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:

CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs

Nature volume 440, pages 540–544 (2006)Cite this article

Abstract

Naive lymphocytes continually enter and exit lymphoid organs in a recirculation process that is essential for immune surveillance. During immune responses, the egress process can be shut down transiently1. When this occurs locally it increases lymphocyte numbers in the responding lymphoid organ; when it occurs systemically it can lead to immunosuppression as a result of the depletion of recirculating lymphocytes. Several mediators of the innate immune system are known to cause shutdown, including interferon α/β (IFN-α/β) and tumour necrosis factor2,3,4,5, but the mechanism has been unclear. Here we show that treatment with the IFN-α/β inducer polyinosine polycytidylic acid (hereafter ‘poly(I:C)’) inhibited egress by a mechanism that was partly lymphocyte-intrinsic. The transmembrane C-type lectin CD69 was rapidly induced and CD69-/- cells were poorly retained in lymphoid tissues after treatment with poly(I:C) or infection with lymphocytic choriomeningitis virus. Lymphocyte egress requires sphingosine 1-phosphate receptor-1 (S1P1), and IFN-α/β was found to inhibit lymphocyte responsiveness to S1P. By contrast, CD69-/- cells retained S1P1 function after exposure to IFN-α/β. In coexpression experiments, CD69 inhibited S1P1 chemotactic function and led to downmodulation of S1P1. In a reporter assay, S1P1 crosslinking led to co-crosslinking and activation of a CD69–CD3ζ chimaera. CD69 co-immunoprecipitated with S1P1 but not the related receptor, S1P3. These observations indicate that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream of IFN-α/β, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Lymphocyte-intrinsic IFNAR1 requirement during poly(I:C)-induced lymphocyte sequestration and downregulation of S1P 1 by IFN-α/β.
Figure 2: CD69-deficient cells are less efficiently sequestered after treatment with poly(I:C) and LCMV infection and retain S1P responsiveness.
Figure 3: CD69 interacts with S1P 1 causing downregulation and inhibition of S1P 1 function.
Figure 4: Mouse and human CD69 interact with S1P1.

Similar content being viewed by others

References

  1. Hall, J. G. & Morris, B. The immediate effect of antigens on the cell output of a lymph node. Br. J. Exp. Pathol. 46, 450–454 (1965)

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Degre, M. Influence of polyinosinic:polycytidylic acid on the circulating white blood cells in mice. Proc. Soc. Exp. Biol. Med. 142, 1087–1091 (1973)

    Article  CAS  PubMed  Google Scholar 

  3. Korngold, R., Blank, K. J. & Murasko, D. M. Effect of interferon on thoracic duct lymphocyte output: induction with either poly I:poly C or vaccinia virus. J. Immunol. 130, 2236–2240 (1983)

    CAS  PubMed  Google Scholar 

  4. Kalaaji, A. N., Abernethy, N. J., McCullough, K. & Hay, J. B. Recombinant bovine interferon-alpha I 1 inhibits the migration of lymphocytes from lymph nodes but not into lymph nodes. Reg. Immunol. 1, 56–61 (1988)

    CAS  PubMed  Google Scholar 

  5. Young, A. J., Seabrook, T. J., Marston, W. L., Dudler, L. & Hay, J. B. A role for lymphatic endothelium in the sequestration of recirculating gamma delta T cells in TNF-alpha-stimulated lymph nodes. Eur. J. Immunol. 30, 327–334 (2000)

    Article  CAS  PubMed  Google Scholar 

  6. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Allende, M. L., Dreier, J. L., Mandala, S. & Proia, R. L. Expression of the sphingosine-1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem. 279, 15396–15401 (2004)

    Article  CAS  PubMed  Google Scholar 

  8. Feng, C. et al. A potential role for CD69 in thymocyte emigration. Int. Immunol. 14, 535–544 (2002)

    Article  CAS  PubMed  Google Scholar 

  9. Nakayama, T. et al. The generation of mature, single-positive thymocytes in vivo is dysregulated by CD69 blockade or overexpression. J. Immunol. 168, 87–94 (2002)

    Article  CAS  PubMed  Google Scholar 

  10. Lauzurica, P. et al. Phenotypic and functional characteristics of hematopoietic cell lineages in CD69-deficient mice. Blood 95, 2312–2320 (2000)

    CAS  PubMed  Google Scholar 

  11. Murata, K. et al. CD69-null mice protected from arthritis induced with anti-type II collagen antibodies. Int. Immunol. 15, 987–992 (2003)

    Article  CAS  PubMed  Google Scholar 

  12. Testi, R., D'Ambrosio, D., De Maria, R. & Santoni, A. The CD69 receptor: a multipurpose cell-surface trigger for hematopoietic cells. Immunol. Today 15, 479–483 (1994)

    Article  CAS  PubMed  Google Scholar 

  13. Sancho, D., Gomez, M. & Sanchez-Madrid, F. CD69 is an immunoregulatory molecule induced following activation. Trends Immunol. 26, 136–140 (2005)

    Article  CAS  PubMed  Google Scholar 

  14. Risso, A. et al. CD69 in resting and activated T lymphocytes. Its association with a GTP binding protein and biochemical requirements for its expression. J. Immunol. 146, 4105–4114 (1991)

    CAS  PubMed  Google Scholar 

  15. Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nature Immunol. 5, 713–720 (2004)

    Article  CAS  Google Scholar 

  16. Chu, P. et al. Systematic identification of regulatory proteins critical for T-cell activation. J. Biol. 2, 21.1–21.16 (2003)

    Article  Google Scholar 

  17. Brinkmann, V., Cyster, J. G. & Hla, T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am. J. Transplant. 4, 1019–1025 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Rosen, H., Alfonso, C., Surh, C. D. & McHeyzer-Williams, M. G. Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist. Proc. Natl Acad. Sci. USA 100, 10907–10912 (2003)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schwab, S. R. et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309, 1735–1739 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B. & Lanier, L. L. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Lopez-Cabrera, M. et al. Transcriptional regulation of the gene encoding the human C-type lectin leukocyte receptor AIM/CD69 and functional characterization of its tumor necrosis factor-alpha-responsive elements. J. Biol. Chem. 270, 21545–21551 (1995)

    Article  CAS  PubMed  Google Scholar 

  22. Graeler, M. & Goetzl, E. J. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J. 16, 1874–1878 (2002)

    Article  CAS  PubMed  Google Scholar 

  23. Esplugues, E. et al. Enhanced antitumor immunity in mice deficient in CD69. J. Exp. Med. 197, 1093–1106 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ramirez, R., Carracedo, J., Zamzami, N., Castedo, M. & Kroemer, G. Pertussis toxin inhibits activation-induced cell death of human thymocytes, pre-B leukemia cells and monocytes. J. Exp. Med. 180, 1147–1152 (1994)

    Article  CAS  PubMed  Google Scholar 

  25. Sancho, D. et al. Functional analysis of ligand-binding and signal transduction domains of CD69 and CD23 C-type lectin leukocyte receptors. J. Immunol. 165, 3868–3875 (2000)

    Article  CAS  PubMed  Google Scholar 

  26. Bikah, G., Pogue-Caley, R. R., McHeyzer-Williams, L. J. & McHeyzer-Williams, M. G. Regulating T helper cell immunity through antigen responsiveness and calcium entry. Nature Immunol. 1, 402–412 (2000)

    Article  CAS  Google Scholar 

  27. Rosen, H. & Liao, J. Sphingosine 1-phosphate pathway therapeutics: a lipid ligand-receptor paradigm. Curr. Opin. Chem. Biol. 7, 461–468 (2003)

    Article  CAS  PubMed  Google Scholar 

  28. Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994)

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Lo, C. G., Xu, Y., Proia, R. L. & Cyster, J. G. Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J. Exp. Med. 201, 291–301 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rosen, D. B. et al. Cutting edge: Lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. J. Immunol. 175, 7796–7799 (2005)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. Nakayama and S. Zeigler for CD69-/- mice; K. Murali-Krishna for Ifnar1-/- mice; R. Proia for S1p1+/- mice; S. Jahn for technical assistance; C. Allen, S. Schwab and C. McArthur for help with cell sorting; K. Kabashima for fetal liver chimeras; O. Lam for mouse husbandry; and S. Schwab and C. Lo for comments on the manuscript. L.R.S. is supported by the UCSF Medical Scientist Training Program; D.B.R. is supported by the Genentech Graduate Fellowship; M.M. was supported by the Pfizer Postdoctoral Fellowship in Immunology and Rheumatology, a research award from the Arthritis Foundation, the Rosalind Russell Medical Research Center for Arthritis at UCSF, and the Sandler Family Supporting Foundation; L.L.L. is an American Cancer Society Research Professor; J.G.C. is an Investigator of the Howard Hughes Medical Institute. This work was supported in part by grants from the NIH (to L.L.L. and J.G.C.).

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute,

    Lawrence R. Shiow, Ying Xu, Jinping An & Jason G. Cyster

  2. Department of Microbiology and Immunology,

    Lawrence R. Shiow, David B. Rosen, Ying Xu, Jinping An, Lewis L. Lanier & Jason G. Cyster

  3. Department of Medicine,

    Naděžda Brdičková & Mehrdad Matloubian

  4. Biomedical Sciences Graduate Program, University of California, San Francisco, California, 94143, San Francisco, USA

    Lawrence R. Shiow & David B. Rosen

Authors
  1. Lawrence R. Shiow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David B. Rosen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naděžda Brdičková
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jinping An
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lewis L. Lanier
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jason G. Cyster
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mehrdad Matloubian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jason G. Cyster or Mehrdad Matloubian.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains Supplementary Figures 1–4 with corresponding legends, Supplementary Methods and additional references. (PDF 1143 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shiow, L., Rosen, D., Brdičková, N. et al. CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440, 540–544 (2006). https://doi.org/10.1038/nature04606

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04606

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

Advanced 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