK1: TRAF6 complex.IRAK1: TRAF6 complex.
• TAK1+complex → * TAK1kinase activityTAK1+complex → * TAK1kinase activity

25. Initiation of an enzyme
cascade
• **TAK1 activate 2 signal transductionTAK1 activate 2 signal transduction
pathways by PO4n.pathways by PO4n.
• Mitogen activated protein kinase [MAPMitogen activated protein kinase [MAP
kinase] pathway.kinase] pathway.
• NFNFκκB pathway [Nuclear Factor Kappa –B pathway [Nuclear Factor Kappa –
lightchain - enhancer of activated B cells.)lightchain - enhancer of activated B cells.)

26. MAP kinase pathway.MAP kinase pathway.
• Signal transducing enzyme cascades.Signal transducing enzyme cascades.
• End product of cascade enter nucleusEnd product of cascade enter nucleus
&&
promote PO4n of TFspromote PO4n of TFs
which affect cell cycle/cellularwhich affect cell cycle/cellular
differentiationdifferentiation

27. NFNFκκB pathwayB pathway
• TAK1 PO4s IKK – key step inTAK1 PO4s IKK – key step in ** NFNFκκBB
pathway.pathway.
• NFNFκκB – powerful TF; inhibited by unPO4tdB – powerful TF; inhibited by unPO4td
cyto. Protein Icyto. Protein IκκB.B.
• IKK PO4sIKK PO4s IIκκB → release ofB → release of NFNFκκB → migrateB → migrate
to nucleus.to nucleus.
• NFNFκκB in nucleus initiates transcription ofB in nucleus initiates transcription of
many genes for effector fns of innatemany genes for effector fns of innate
immunity.immunity.

30. Pathways different for different
TLRs
• TLR3 uses MyD88 independentTLR3 uses MyD88 independent
pathway.pathway.
• TLR4 uses both MyD88 dependent &TLR4 uses both MyD88 dependent &
independent pathways.independent pathways.

32. • Promote expression of genes that contributePromote expression of genes that contribute
to inflammation.to inflammation.
• Induces changes in APCs & make themInduces changes in APCs & make them
more efficient in Ag presentation.more efficient in Ag presentation.
• Causes synthesis & export of intercellularCauses synthesis & export of intercellular
signaling molecules that effect behaviour ofsignaling molecules that effect behaviour of
leukocytes & other cells.leukocytes & other cells.
• Engagement of TLRsEngagement of TLRs ↑ phagocytic activity of↑ phagocytic activity of
macrophages & neutrophils.macrophages & neutrophils.