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Mechanisms of Lymphocyte Activation and Immune Regulation X pp 11–18Cite as

Toll-Like Receptors: Linking Innate and Adaptive Immunity

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 560))

Abstract

Work in recent years has shown an essential role for Toll-like receptors (TLRs) in the activation of innate and adaptive immunity in vertebrate animals. These germ-line encoded receptors, expressed on a diverse variety of cells and tissues, recognize conserved molecular products derived from various classes of pathogens, including Gram-positive and -negative bacteria, DNA and RNA viruses, fungi and protozoa. Ligand recognition induces a conserved host defense program, which includes production of inflammatory cytokines, upregulation of costimulatory molecules, and induction of antimicrobial defenses. Importantly, activation of dendritic cells by TLR ligands is necessary for their maturation and consequent ability to initiate adaptive immune responses. How responses are tailored by individual TLRs to contain specific classes of pathogens is not yet clear.

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References

  1. Janeway CA, Jr.: Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989, 54 Pt 1: 1–13.

    PubMed  CAS  Google Scholar 

  2. Janeway CA, Jr., Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20: 197–216.

    Article  PubMed  CAS  Google Scholar 

  3. Takeda K, Kaishe T, Akira S: Toll-like receptors. Annu Rev Immunol 2003, 21:335–376.

    Article  PubMed  CAS  Google Scholar 

  4. Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R: Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2001, 2:947–950.

    Article  PubMed  CAS  Google Scholar 

  5. Pasare C, Medzhitov R: Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003, 299:1033–1036.

    Article  PubMed  CAS  Google Scholar 

  6. Poltorak A, He X, Smimova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, et al.: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998, 282:2085–2088.

    Article  PubMed  CAS  Google Scholar 

  7. Qureshi ST, Lariviere L, Leveque G, Clermont S, Moore KJ, Gros P, Malo D: Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med 1999, 189:615–625.

    Article  PubMed  CAS  Google Scholar 

  8. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S: Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 1999, 11:443–451.

    Article  PubMed  CAS  Google Scholar 

  9. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA: Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001, 413:732–738.

    Article  PubMed  CAS  Google Scholar 

  10. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S: Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8. Science 2004.

    Google Scholar 

  11. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis ESC: Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA. Science 2004.

    Google Scholar 

  12. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, et al.: A Toll-like receptor recognizes bacterial DNA. Nature 2000, 408:740–745.

    Article  PubMed  CAS  Google Scholar 

  13. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A: Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 2003, 198:513–520.

    Article  PubMed  CAS  Google Scholar 

  14. Barton GM, Medzhitov R: Toll-like receptor signaling pathways. Science 2003, 300:1524–1525.

    Article  PubMed  CAS  Google Scholar 

  15. Asca A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK: Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 2002, 277:15028–15034.

    Article  CAS  Google Scholar 

  16. Ohashi K, Burkart V, Flohe S, Kolb H: Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 2000, 164:558–561.

    PubMed  CAS  Google Scholar 

  17. Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H: HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 2002, 277:15107–15112.

    Article  PubMed  CAS  Google Scholar 

  18. Bausinger H, Lipsker D, Ziylan U, Manie S, Briand JP, Cazenave JP, Muller S, Haeuw JF, Ravanat C, de la Salle H, et al.: Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur J Immunol 2002, 32:3708–3713.

    Article  PubMed  CAS  Google Scholar 

  19. Gao B, Tsan MF: Recombinant Human Heat Shock Protein 60 Does Not Induce the Release of Tumor Necrosis Factor alpha from Murine Macrophages. J Biol Chem 2003, 278:22523–22529.

    Article  PubMed  CAS  Google Scholar 

  20. Gao B, Tsan MF: Endotoxin contamination in recombinant human heat shock protein 70 (Hsp 70) preparation is responsible for the induction of tumor necrosis factor alpha release by murine macrophages. J Biol Chem 2003, 278:174–179.

    Article  PubMed  CAS  Google Scholar 

  21. Starr TK, Jameson SC, Hogquist KA: Positive and negative selection of T cells. Annu Rev Immunol 2003, 21:139–176.

    Article  PubMed  CAS  Google Scholar 

  22. Goodnow CC, Crosbic J, Adelstein S, Lavoic TB, Smith-Gill SJ, Brink RA, Pritchard-Briscoe H, Wotherspoon JS, Loblay RH, Raphael K, et al.: Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 1988, 334:676–682.

    Article  PubMed  CAS  Google Scholar 

  23. Hartley SB, Crosbie J, Brink R, Kantor AB, Basten A, Goodnow CC: Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 1991, 353:765–769.

    Article  PubMed  CAS  Google Scholar 

  24. Cyster JG, Hartley SB, Goodnow CC: Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature 1994, 371:389–395.

    Article  PubMed  CAS  Google Scholar 

  25. Cyster JG, Goodnow CC: Antigen-induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate. Immunity 1995, 3:691–701.

    Article  PubMed  CAS  Google Scholar 

  26. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, et al.: Projection of an immunological self shadow within the thymus by the aire protein. Science 2002, 298:1395–1401.

    Article  PubMed  CAS  Google Scholar 

  27. Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC: Aire regulates negative selection of organ-specific T cells. Nat Immunol 2003, 4:350–354.

    Article  PubMed  CAS  Google Scholar 

  28. Peterson P, Nagamine K, Scott H, Heino M, Kudoh J, Shimizu N, Antonarakis SE, Krohn KJ: APECED: a monogenic autoimmune disease providing new clues to self-tolerance. Immunol Today 1998, 19:384–386.

    Article  PubMed  CAS  Google Scholar 

  29. Punt JA, Osborne BA, Takahama Y, Sharrow SO, Singer A: Negative selection of CD4+CD8+ thymocytes by T cell recptor-induced apoptosis requires a costimulatory signal that can be provided by CD28. J Exp Med 1994, 179:709–713.

    Article  PubMed  CAS  Google Scholar 

  30. Punt JA, Havran W, Abe R, Sarin A, Singer A: T cell receptor (TCR)-induced death of immature CD4+CD8+ thymocytes by two distinct mechanisms differing in their requirement for CD28 costimulation: implications for negative selection in the thymus. J Exp Med 1997, 186:1911–1922.

    Article  PubMed  CAS  Google Scholar 

  31. Kishimoto H, Cai Z, Brunmark A, Jackson MR, Peterson PA, Sprent J: Differing roles for B7 and intercellular adhesion molecule-1 in negative selection of thymocytes. J Exp Med 1996, 184:531–537

    Article  PubMed  CAS  Google Scholar 

  32. Sprent J, Kishimoto H: The thymus and negative selection. Immunol Rev 2002, 185:126–135.

    Article  PubMed  CAS  Google Scholar 

  33. Lenschow DJ, Walunas TL, Bluestone JA: CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996, 14:233–258.

    Article  PubMed  CAS  Google Scholar 

  34. Liu Y, Janeway CA, Jr.: Cells that present both specific ligand and costimulatory activity are the most efficient inducers of clonal expansion of normal CD4 T cells. Proc Natl Acad Sci U S A 1992, 89:3845–3849

    Article  PubMed  CAS  Google Scholar 

  35. Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 1998, 392:245–252

    Article  PubMed  CAS  Google Scholar 

  36. Medzhitov R: Toll-like receptors and innate immunity. Nat Rev Immunol 2001, 1:135–145.

    Article  PubMed  CAS  Google Scholar 

  37. Belz GT, Behrens GM, Smith CM, Miller JF, Jones C, Lejon K, Fathman CG, Mueller SN, Shortman K, Carbone FR, et al.: The CD8alpha(+) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens. J Exp Med 2002, 196:1099–1104.

    Article  PubMed  CAS  Google Scholar 

  38. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, Ravetch JV, Steinman RM, Nussenzweig MC: Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 2001, 194:769–779.

    Article  PubMed  CAS  Google Scholar 

  39. Menges M, Rossner S, Voigtlander C, Schindler H, Kukutsch NA, Bogdan C, Erb K, Schuler G, Lutz MB: Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity. J Exp Med 2002, 195:15–21.

    Article  PubMed  CAS  Google Scholar 

  40. Wakkach A, Fournier N, Brun V, Breittmayer JP, Cottrez F, Groux H: Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity 2003, 18:605–617.

    Article  PubMed  CAS  Google Scholar 

  41. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune discases. J Immunol 1995, 155:1151–1164.

    PubMed  CAS  Google Scholar 

  42. Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003, 4:330–336.

    Article  PubMed  CAS  Google Scholar 

  43. Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299:1057–1061.

    Article  PubMed  CAS  Google Scholar 

  44. Asano M, Toda M, Sakaguchi N, Sakaguchi S: Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996, 184:387–396.

    Article  PubMed  CAS  Google Scholar 

  45. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG: A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997, 389:737–742.

    Article  PubMed  CAS  Google Scholar 

  46. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL: Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994, 265:1237–1240.

    Article  PubMed  CAS  Google Scholar 

  47. Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Boleskei PL, Wagner M, et al.: Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 2001, 291:1544–1547.

    Article  PubMed  CAS  Google Scholar 

  48. Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ: Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 2000, 1:113–118.

    Article  PubMed  CAS  Google Scholar 

  49. Krug A, Luker GD, Barchet W, Leib DA, Akira S, Colomna M: Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood 2004, 103:1433–1437.

    Article  PubMed  CAS  Google Scholar 

  50. Steinman RM, Hawiger D, Nussenzweig MC: Tolerogenic dendritic cells. Annu Rev Immunol 2003, 21:685–711.

    Article  PubMed  CAS  Google Scholar 

  51. Kaisho T, Takeuchi O, Kawai T, Hoshino K, Akira S: Endotoxin-induced maturation of MyD88-deficient dendritic cells. J Immunol 2001, 166:5688–5694.

    PubMed  CAS  Google Scholar 

  52. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudelle BC, Shlomchik MJ, Marshak-Rothstein A: Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002, 416:603–607.

    Article  PubMed  CAS  Google Scholar 

  53. Rui L, Vinuesa CG, Blasioli J, Goodnow CC: Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. Nat Immunol 2003, 4:594–600.

    Article  PubMed  CAS  Google Scholar 

  54. Drakesmith H, Chain B, Beverley P: How can dendritic cells cause autoimmune disease? Immunol Today 2000, 21:214–217.

    Article  PubMed  CAS  Google Scholar 

  55. Alonzi T, Fattori E, Lazzaro D, Costa P, Probert L, Kollias G, De Benedetti F, Poli V, Ciliberto G: Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 1998, 187:461–468.

    Article  PubMed  CAS  Google Scholar 

  56. Kobayashi H, Ohshima S, Nishioka K, Yamaguchi N, Umeshita-Sasai M, Ishii T, Mima T, Kishimoto T, Kawase I, Saeki Y: Antigen induced arthritis (AIA) can be transferred by bone marrow transplantation: evidence that interleukin 6 is essential for induction of AIA. J Rheumatol 2002, 29:1176–1182.

    PubMed  CAS  Google Scholar 

  57. Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Nomura S, Kopf M, Katada Y, Tanaka T, Suemura M, et al.: Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci U S A 1998, 95:8222–8226.

    Article  PubMed  CAS  Google Scholar 

  58. Richards HB, Satoh M, Shaw M, Libert C, Poli V, Reeves WH: Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. J Exp Med 1998, 188:985–990.

    Article  PubMed  CAS  Google Scholar 

  59. Rose NR: The role of infection in the pathogenesis of autoimmune disease. Semin Immunol 1998, 10:5–13.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, 300 Cedar Street, TAC S660, New Haven, CT, 06510

    Ruslan Medzhitov

Authors
  1. Chandrashekhar Pasare
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  2. Ruslan Medzhitov
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Editor information

Editors and Affiliations

  1. University of California Irvine, Irvine, California

    Sudhir Gupta

  2. NIAID, NIH, Bethesda, Maryland

    William E. Paul

  3. Rockefeller University, New York, New York

    Ralph Steinman

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© 2005 Springer Science + Business Media, Inc.

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Pasare, C., Medzhitov, R. (2005). Toll-Like Receptors: Linking Innate and Adaptive Immunity. In: Gupta, S., Paul, W.E., Steinman, R. (eds) Mechanisms of Lymphocyte Activation and Immune Regulation X. Advances in Experimental Medicine and Biology, vol 560. Springer, Boston, MA. https://doi.org/10.1007/0-387-24180-9_2

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