A human homologue of the Drosophila Toll protein signals activation of adaptive immunity (original) (raw)

Nature volume 388, pages 394–397 (1997)Cite this article

Abstract

Induction of the adaptive immune response depends on the expression of co-stimulatory molecules and cytokines by antigen-presenting cells. The mechanisms that control the initial induction of these signals upon infection are poorly understood. It has been proposed that their expression is controlled by the non-clonal, or innate, component of immunity that preceded in evolution the development of an adaptive immune system in vertebrates1. We report here the cloning and characterization of a human homologue of the Drosophila toll protein (Toll) which has been shown to induce the innate immune response in adult Drosophila2,3,4. Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor. Both Drosophila Toll and the IL-1 receptor are known to signal through the NF-κB pathway5,6,7. We show that a constitutively active mutant of human Toll transfected into human cell lines can induce the activation of NF-κB and the expression of NF-κB-controlled genes for the inflammatory cytokines IL-1, IL-6 and IL-8, as well as the expression of the co-stimulatory molecule B7.1, which is required for the activation of naive T cells.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Janeway, C. A. J Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symp. Quant. Biol. 54, 1–13 (1989).
    Article CAS Google Scholar
  2. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M. & Hoffmann, J. A. The dorsoventral regulatory gene cassette spatzle/toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996).
    Article CAS Google Scholar
  3. Rosetto, M., Engström, Y., Baldari, C. T., Telford, J. L. & Hultmark, D. Signals from the IL-1 receptor homolog, Toll, can activate an immune response in a Drosophila hemocyte cell line. Biochem. Biophys. Res. Commun. 209, 111–116 (1995).
    Article CAS Google Scholar
  4. Ip, Y. T. & Levine, M. Molecular genetics of Drosophila immunity. Curr. Opin. Genet. Dev. 4, 672–677 (1994).
    Article CAS Google Scholar
  5. Wasserman, S. A. Aconserved signal transduction pathway regulating the activity of rel-like proteins dorsal and NF-κB. Mol. Biol. Cell 4, 767–771 (1993).
    Article CAS Google Scholar
  6. Hultmark, D. Insect immunology: Ancient relationships. Nature 367, 116–117 (1994).
    Article ADS CAS Google Scholar
  7. Belvin, M. P. & Anderson, K. V. Aconserved signaling pathway: the Drosophila Toll–dorsal pathway. Annu. Rev. Cell Dev. Biol. 12, 393–416 (1996).
    Article CAS Google Scholar
  8. Morisato, D. & Anderson, K. V. The spatzle gene encodes a component of the extracellular signaling pathway establishing the dorsal–ventral pattern of the Drosophila embryo. Cell 76, 677–688 (1994).
    Article CAS Google Scholar
  9. Gay, N. J. & Keith, F. J. Drosophila Toll and IL-1 receptor. Nature 351, 355–356 (1991).
    Article ADS CAS Google Scholar
  10. Whitham, S. et al. The product of the tobacco mosaic virus resistance gene N: similarity to toll and the interleukin-1 receptor. Cell 78, 1101–1115 (1994).
    Article CAS Google Scholar
  11. Altschul, S. F., Boguski, M. S., Gish, W. & Wootton, J. C. Issues in searching molecular sequence databases. Nature Genet. 6, 119–129 (1994).
    Article CAS Google Scholar
  12. Lennon, G., Auffray, C., Polymeropoulos, M. & Soares, M. B. The IMAGE Consortium: an integrated molecular analysis of genomes and their expression. Genomics 33, 151–152 (1996).
    Article CAS Google Scholar
  13. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual(Cold Spring Harbor Laboratory Press, New York, (1989)).
    Google Scholar
  14. Innis, M. A., Gelfand, D. H., Sninsky, J. J. & White, T. J. (eds) PCR Protocols: A Guide to Methods and Applications(Academic, Orlando, (1992)).
    Google Scholar
  15. Miyake, K., Yamashita, Y., Ogata, M., Sudo, T. & Kimoto, M. RP105, a novel B cell surface molecule implicated in B cell activation, is a member of the leucine-rich repeat protein family. J. Immunol. 154, 3333–3340 (1995).
    CAS PubMed Google Scholar
  16. Schneider, D. S., Hudson, K. L., Lin, T. Y. & 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. 5, 797–807 (1991).
    Article CAS Google Scholar
  17. Takahashi, N., Takahashi, Y. & Putnam, F. W. Periodicity of leucine and tandem repetition of a 24-amino acid segment in the primary structure of leucine-rich alpha 2-glycoprotein of human serum. Proc. Natl Acad. Sci. USA 82, 1906–1910 (1985).
    Article ADS CAS Google Scholar
  18. Winans, K. A. & Hashimoto, C. Ventralization of the Drosophila embryo by deletion of extracellular leucine-rich repeats in the Toll protein. Mol. Biol. Cell. 6, 587–596 (1995).
    Article CAS Google Scholar
  19. Fearon, D. T. & Locksley, R. M. The instructive role of innate immunity in the acquired immune response. Science 272, 50–53 (1996).
    Article ADS CAS Google Scholar
  20. Medzhitov, R. & Janeway, C. A. J On the semantics of immune recognition. Res. Immunol. 147, 208–214 (1996).
    Article CAS Google Scholar
  21. Yamamura, M. et al. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science 254, 277–279 (1991).
    Article ADS CAS Google Scholar

Download references

Acknowledgements

We thank our colleagues for discussions; P. G. Waterbury for DNA sequencing; S.Ghosh and R. Voll for pB2XLuc plasmid and for helpful suggestions; and J. Flaxenberg for assistance. We acknowledge the Howard Hughes Medical Institute and the NIAID, NIH for support of this work.

Author information

Authors and Affiliations

  1. *Section of Immunobiology, Yale University School of Medicine, New Haven, 06520-8011, Connecticut, USA
    Ruslan Medzhitov & Charles A. Janeway Jr
  2. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 06520-8011, Connecticut, USA
    Paula Preston-Hurlburt

Authors

  1. Ruslan Medzhitov
    You can also search for this author inPubMed Google Scholar
  2. Paula Preston-Hurlburt
    You can also search for this author inPubMed Google Scholar
  3. Charles A. Janeway Jr
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toCharles A. Janeway Jr.

Rights and permissions

About this article

Cite this article

Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.Nature 388, 394–397 (1997). https://doi.org/10.1038/41131

Download citation