Kashmeera N.A.Kashmeera N.A.IV Sem MSc.ZoologyIV Sem MSc.ZoologyRoll No. 37Roll No. 37Christ collegeChrist college
Innate immunity uses a variety ofInnate immunity uses a variety ofreceptors 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 ofpathogens.pathogens.Complete set of TLRs in humans canComplete set of TLRs in humans candetect broad variety of viruses,bacteria,fungidetect broad variety of viruses,bacteria,fungi& even some protozoa.& even some protozoa.
TLRs have :TLRs have :Exterior domainExterior domainMembrane spanning domainMembrane spanning domainTIR domain / interior domainTIR domain / interior domain
EXTERIOR DOMAINEXTERIOR DOMAINContains 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 extracellularligand-binding region of TLR.ligand-binding region of TLR.
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 conservedsequences 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 sitesfor intracellular proteins in signallingfor intracellular proteins in signallingpathways.pathways.
• Indispensable components of pathogens.Indispensable components of pathogens.• Cannot mutate to forms lacking theseCannot mutate to forms lacking thesecomponents.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
Location of TLRLocation of TLRDepend on nature of ligand.Depend on nature of ligand.Extracellular ligand – surface ofExtracellular ligand – surface ofcell.cell.Intracellular ligand - intracellularIntracellular ligand - intracellularmembranemembrane
TLR Signaling pathway results inTLR Signaling pathway results ininduction of many signature featuresinduction of many signature featuresof innate immunity , includingof innate immunity , includinggeneration of inflammatory cytokinesgeneration of inflammatory cytokines& chemokines,& chemokines,generation of antimicrobial peptides,generation of antimicrobial peptides,& so on.& so on.
Initiation by interaction ofInitiation by interaction ofsignal with receptorsignal with receptorMicrobial products + ECMicrobial products + ECportion of TLR.portion of TLR.Cytoplasmic TIR domain –Cytoplasmic TIR domain –binding sites for otherbinding sites for othercomponents of pathway.components of pathway.
Signal-induced assembly ofSignal-induced assembly ofpathway components/ involvementpathway components/ involvementof an adaptor moleculeof an adaptor molecule• Adaptor proteins containing TIRAdaptor proteins containing TIRdomains,interact with TIR domain of TLRs.domains,interact with TIR domain of TLRs.• Common adaptor protein for TLRs isCommon adaptor protein for TLRs isMyD88.MyD88.• MyD88 promote association of 2 PKs, IRAK1MyD88 promote association of 2 PKs, IRAK1& IRAK4& IRAK4
Protein kinase – mediatedProtein kinase – mediatedphosphorylationphosphorylation• PK IRAK4,of IRAK1:IRAK4 complex, PO4sPK IRAK4,of IRAK1:IRAK4 complex, PO4sIRAK1.IRAK1.• New PO4 provides docking site on IRAK1 forNew PO4 provides docking site on IRAK1 forTRAF6.TRAF6.• TRAF6 binds & dissociates with IRAK1→TRAF6 binds & dissociates with IRAK1→IRAK1: TRAF6 complex.IRAK1: TRAF6 complex.• TAK1+complex → * TAK1kinase activityTAK1+complex → * TAK1kinase activity
Initiation of an enzymecascade• **TAK1 activate 2 signal transductionTAK1 activate 2 signal transductionpathways by PO4n.pathways by PO4n.• Mitogen activated protein kinase [MAPMitogen activated protein kinase [MAPkinase] 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.)
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 TFswhich affect cell cycle/cellularwhich affect cell cycle/cellulardifferentiationdifferentiation
NFNFκκB pathwayB pathway• TAK1 PO4s IKK – key step inTAK1 PO4s IKK – key step in ** NFNFκκBBpathway.pathway.• NFNFκκB – powerful TF; inhibited by unPO4tdB – powerful TF; inhibited by unPO4tdcyto. Protein Icyto. Protein IκκB.B.• IKK PO4sIKK PO4s IIκκB → release ofB → release of NFNFκκB → migrateB → migrateto nucleus.to nucleus.• NFNFκκB in nucleus initiates transcription ofB in nucleus initiates transcription ofmany genes for effector fns of innatemany genes for effector fns of innateimmunity.immunity.
Pathways different for differentTLRs• TLR3 uses MyD88 independentTLR3 uses MyD88 independentpathway.pathway.• TLR4 uses both MyD88 dependent &TLR4 uses both MyD88 dependent &independent pathways.independent pathways.
• Promote expression of genes that contributePromote expression of genes that contributeto inflammation.to inflammation.• Induces changes in APCs & make themInduces changes in APCs & make themmore efficient in Ag presentation.more efficient in Ag presentation.• Causes synthesis & export of intercellularCauses synthesis & export of intercellularsignaling molecules that effect behaviour ofsignaling molecules that effect behaviour ofleukocytes & other cells.leukocytes & other cells.• Engagement of TLRsEngagement of TLRs ↑ phagocytic activity of↑ phagocytic activity ofmacrophages & neutrophils.macrophages & neutrophils.