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7 - Toll-Like Receptor-Dependent Activation of Antigen Presenting Cells by Hsp60, gp96 and Hsp70

Published online by Cambridge University Press:  10 August 2009

By
Ramunas M. Vabulas  and
Hermann Wagner
Edited by
Brian Henderson  and
A. Graham Pockley
Ramunas M. Vabulas
Affiliation:
Max-Planck-Institut für Biochemie, Martinsried, Germany
Hermann Wagner
Affiliation:
Institut für Med. Mikrobiologie, Immunologie u. Hygiene, Technische Universität München, München, Germany
Brian Henderson
Affiliation:
University College London
A. Graham Pockley
Affiliation:
University of Sheffield
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Summary

Discovery of Toll-like receptors

The basic concept of the immune system postulates an ability to discriminate between self and non-self and to free the organism from the latter. Two major contributions advanced the comprehension of the cellular basis of self- versus non-self-discrimination. The first was the hypothesis regarding the expansion of antigen-recognising clones on encounter with a respective antigen, which allowed antigenic specificities of the resulting immune reactions to be explained. The co-stimulatory signal hypothesis represented another essential advancement. It postulated the necessity of a second, antigen-independent signal for lymphocyte activation. Its nature was put into an elegant metaphor of the ‘immunologist's dirty little secret’ [1], referring to substances of microbial origin that should be present concomitant with an antigen to prime an immune response to it.

Of a number of host receptors participating in detection of microbial constituents [2], Toll-like receptors (TLRs) currently represent the most interesting group. Their importance is assumed from the prominent cell activating capacity which they display after engagement with their cognate ligands. The name originates from the Drosophila homologue Toll, which was discovered as a part of the dorsoventral patterning cascade during the developmental larva stage of the fruit fly, and this seminal study established an additional, anti-microbial function for Toll in adult flies [3]. It demonstrated that mutants of the genes in the cassette between the Toll ligand Spätzle down to the IκB homologue Cactus showed a compromised inducibility of the anti-fungal peptide drosomycin upon fungal challenge and consequently succumbed to the infection.

Type
Chapter
Information
Molecular Chaperones and Cell Signalling , pp. 113 - 132
Publisher: Cambridge University Press
Print publication year: 2005

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References

Janeway, C A J.Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989, 54 Pt 1: 1–13Google Scholar
Gordon, S. Pattern recognition receptors: doubling up for the innate immune response. Cell 2002, 111: 927–930Google Scholar
Lemaitre, B, Nicolas, E, Michaut, L, Reichhart, J M and Hoffmann, J A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996, 86: 973–983Google Scholar
Medzhitov, R, Preston-Hurlburt, P and Janeway, C A J. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997, 388: 394–397Google Scholar
Kobe, B and Deisenhofer, J. A structural basis of the interactions between leucine-rich repeats and protein ligands. Nature 1995, 374: 183–186Google Scholar
Bell, J K, Mullen, G E, Leifer, C A, Mazzoni, A, Davies, D R and Segal, D M. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol 2003, 24: 528–533Google Scholar
Gay, N J and Keith, F J. Drosophila Toll and IL-1 receptor. Nature 1991, 351: 355–356Google Scholar
Schneider, D S, Hudson, K L, Lin, T Y and Anderson, K V. Dominant and recessive mutations define functional domains of Toll, a transmembrane protein required for dorsal-ventral polarity in the Drosophila embryo. Genes Dev 1991, 5: 797–807Google Scholar
Whitham, S, Dinesh-Kumar, S P, Choi, D, Hehl, R, Corr, C and Baker, B. The product of the tobacco mosaic virus resistance gene N: similarity to toll and the interleukin-1 receptor. Cell 1994, 78: 1101–1115Google Scholar
Rock, F L, Hardiman, G, Timans, J C, Kastelein, R A and Bazan, J F. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 1998, 95: 588–593Google Scholar
Xu, Y, Tao, X, Shen, B, Horng, T, Medzhitov, R, Manley, J L and Tong, L. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 2000, 408: 111–115Google Scholar
Adachi, O, Kawai, T, Takeda, K, Matsumoto, M, Tsutsui, H, Sakagami, M, Nakanishi, K and Akira, S. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 1998, 9: 143–150Google Scholar
Kawai, T, Adachi, O, Ogawa, T, Takeda, K and Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999, 11: 115–122Google Scholar
Suzuki, N, Suzuki, S, Duncan, G S, Millar, D G, Wada, T, Mirtsos, C, Takada, H, Wakeham, A, Itie, A, Li, S, Penninger, J M, Wesche, H, Ohashi, P S, Mak, T W and Yeh, W C. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002, 416: 750–756Google Scholar
Kobayashi, K, Hernandez, L D, Galan, J E, Janeway, C A J, Medzhitov, R and Flavell, R A. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 2002, 110: 191–202Google Scholar
Deng, L, Wang, C, Spencer, E, Yang, L, Braun, A, You, J, Slaughter, C, Pickart, C and Chen, Z J. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 2000, 103: 351–361Google Scholar
Wang, C, Deng, L, Hong, M, Akkaraju, G R, Inoue, J and Chen, Z J. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 2001, 412: 346–351Google Scholar
Horng, T, Barton, G M, Flavell, R A and Medzhitov, R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 2002, 420: 329–333Google Scholar
Yamamoto, M, Sato, S, Hemmi, H, Sanjo, H, Uematsu, S, Kaisho, T, Hoshino, K, Takeuchi, O, Kobayashi, M, Fujita, T, Takeda, K and Akira, S. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 2002, 420: 324–329Google Scholar
Hoebe, K, Du, X, Georgel, P, Janssen, E, Tabeta, K, Kim, S O, Goode, J, Lin, P, Mann, N, Mudd, S, Crozat, K, Sovath, S, Han, J and Beutler, B. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 2003, 424: 743–748Google Scholar
Yamamoto, M, Sato, S, Hemmi, H, Hoshino, K, Kaisho, T, Sanjo, H, Takeuchi, O, Sugiyama, M, Okabe, M, Takeda, K and Akira, S. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003, 301: 640–643Google Scholar
Yamamoto, M, Sato, S, Hemmi, H, Uematsu, S, Hoshino, K, Kaisho, T, Takeuchi, O, Takeda, K and Akira, S. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003, 4: 1144–1150Google Scholar
Kaufmann, S H E. Heat shock proteins and the immune response. Immunol Today 1990, 11: 129–136Google Scholar
Hartl, F U and Hayer-Hartl, M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 2002, 295: 1852–1858Google Scholar
Udono, H and Srivastava, P K. Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 1993, 178: 1391–1396Google Scholar
Arnold, D, Faath, S, Rammensee, H-G and Schild, H. Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp96. J Exp Med 1995, 182: 885–889Google Scholar
Suto, R and Srivastava, P K. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 1995, 269: 1585–1588Google Scholar
Kol, A, Sukhova, G K, Lichtman, A H and Libby, P. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumour necrosis factor-a and matrix metalloproteinase expression. Circulation 1998, 98: 300–307Google Scholar
Chen, W, Syldath, U, Bellmann, K, Burkart, V and Kold, H. Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J Immunol 1999, 162: 3212–3219Google Scholar
Kol, A, Bourcier, T, Lichtman, A and Libby, P. Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Invest 1999, 103: 571–577Google Scholar
Kol, A, Lichtman, A H, Finberg, R W, Libby, P and Kurt-Jones, E A. Heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol 2000, 164: 13–17Google Scholar
Wright, S D, Ramos, R A, Tobias, P S, Ulevitch, R J and Mathison, J C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 1990, 249: 1431–1433Google Scholar
Pugin, J, Heumann, I D, Tomasz, A, Kravchenko, V V, Akamatsu, Y, Nishijima, M, Glauser, M P, Tobias, P S and Ulevitch, R J. CD14 is a pattern recognition receptor. Immunity 1994, 1: 509–516Google Scholar
da Silva Correia, J, Soldau, K, Christen, U, Tobias, P S and Ulevitch, R J. Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. Transfer from CD14 to TLR4 and MD-2. J Biol Chem 2001, 276: 21129–21135Google Scholar
Ohashi, K, Burkart, V, Flohé, S and Kolb, H. Heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex. J Immunol 2000, 164: 558–561Google Scholar
Poltorak, A, He, X, Smirnova, I, Liu, M Y, Huffel, C, Du, X, Birdwell, D, Alejos, E, Silva, M, Galanos, C, Freudenberg, M, Ricciardi-Castagnoli, P, Layton, B and Beutler, B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998, 282: 2085–2088Google Scholar
Vabulas, R M, Ahmad-Nejad, P, da Costa, C, Miethke, T, Kirschning, C J, Hacker, H and Wagner, H. Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem 2001, 276: 31332–31339Google Scholar
Alexopoulou, L, Holt, A C, Medzhitov, R and Flavell, R A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001, 413: 732–738Google Scholar
Shimazu, R, Akashi, S, Ogata, H, Nagai, Y, Fukudome, K, Miyake, K and Kimoto, M. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 1999, 189: 17777–17782Google Scholar
Ahmad-Nejad, P, Hacker, H, Rutz, M, Bauer, S, Vabulas, R M and Wagner, H. Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur J Immunol 2002, 32: 1958–1968Google Scholar
Billack, B, Heck, D E, Mariano, T M, Gardner, C R, Sur, R, Laskin, D L and Laskin, J D. Induction of cyclooxygenase-2 by heat shock protein 60 in macrophages and endothelial cells. Am J Physiol (Cell Physiol) 2002, 283: C1267–1277Google Scholar
Sasu, S, LaVerda, D, Qureshi, N, Golenbock, D T and Beasley, D. Chlamydia pneumoniae and chlamydial heat shock protein 60 stimulate proliferation of human vascular smooth muscle cells via toll-like receptor 4 and p44/p42 mitogen-activated protein kinase activation. Circ Res 2001, 89: 244–250Google Scholar
Zhang, L, Pelech, S L, Mayrand, D, Grenier, D, Heino, J and Uitto, V J. Bacterial heat shock protein-60 increases epithelial cell proliferation through the ERK1/2 MAP kinases. Exp Cell Res 2001, 266: 11–20Google Scholar
Bulut, Y, Faure, E, Thomas, L, Karahashi, H, Michelsen, K S, Equils, O, Morrison, S G, Morrison, R P and Arditi, M. Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J Immunol 2002, 168: 1435–1440Google Scholar
Flohé, S B, Bruggemann, J, Lendemans, S, Nikulina, M, Meierhoff, G, Flohé, S and Kolb, H. Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype. J Immunol 2003, 170: 2340–2348Google Scholar
Zanin-Zhorov, A, Nussbaum, G, Franitza, S, Cohen, I R and Lider, O. T cells respond to heat shock protein 60 via TLR2: activation of adhesion and inhibition of chemokine receptors. FASEB J 2003, 17: 1567–1569Google Scholar
Latz, E, Visintin, A, Lien, E, Fitzgerald, K A, Monks, B G, Kurt-Jones, E A, Golenbock, D T and Espevik, T. Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J Biol Chem 2002, 277: 47834–47843Google Scholar
Basu, S, Binder, R J, Suto, R, Anderson, K M and Srivastava, P K. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activates the NF-kB pathway. Int Immunol 2000, 12: 1539–1546Google Scholar
Singh-Jasuja, H, Scherer, H U, Hilf, N, Arnold-Schild, D, Rammensee, H-G, Toes, R E M and Schild, H. The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor. Eur J Immunol 2000, 30: 2211–2215Google Scholar
Baker-LePain, J C, Sarzotti, M, Fields, T A, Li, C Y and Nicchitta, C V. GRP94 (gp96) and GRP94 N-terminal geldanamycin binding domain elicit tissue nonrestricted tumor suppression. J Exp Med 2002, 196: 1447–1459Google Scholar
Vabulas, R M, Braedel, S, Hilf, N, Singh-Jasuja, H, Herter, S, Ahmad-Nejad, P, Kirschning, C J, Da Costa, C, Rammensee, H G, Wagner, H and Schild, H. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J Biol Chem 2002, 277: 20847–20853Google Scholar
Randow, F and Seed, B. Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability. Nat Cell Biol 2001, 3: 891–896Google Scholar
Asea, A, Kraeft, S-K, Kurt-Jones, E A, Stevenson, M A, Chen, L B, Finberg, R W, Koo, G C and Calderwood, S K. Hsp70 stimulates cytokine production through a CD14-dependent pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000, 6: 435–442Google Scholar
Kuppner, M C, Gastpar, R, Gelwer, S, Nossner, E, Ochmann, O, Scharner, A and Issels, R D. The role of heat shock protein (hsp70) in dendritic cell maturation: hsp70 induces the maturation of immature dendritic cells but reduces DC differentiation from monocyte precursors. Eur J Immunol 2001, 31: 1602–1609Google Scholar
Vabulas, R M, Ahmad-Nejad, P, Ghose, S, Kirschning, C J, Issels, R D and Wagner, H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 2002, 277: 15107–15112Google Scholar
Asea, A, Rehli, M, Kabingu, E, Boch, J A, Baré, O, Auron, P E, Stevenson, M A and Calderwood, S K. Novel signal transduction pathway utilized by extracellular HSP70. Role of Toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002, 277: 15028–15034Google Scholar
Dybdahl, B, Wahba, A, Lien, E, Flo, T H, Waage, A, Qureshi, N, Sellevold, O F, Espevik, T and Sundan, A. Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through Toll-like receptor-4. Circulation 2002, 105: 685–690Google Scholar
Kakimura, J, Kitamura, Y, Takata, K, Umeki, M, Suzuki, S, Shibagaki, K, Taniguchi, T, Nomura, Y, Gebicke-Haerter, P J, Smith, M A, Perry, G and Shimohama, S. Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. FASEB J 2002: 601–603Google Scholar
Underhill, D M. Toll-like receptors: networking for success. Eur J Immunol 2003, 33: 1767–1775Google Scholar
Binder, R J, Han, D K and Srivastava, P K. CD91: a receptor for heat shock protein gp96. Nat Immunol 2000, 1: 151–155Google Scholar
Berwin, B, Hart, J P, Rice, S, Gass, C, Pizzo, S V, Post, S R and Nicchitta, C V. Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO J 2003, 22: 6127–6136Google Scholar
Basu, S, Binder, R J, Ramalingam, T and Srivastava, P K. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70 and calreticulin. Immunity 2001, 14: 303–313Google Scholar
Delneste, Y, Magistrelli, G, Gauchat, J, Haeuw, J, Aubry, J, Nakamura, K, Kawakami-Honda, N, Goetsch, L, Sawamura, T, Bonnefoy, J and Jeannin, P. Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity 2002, 17: 353–362Google Scholar
Wang, Y, Kelly, C G, Karttunen, T, Whittall, T, Lehner, P J, Duncan, L, MacAry, P, Younson, J S, Singh, M, Oehlmann, W, Cheng, G, Bergmeier, L and Lehner, T. CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 2001, 15: 971–983Google Scholar
Becker, T, Hartl, F U and Wieland, F. CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 2002, 158: 1277–1285Google Scholar
Eden, W. Stress proteins as targets for anti-inflammatory therapies. Drug Discov Today 2000, 5: 115–120Google Scholar
Reed, R C, Berwin, B, Baker, J P and Nicchitta, C V. GRP94/gp96 elicits ERK activation in murine macrophages. A role for endotoxin contamination in NF-kappa B activation and nitric oxide production. J Biol Chem 2003, 278: 31853–31860Google Scholar
Bausinger, H, Lipsker, D, Ziylan, U, Manie, S, Briand, J P, Cazenave, J P, Muller, S, Haeuw, J F, Ravanat, C, Salle, H and Hanau, D. Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur J Immunol 2002, 32: 3708–3713Google Scholar
Gao, B and Tsan, M F. Endotoxin contamination in recombinant human Hsp70 preparation is responsible for the induction of TNFα release by murine macrophages. J Biol Chem 2003, 278: 174–179Google Scholar
Gao, B and Tsan, M F. Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor alpha from murine macrophages. J Biol Chem 2003, 278: 22523–22529Google Scholar
Millar, D G, Garza, K M, Odermatt, B, Elford, A R, Ono, N, Li, Z and Ohashi, P S. Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med 2003, 9: 1469–1476Google Scholar
Liu, B, Dai, J, Zheng, H, Stoilova, D, Sun, S and Li, Z. Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proc Nat Acad Sci USA 2003, 100: 15824–15829Google Scholar
Matzinger, P. The Danger Model: A renewed sense of self. Science 2002, 296: 301–305Google Scholar
Gallucci, S, Lolkema, M and Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nat Med 1999, 11: 1249–1255Google Scholar
Sauter, B, Albert, M L, Francisco, L, Larsson, M, Somersan, S and Bhardwaj, N. Consequences of cell death: exposure to necrotic tumour cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med 2000, 191: 423–433Google Scholar
Li, M, Carpio, D F, Zheng, Y, Bruzzo, P, Singh, V, Ouaaz, F, Medzhitov, R M and Beg, A A. An essential role of the NF-kappa B/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. J Immunol 2001, 166: 7128–7135Google Scholar
Somersan, S, Larsson, M, Fonteneau, J F, Basu, S, Srivastava, P and Bhardwaj, N. Primary tumor tissue lysates are enriched in heat shock proteins and induce the maturation of human dendritic cells. J Immunol 2001, 167: 4844–4852Google Scholar
Bukau, B and Horwich, A L. The Hsp70 and Hsp60 chaperone machines. Cell 1998, 92: 351–366Google Scholar

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