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:

Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2

Abstract

Semaphorins are a family of phylogenetically conserved soluble and transmembrane proteins1,2. Although many soluble semaphorins deliver guidance cues to migrating axons during neuronal development3,4,5, some members are involved in immune responses6,7,8,9. For example, CD100 (also known as Sema4D), a class IV transmembrane semaphorin, signals through CD72 to effect nonredundant roles in immune responses7,10,11,12,13 in a ligand–receptor system that is distinct from any seen previously in the nervous system14,15. Here we report that the class IV semaphorin Sema4A, which is expressed in dendritic cells and B cells, enhances the in vitro activation and differentiation of T cells and the in vivo generation of antigen-specific T cells. Treating mice with monoclonal antibodies against Sema4A blocks the development of an experimental autoimmune encephalomyelitis that is induced by an antigenic peptide derived from myelin oligodendrocyte glycoprotein. In addition, expression cloning shows that the Sema4A receptor is Tim-2, a member of the family of T-cell immunoglobulin domain and mucin domain (Tim) proteins that is expressed on activated T 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: Analysis of Sema4A expression.
Figure 2: Sema4A enhances T-cell activation.
Figure 3: Sema4A is involved in T-cell activation in vivo.
Figure 4: Tim-2 is a receptor for Sema4A.

Similar content being viewed by others

References

  1. Semaphorin Nomenclature Committee. Unified nomenclature for the semaphorins/collapsins. Cell 97, 551–552 (1999)

    Article  Google Scholar 

  2. Yu, H. H. & Kolodkin, A. L. Semaphorin signaling: a little less per-plexin. Neuron 22, 11–14 (1999)

    Article  CAS  Google Scholar 

  3. Kolodkin, A. L., Matthes, D. J. & Goodman, C. S. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75, 1389–1399 (1993)

    Article  CAS  Google Scholar 

  4. Luo, Y., Raible, D. & Raper, J. A. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75, 217–227 (1993)

    Article  CAS  Google Scholar 

  5. Tessier-Lavigne, M. & Goodman, S. C. The molecular biology of axon guidance. Science 274, 1123–1133 (1996)

    Article  ADS  CAS  Google Scholar 

  6. Delaire, S., Elhabazi, A., Bensussan, A. & Boumsell, L. CD100 is a leukocyte semaphorin. Cell Mol. Life Sci. 54, 1265–1276 (1998)

    Article  CAS  Google Scholar 

  7. Kumanogoh, A. & Kikutani, H. The CD100-CD72 interaction: a novel mechanism of immune regulation. Trends Immunol. 22, 670–676 (2001)

    Article  CAS  Google Scholar 

  8. Comeau, M. R. et al. A poxvirus-encoded semaphorin induces cytokine production from monocytes and binds to a novel cellular semaphorin receptor, VESPR. Immunity 8, 473–482 (1998)

    Article  CAS  Google Scholar 

  9. Xu, X. et al. Human semaphorin K1 is glycosylphosphatidylinositol-linked and defines a new subfamily of viral-related semaphorins. J. Biol. Chem. 273, 22428–22434 (1998)

    Article  CAS  Google Scholar 

  10. Kumanogoh, A. et al. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity 13, 621–631 (2000)

    Article  CAS  Google Scholar 

  11. Shi, W. et al. The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity 13, 633–642 (2000)

    Article  CAS  Google Scholar 

  12. Wang, X. et al. Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses. Blood 97, 3498–3504 (2001)

    Article  CAS  Google Scholar 

  13. Watanabe, C. et al. Enhanced immune responses in transgenic mice expressing a truncated form of the lymphocyte semaphorin CD100. J. Immunol. 167, 4321–4328 (2001)

    Article  CAS  Google Scholar 

  14. Tamagnone, L. et al. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99, 71–80 (1999)

    Article  CAS  Google Scholar 

  15. Tamagnone, L. & Comoglio, P. M. Signalling by semaphorin receptors: cell guidance and beyond. Trends Cell Biol. 10, 377–383 (2000)

    Article  CAS  Google Scholar 

  16. Puschel, A. W., Adams, R. H. & Betz, H. Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension. Neuron 14, 941–948 (1995)

    Article  CAS  Google Scholar 

  17. Fang, D. et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nature Immunol. 3, 281–287 (2002)

    Article  CAS  Google Scholar 

  18. Kumanogoh, A. et al. Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. J. Immunol. 169, 1175–1181 (2002)

    Article  CAS  Google Scholar 

  19. Chang, T. T. et al. Studies in B7-deficient mice reveal a critical role for B7 costimulation in both induction and effector phases of experimental autoimmune encephalomyelitis. J. Exp. Med. 190, 733–740 (1999)

    Article  CAS  Google Scholar 

  20. Alexander, B. H. et al. DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13, 345–353 (2000)

    Article  Google Scholar 

  21. Mclntire, J. J. et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nature Immunol. 2, 1109–1116 (2001)

    Article  Google Scholar 

  22. Monney, L. et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541 (2002)

    Article  CAS  Google Scholar 

  23. Adachi, T., Flaswinkel, H., Yakura, H., Reth, M. & Tsubata, T. The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 upon tyrosine phosphorylation. J. Immunol. 160, 4662–4665 (1998)

    CAS  PubMed  Google Scholar 

  24. Pan, C., Baumgarth, N. & Parnes, J. R. CD72-deficient mice reveal nonredundant roles of CD72 in B cell development and activation. Immunity 11, 495–506 (1999)

    Article  CAS  Google Scholar 

  25. Suda, T. & Nagata, S. Purification and characterization of the Fas-ligand that induces apoptosis. J. Exp. Med. 179, 873–879 (1994)

    Article  CAS  Google Scholar 

  26. Inaba, K. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony stimulating factor. J. Exp. Med. 176, 1693–1702 (1992)

    Article  CAS  Google Scholar 

  27. Seed, B. & Aruffo, A. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. Proc. Natl Acad. Sci. USA 84, 3365–3369 (1987)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Kubota for secretarial assistance; E. L. Barsoumian for critically reading the manuscript; and K. Nakamura, K. Shiozaki, S. Koga and J. Fujikake for technical support. This study was supported by research grants from the Ministry of Education, Culture, Science and Technology of Japan to H.K. and A.K.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hitoshi Kikutani.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumanogoh, A., Marukawa, S., Suzuki, K. et al. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419, 629–633 (2002). https://doi.org/10.1038/nature01037

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01037

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