Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function

Abstract

Dendritic cells are rare haematopoietic cells that reside in a number of organs and tissues. By capturing, processing and presenting antigens to T cells, dendritic cells are essential for immune surveillance and the regulation of specific immunity1,2,3,4. Several members of the tumour necrosis factor receptor (TNFR) superfamily are integral to the regulation of the immune response. These structurally related proteins modulate cellular functions ranging from proliferation and differentiation to inflammation and cell survival or death5,6. The functional activity of dendritic cells is greatly increased by signalling through the TNFR family member CD40 (refs 7, 8). Here we report the characterization of RANK (for receptor activator of NF-κB), a new member of the TNFR family derived from dendritic cells, and the isolation of a RANK ligand (RANKL) by direct expression screening. RANKL augments the ability of dendritic cells to stimulate naive T-cell proliferation in a mixed lymphocyte reaction, and increases the survival of RANK+T cells generated with interleukin-4 and transforming growth factor (TGF)-β. Thus RANK and RANKL seem to be important regulators of interactions between T cells and dendritic cells.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Sequence and expression of RANK.
Figure 2: Sequence and expression of RANKL.
Figure 3: Functional expression of RANK in transfected 293EBNA and in PBTs.
Figure 4: RANK expression and function on CD1a+dendritic cells.

Similar content being viewed by others

References

  1. Steinmann, R. M. The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol. 9, 271–296 (1991).

    Article  Google Scholar 

  2. Caux, C. & Banchereau, J. in Blood Cell Biochemistry Vol. 7,Hemopoietic growth factors and their receptors (eds Whetton, A. & Gordon, J.) 263 (Plenum, London, (1996)).

    Google Scholar 

  3. Dubois, B. et al. Dendritic cells enhance growth and differentiation of CD40-activated B lymphocytes. J. Exp. Med. 185, 941–951 (1997).

    Article  CAS  Google Scholar 

  4. Austyn, J. M. New insights into the mobilization and phagocytic activity of dendritic cells. J. Exp. Med. 183, 1287–1292 (1996).

    Article  CAS  Google Scholar 

  5. Smith, C. A., Farrah, T. & Goodwin, R. G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 76, 959–962 (1994).

    Article  CAS  Google Scholar 

  6. Baker, S. J. & Reddy, E. P. Transducers of life and death: TNF superfamily and associated proteins. Oncogene 12, 1–9 (1996).

    CAS  PubMed  Google Scholar 

  7. Caux, C. et al. Activation of human dendritic cells through CD40 cross-linking. J. Exp. Med. 180, 1263–1272 (1994).

    Article  CAS  Google Scholar 

  8. Cella, M. et al. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J. Exp. Med. 184, 747–752 (1996).

    Article  CAS  Google Scholar 

  9. Armitage, R. J. et al. Molecular and biological characterization of a murine ligand for CD40. Nature 357, 80–82 (1992).

    Article  ADS  CAS  Google Scholar 

  10. Baeuerle, P. A. & Henkel, T. Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12, 141–179 (1994).

    Article  CAS  Google Scholar 

  11. Rothe,, Sarma, V., Dixit, V. M. & Goeddel, D. V. TRAF2-mediated activation of NF-κB by TNF receptor 2 and CD40. Science 269, 1424–1427 (1995).

    Article  ADS  CAS  Google Scholar 

  12. Armitage, R. J. Tumor necrosis factor receptor superfamily members and their ligands. Curr. Opin. Immunol. 6, 407–413 (1994).

    Article  CAS  Google Scholar 

  13. de Jong, R. et al. Differential effect of transforming growth factor-β1 on the activation of human naive and memory CD4+ T lymphocytes. Int. Immunol. 6, 631–638 (1994).

    Article  CAS  Google Scholar 

  14. Fukaura, H. et al. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J. Clin. Invest. 98, 70–77 (1996).

    Article  CAS  Google Scholar 

  15. Weiner, H. L. et al. Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu. Rev. Immunol. 12, 809–837 (1994).

    Article  CAS  Google Scholar 

  16. Madsen, M., Johnsen, H. E., Hansen, P. W. & Christiansen, S. E. Isolation of human T and B lymphocytes by E-rosette gradient centrifugation. Characterization of the isolated subpopulations. J.Immunol. Methods 33, 323–336 (1980).

    Article  CAS  Google Scholar 

  17. Larsen, A. et al. Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains. J. Exp. Med. 172, 1559–1570 (1990).

    Article  CAS  Google Scholar 

  18. Anderson, D. M. et al. Functional characterization of the human interleukin-15 receptor α chain and close linkage of IL15RA and IL2RA genes. J. Biol. Chem. 270, 29862–29869 (1995).

    Article  CAS  Google Scholar 

  19. Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. Basic local alignment search tool. J.Mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  20. Idzerda, R. L. et al. Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily. J. Exp. Med. 171, 861–873 (1990).

    Article  CAS  Google Scholar 

  21. Goodwin, R. G. et al. Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell 60, 941–951 (1990).

    Article  CAS  Google Scholar 

  22. Giri, J. G. et al. Utilization of the β and γ chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 13, 2822–2830 (1994).

    Article  CAS  Google Scholar 

  23. McMahan, C. J. et al. Anovel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J. 10, 2821–2832 (1991).

    Article  CAS  Google Scholar 

  24. Baum, P. R. et al. Molecular characterization of murine and human OX40/OX40 ligand systems: identiffication of a human OX40 ligand as the HTLV-1 regulated protein gp34. EMBO J. 13, 3992–4001 (1994).

    Article  CAS  Google Scholar 

  25. Hoffmann, A. & Roeder, R. G. Purification of his-tagged proteins in non-denaturing conditions suggests a convenient method for protein interaction studies. Nucleic Acids Res. 19, 6337–6338 (1991).

    Article  CAS  Google Scholar 

  26. Goodwin, R. G. et al. Molecular and biological characterization of a ligand for CD27 defines a new family of cytokines with homology to tumor necrosis factor. Cell 73, 447–456 (1993).

    Article  CAS  Google Scholar 

  27. Walter, M. A., Spillett, D. J., Thomas, P., Weisenbach, J. & Goodfellow, P. N. Amethod for constructing radiation hybrid maps of whole genomes. Nature Genet. 7, 22–28 (1994).

    Article  CAS  Google Scholar 

  28. Mosley, B. et al. The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane bound forms. Cell 59, 335–348 (1989).

    Article  CAS  Google Scholar 

  29. Yao, Z. et al. Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811–821 (1995).

    Article  CAS  Google Scholar 

  30. Wong, B. R. et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J. Biol. Chem. 272, 25190–25194 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. T. Hollingsworth, C.-P. Huang, M. S. Timour and J. S. Bertles for DNA sequencing; S. C. Braddy and D. E. Hirschstein for cell sorting; M. J. Petersen, S. A. Sherer, Z. Sadeghi and P. J. Smolak for technical assistance; M. Hall for graphical assistance; A. Bannister for editorial assistance; and M. Caligiuri of the Roswell Park Cancer Institute for human bone-marrow samples.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dirk M. Anderson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anderson, D., Maraskovsky, E., Billingsley, W. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175–179 (1997). https://doi.org/10.1038/36593

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/36593

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing