Toll‐like Receptors

Tsukasa Seya, Hokkaido University, Kita‐ku, Sapporo, Japan
Kensuke Miyake, The University of Tokyo, Minato‐ku, Tokyo, Japan

Published online: December 2009

DOI: 10.1002/9780470015902.a0004028.pub2

Toll-like receptors (TLRs) are mainly expressed on antigen-presenting cells (APCs) and function as adjuvant receptors that modulate cellular immunity. Their pleiotropic functions depend on a variety of signals. Ten members of the TLR family in humans and 10~20 TLRs in other vertebrates cope with microbial pattern molecules, that is, TLR agonists. In addition, a number of molecules negatively or positively regulate the TLR signal pathways. TLR agonists are capable of activating either of the two main TLR pathways driven by the adaptors, myeloid differentiation primary-response gene 88 (MyD88) and TRIF (TIR-containing adaptor-inducing interferon- TIR-containing adaptor molecule-1, TICAM-1), which confer differential maturation modes on myeloid (mDCs) and plasmacytoid dendritic cells (pDCs). Natural killer (NK), CD8 T, CD4 T and B cells are activated through matured dendritic cells. TLRs are therefore involved in not only inducing the acute phase of inflammatory responses but also raising the acquired immune responses including allergy, cancer and infectious immunity.

Key concepts

  • Innate immune system consists of TLRs, lectin receptors and complement receptors; they recognize foreign and host materials marked or labelled with their ligands.
  • TLR signal pathways activate transcription factors in affected cells and induce host-defence agents, including antimicrobial peptides, chemical mediators, cytokines, chemokines and cell-adhesion molecules.
  • Dendritic cells play a pivotal role in evoking acquired immunity by liberation of cytokines/chemokines and cell-to-cell contact.
  • There are four adaptors connecting with the TLR TIR domains. These adaptors also possess the TIR domain and directly bind their counterparts. Only myeloid differentiation primary-response gene 88 (MyD88) and TICAM-1 (TRIF) are signalling adaptors.
  • Land-living vertebrates possess mammalian (M)-type TLR family, a representative of which is human TLRs. Water-living vertebrates possess the TLR20 family in addition to the M-type TLR family.
  • Plasmacytoid DC is formerly called interferon-producing cells (IPC).
  • Tumour necrosis factor receptor–associated factor (TRAF) family proteins act as E3 ubiquitin ligases and closely associated with molecules in the TLR pathways.

Keywords: innate immunity; dendritic cells; adjuvants; MyD88; TRIF (TICAM-1)

Figure 1. Evolutional view of TLRs. Unrooted phylogenetic tree of TLRs in vertebrates. The tree was constructed by the Clustal W programme. The relationships were calculated on the basis of the amino acid sequences of TIR domains. Bootstrap values (<800) were indicated. Asterisk indicates trichotomy. ch, chicken; fu, fugu; hu, human; la, lamprey; mo, mouse; xe; Xenopus tropicalis, ze; zebrafish.
Figure 2. TLR family members and their ligands. TLRs can recognize a variety of microorganism-derived components. Lipid ligands, derived mainly from membrane components, are recognized by TLR2 and TLR4. TLR2 recognizes its ligands by forming heterodimers with TLR1, TLR6 or possibly TLR10. TLR4 requires another secreted molecule, MD-2 for ligand recognition. CD14 is required for initial recognition of LPS/LBP complex. A flagella-derived protein, flagellin, is recognized by TLR5. These TLRs are localized on the cell surface as mature forms. Nucleic acids and their relatives are recognized by TLR3, TLR7 or TLR9, which are localized in cytoplasmic compartments. TLR proteins are present as immature forms in ER and sorted to their working places with putative shaperons. TLR3, TLR7 or TLR9 are complexed with Unc93b in ER.
Figure 3. Overview of dendritic cell TLR output. Myeloid dendritic cells (mDCs) mature in response to TLR signalling. The MyD88 and TRIF (TICAM-1) pathways in mDCs are critical for driving cell-mediated immunity. They contribute mDC maturation to establishing antigen-specific T-cell proliferation, CTL and TH1 responses. mDC-mediated NK-cell activation is characterized by its TRIF-dependent properties which activate the transcription factor IRF-3. Induction of variable CD4 T cells such as TH2, TH17 and Treg are partly attributable to mDC maturation through the TLR pathways. NK and Treg are also modulated by the cytoplasmic IPS-1 pathway that activates the IPS-1 pathway for IRF-3 activation and IL-6 production.
Figure 4. The TLR signalling pathways. (a) MyD88 is the key signalling adaptor for all TLRs with the exception of TLR3 and certain TLR4 signals, IL-1R and IL-18R. Its main role is the activation of NF-B. It is directly recruited to the TIR domains in certain TLRs (here, shown for TLR5, TLR7, TLR8 and TLR9), and acts to recruit IRAK-4 (IL-1R-associated kinase 4). This leads to a pathway involving IRAK-1, tumour-necrosis-factor-receptor-associated factor 6 (TRAF6), transforming-growth-factor-activated kinase (TAK1) and the ubiquitylating factors ubiquitin-conjugating enzyme E2 variant 1 (UEV1A) and ubiquitin-conjugating enzyme 13 (UBC13), which modify and activate TRAF6 and TAK1. This leads to the activation of the inhibitor of NI-B kinase (IKK) complex and IF-B and the upstream kinases for p38 and JNK (JUN N-terminal kinase). MyD88 is targeted by negative regulators, such as a shorter form known as MyD88s, which interfere with IRAK-4 recruitment, and fatty acid synthase (FAS)-associated via death domain (FADD). IRAK-M can also inhibit signalling by preventing the release of IRAK-1 and IRAK-4 from MyD88. MyD88 also couples to IRF-5 and IRF-1. In the latter case, MyD88 traffics to the nucleus with IRF-1. In the case of TLR2 and TLR4 signalling, a bridging adaptor, MyD88-adaptor-like protein (Mal) , is required for MyD88 recruitment. This is subject to regulation by Bruton's tyrosine kinase (BTK) and suppressor of cytokine signalling 1 (SOCS1), which promotes Mal degradation. In the case of signalling by TLR7, TLR8 and TLR9, the MyD88–IRAK-4 pathway also leads through TRAF6 and TRAF3 to the activation of IRF-7. Finally, interferon receptor 1 (IFNR1) can also engage with MyD88 and through mixed-lineage kinase 3 (MLK3) leads to activation of p38. Target genes for each of these pathways are shown. MKK, mitogen-activated protein kinase kinase; TAB, TAK1-binding protein; TNF, tumour necrosis factor; Ub, ubiquitin. (b) IFN-inducing pathway involving TLRs. TLR9 and TLR7 signal exclusively via MyD88 to activate IRF-7 and NF-B. IRF-7 activation activates the IFN promoter in pDCs. TLR3 uses TICAM-1 but not MyD88 in mDCs to induce activation of IRF-3 and the IFN promoter. TRIF/TICAM-1 recruit RIP1, which together with TRAF6 activates NF-B. TLR4 signals via both MyD88 and TRIF/TICAM-1 in mDCs. TIRAP/Mal and TRAM/TICAM-2 are adapters involved in coupling TLR4 to MyD88 and TRIF, respectively. Either MyD88 or TRIF promotes activation of NF-B and MAPKs, leading to transcription of cytokine genes. TRIF in the TLR4 pathway also activates IRF-3, allowing weak IFN production.
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 References
    Alexopoulou L, Holt AC, Medzhitov R and Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413: 732–738.
    Benko S, Philpott DJ and Girardin SE (2008) The microbial and danger signals that activate Nod-like receptors. Cytokine 43: 368–373.
    Carty M, Goodbody R, Schröder M et al. (2006) The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nature Immunology 7: 1074–1081.
    Christensen SR, Shupe J, Nickerson K et al. (2006) Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25: 417–428.
    Diebold SS, Kaisho T, Hemmi H et al. (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303: 1529–1531.
    Ding AH, Porteu F, Sanchez E et al. (1990) Shared actions of endotoxin and taxol on TNF receptors and TNF release. Science 248: 370–372.
    Ebihara T, Shingai M, Matsumoto M et al. (2008) Hepatitis C virus-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells. Hepatology 48: 48–58.
    Ewald SE, Lee BL, Lau L et al. (2008) The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456: 658–662.
    Fitzgerald KA, McWhirter SM, Faia KL et al. (2003a) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nature Immunology 4: 491–496.
    Fitzgerald KA, Palsson-McDermott EM, Bowie AG et al. (2001) Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413: 78–83.
    Fitzgerald KA, Rowe DC, Barnes BJ et al. (2003b) LPS-TLR4 Signaling to IRF-3/7 and NF-{kappa}B involves the Toll adapters TRAM and TRIF. Journal of Experimental Medicine 198: 1043–1055.
    Franchi L, Warner N, Viani K and Nuñez G (2009) Function of Nod-like receptors in microbial recognition and host defense. Immunological Reviews 227: 106–128.
    Gavin AL, Hoebe K, Duong B et al. (2006) Adjuvant-enhanced antibody responses in the absence of Toll-like receptor signaling. Science 314: 1936–1938.
    Gewirtz AT, Navas TA, Lyons S et al. (2001) Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. Journal of Immunology 167: 1882–1885.
    Häcker H, Redecke V, Blagoev B et al. (2006) Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439: 204–207.
    Hayashi F, Smith KD, Ozinsky A et al. (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410: 1099–1103.
    Haziot A, Ferrero E, Kontgen F et al. (1996) Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice. Immunity 4: 407–414.
    Heil F, Hemmi H, Hochrein H et al. (2004) Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303: 1526–1529.
    Hemmi H, Kaisho T, Takeuchi O et al. (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nature Immunology 3: 196–200.
    Hemmi H, Takeuchi O, Kawai T et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408: 740–745.
    Honda K, Ohba Y, Yanai H et al. (2005) Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434: 1035–1040.
    Honda K, Yanai H, Negishi H et al. (2005) IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434: 772–777.
    Horng T, Barton GM, Flavell RA and Medzhitov R (2002) The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420: 329–333.
    Hoshino K, Takeuchi O, Kawai T et al. (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. Journal of Immunology 162: 3749–3752.
    Ito T, Amakama R, Kaisho T et al. (2002) Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets. Journal of Experimental Medicine 195: 1507–1512.
    Iwasaki A and Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nature Immunology 5: 987–995.
    Jack RS, Fan X, Bernheiden M et al. (1997) Lipopolysaccharide-binding protein is required to combat a murine gram-negative bacterial infection. Nature 389: 742–745.
    Jana M, Palencia CA and Pahan K (2008) Fibrillar amyloid-beta peptides activate microglia via TLR2: implications forAlzheimer's disease. Journal of Immunology 181: 7254–7762.
    Kawai T, Takeuchi O, Fujita T et al. (2001) Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. Journal of Immunology 167: 5887–5894.
    Kawasaki K, Akashi S, Shimazu R et al. (2000) Mouse Toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. Journal of Biological Chemistry 275: 2251–2254.
    Kim YM, Brinkmann MM, Paquet ME et al. (2008) UNC93B1 delivers nucleotide-sensing Toll-like receptors to endolysosomes. Nature 452: 234–238.
    Kim HM, Park BS, Kim JI et al. (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130: 906–917.
    Kono H and Rock KL (2008) How dying cells alert the immune system to danger. Nature Reviews Immunology 8: 279–289.
    Kurt-Jones EA, Popova L, Kwinn L et al. (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nature Immunology 1: 398–401.
    Latz E, Schoenemeyer A, Visintin A et al. (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunology 5: 190–198.
    Matsumoto F, Saitoh S, Fukui R et al. (2008) Cathepsins are required for Toll-like receptor 9 responses. Biochemical and Biophysical Research Communications 367: 693–699.
    Matsumoto M, Funami K, Tanabe M et al. (2003) Subcellular localization of Toll-like receptor 3 in human dendritic cells. Journal of Immunology 171: 3154–3162.
    Matsuo A, Oshiumi H, Tsujita T et al. (2008) Teleost TLR22 recognizes RNA duplex to induce IFN and protect cells from birnaviruses. Journal of Immunology 181: 3474–3485.
    Medzhitov R, Preston-Hurlburt P and Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394–397.
    Mullick AE, Soldau K, Kiosses WB et al. (2008) Increased endothelial expression of Toll-like receptor 2 at sites of disturbedblood flow exacerbates early atherogenic events. Journal of Experimental Medicine 205: 373–383.
    Nagai Y, Akashi S, Nagafuku M et al. (2002) Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nature Immunology 3: 667–672.
    Oganesyan G, Saha SK, Guo B et al. (2006) Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439: 208–211.
    Ohto U, Fukase K, Miyake K et al. (2007) Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science 316: 1632–1634.
    Oshiumi H, Matsumoto M, Funami K et al. (2003a) TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nature Immunology 4: 161–167.
    Oshiumi H, Sasai M, Shida K et al. (2003b) TICACM-2: a bridging adapter recruiting to Toll-like receptor 4 TICAM-1 that induces interferon-beta. Journal of Biological Chemistry 278: 49751–49762.
    Ozinsky A, Underhill DM, Fontenot JD et al. (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proceedings of the National Academy of Sciences of the USA 97: 13766–13771.
    Park B, Brinkmann MM, Spooner E et al. (2008) Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nature Immunology 9: 1407–1414.
    Pasare C and Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299: 1033–1036.
    Pasare C and Medzhitov R (2004) Toll-dependent control mechanisms of CD4 T cell activation. Immunity 21: 733–741.
    Poltorak A, He X, Smirnova I et al. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 2085–2088.
    Qureshi ST, Lariviere L, Leveque G et al. (1999) Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). Journal of Experimental Medicine 189: 615–625.
    Raetz CR and Whitfield C (2002) Lipopolysaccharide endotoxins. Annual Review of Biochemistry 71: 635–700.
    Ryzhakov G and Randow F (2007) SINTBAD: a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK. EMBO Journal 26: 3180–3190.
    Sasai M, Shingai M, Funami K et al. (2006) NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type I IFN induction. Journal of Immunology 177: 8676–8683.
    Sharma S, tenOever BR, Grandvaux N et al. (2003) Triggering the interferon antiviral response through an IKK-related pathway. Science 300: 1148–1151.
    Tsujita T, Tsukada H, Nakao M et al. (2004) Sensing bacterial flagellin by membrane and soluble orthologs of Toll-like receptor 5 in rainbow trout (Onchorhynchus mikiss). Journal of Biological Chemistry 279: 48588–48597.
    Yamamoto M, Sato S, Hemmi H et al. (2002) Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420: 324–329.
    Yamamoto M, Sato S, Hemmi H et al. (2003a) Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301: 640–643.
    Yamamoto M, Sato S, Hemmi H et al. (2003b) TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nature Immunology 4: 1144–1150.
    Yarovinsky F, Zhang D, Andersen JF et al. (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308: 1626–1629.
    Zhang D, Zhang G, Hayden MS et al. (2004) A Toll-like receptor that prevents infection by uropathogenic bacteria. Science 303: 1522–1526.
    Zhang SY, Jouanguy E, Sancho-Shimizu V et al. (2007) Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses. Immunological Reviews 220: 225–236.
 Further Reading
    Honda K and Taniguchi T (2006) IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nature Reviews Immunology 6: 644–658.
    Le Bon A and Tough DF (2002) Links between innate and adaptive immunity via type I interferon. Current Opinion in Immunology 14: 432–436.
    Medzhitov R (2007) Recognition of microorganisms and activation of the immune response. Nature 449: 819–8126.
    Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454: 428–435.
    O'Neill LA and Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nature Reviews Immunology 7: 353–364.
    Shortman K and Liu YJ (2002) Mouse and human dendritic cell subtypes. Nature Reviews Immunology 2: 151–161.
    Takeda K, Kaisho T and Akira S (2003) Toll-like receptors. Annual Review of Immunology 21: 335–376.

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Article Title: Toll‐like Receptors
 
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Seya, Tsukasa, and Miyake, Kensuke(Dec 2009) Toll‐like Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0004028.pub2]