The History of Toll-like Receptors - Redefining Innate Immunity

Overview

Journal Nat Rev Immunol

Specialty Allergy & Immunology

Date 2013 May 18

PMID 23681101

Citations 751

Authors

Luke A J ONeill

Douglas Golenbock

Andrew G Bowie

Affiliations

Soon will be listed here.

Abstract

The discovery of Toll-like receptors (TLRs) was an important event for immunology research and was recognized as such with the awarding of the 2011 Nobel Prize in Physiology or Medicine to Jules Hoffmann and Bruce Beutler, who, together with Ralph Steinman, the third winner of the 2011 Nobel Prize and the person who discovered the dendritic cell, were pioneers in the field of innate immunity. TLRs have a central role in immunity - in this Timeline article, we describe the landmark findings that gave rise to this important field of research.

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References

Means T, Latz E, Hayashi F, Murali M, Golenbock D, Luster A . Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest. 2005; 115(2):407-17. PMC: 544604. DOI: 10.1172/JCI23025. View

Alexopoulou L, Holt A, Medzhitov R, Flavell R . Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001; 413(6857):732-8. DOI: 10.1038/35099560. View

Netea M, Wijmenga C, ONeill L . Genetic variation in Toll-like receptors and disease susceptibility. Nat Immunol. 2012; 13(6):535-42. DOI: 10.1038/ni.2284. View

Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T . TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature. 2010; 465(7300):937-41. PMC: 2964153. DOI: 10.1038/nature09102. View

Ku C, von Bernuth H, Picard C, Zhang S, Chang H, Yang K . Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007; 204(10):2407-22. PMC: 2118442. DOI: 10.1084/jem.20070628. View

Zhang D, Zhang G, Hayden M, Greenblatt M, Bussey C, Flavell R . A toll-like receptor that prevents infection by uropathogenic bacteria. Science. 2004; 303(5663):1522-6. DOI: 10.1126/science.1094351. View

Frey E, Miller D, Jahr T, Sundan A, Bazil V, Espevik T . Soluble CD14 participates in the response of cells to lipopolysaccharide. J Exp Med. 1992; 176(6):1665-71. PMC: 2119444. DOI: 10.1084/jem.176.6.1665. View

Oldenburg M, Kruger A, Ferstl R, Kaufmann A, Nees G, Sigmund A . TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. Science. 2012; 337(6098):1111-5. DOI: 10.1126/science.1220363. View

Schumann R, Leong S, Flaggs G, Gray P, Wright S, Mathison J . Structure and function of lipopolysaccharide binding protein. Science. 1990; 249(4975):1429-31. DOI: 10.1126/science.2402637. View

10.

Lemaitre B . The road to Toll. Nat Rev Immunol. 2004; 4(7):521-7. DOI: 10.1038/nri1390. View

11.

Uematsu S, Fujimoto K, Jang M, Yang B, Jung Y, Nishiyama M . Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol. 2008; 9(7):769-76. DOI: 10.1038/ni.1622. View

12.

Hirschfeld M, Ma Y, Weis J, Vogel S, Weis J . Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J Immunol. 2000; 165(2):618-22. DOI: 10.4049/jimmunol.165.2.618. View

13.

Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H . Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003; 301(5633):640-3. DOI: 10.1126/science.1087262. View

14.

Osterloh J, Yang J, Rooney T, Fox A, Adalbert R, Powell E . dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012; 337(6093):481-4. PMC: 5225956. DOI: 10.1126/science.1223899. View

15.

Baeuerle P, Henkel T . Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994; 12:141-79. DOI: 10.1146/annurev.iy.12.040194.001041. View

16.

Krug A, French A, Barchet W, Fischer J, Dzionek A, Pingel J . TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity. 2004; 21(1):107-19. DOI: 10.1016/j.immuni.2004.06.007. View

17.

Jin M, Kim S, Heo J, Lee M, Kim H, Paik S . Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell. 2007; 130(6):1071-82. DOI: 10.1016/j.cell.2007.09.008. View

18.

Hertz C, Kiertscher S, Godowski P, Bouis D, Norgard M, Roth M . Microbial lipopeptides stimulate dendritic cell maturation via Toll-like receptor 2. J Immunol. 2001; 166(4):2444-50. DOI: 10.4049/jimmunol.166.4.2444. View

19.

Hidmark A, von Saint Paul A, Dalpke A . Cutting edge: TLR13 is a receptor for bacterial RNA. J Immunol. 2012; 189(6):2717-21. DOI: 10.4049/jimmunol.1200898. View

20.

Farrar C, Keogh B, McCormack W, OShaughnessy A, Parker A, Reilly M . Inhibition of TLR2 promotes graft function in a murine model of renal transplant ischemia-reperfusion injury. FASEB J. 2011; 26(2):799-807. DOI: 10.1096/fj.11-195396. View