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A function for interleukin 2 in Foxp3-expressing regulatory T cells

An Erratum to this article was published on 01 April 2006

This article has been updated

Abstract

Regulatory T cells (Treg cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most Treg cells constitutively express the high-affinity interleukin 2 (IL-2) receptor α-chain (CD25); however, the precise function of IL-2 in Treg cell biology has remained controversial. To directly assess the effect of IL-2 signaling on Treg cell development and function, we analyzed mice containing the Foxp3gfp knock-in allele that were genetically deficient in either IL-2 (Il2−/−) or CD25 (Il2ra−/−). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of Treg cells. Unexpectedly, Il2−/− and Il2ra−/− Treg cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg−/− mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of Treg cells in vivo.

*Note: In the version of this article initially published, the GEO database accession number is missing. This should be the final subsection of Methods, as follows:  Accession code. GEO: microarray data, GSE4179. The error has been corrected in the PDF version of the article.

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Figure 1: Foxp3-expressing T cells develop in the absence of IL-2 signaling.
Figure 2: Activated phenotype of Foxp3-expressing T cells in the absence of IL-2 signaling.
Figure 3: CD25-deficient Treg cells are not competitive in the periphery.
Figure 4: IL-2 is dispensable for the Treg cell suppressive function.
Figure 5: IL-2 signaling potentiates CD25 and Foxp3 expression in Treg cells.
Figure 6: Gene expression analysis of the effects of IL-2 signaling on Treg cells.
Figure 7: Signal derived from the common γ-chain is required for Foxp3 expression.

Change history

  • 10 March 2006

    In the version of this article initially published, the GEO database accession number is missing. This should be the final subsection of Methods, as follows: Accession code. GEO: microarray data, GSE4179.The error has been corrected in the PDF version of the article.

References

  1. Smith, K.A. Interleukin-2: inception, impact, and implications. Science 240, 1169–1176 (1988).

    Article  CAS  PubMed  Google Scholar 

  2. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472–1476 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Willerford, D.M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Nelson, B.H. IL-2, regulatory T cells, and tolerance. J. Immunol. 172, 3983–3988 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Malek, T.R. & Bayer, A.L. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4, 665–674 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Sakaguchi, S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Malek, T.R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Bayer, A.L., Yu, A., Adeegbe, D. & Malek, T.R. Essential role for interleukin-2 for CD4+CD25+ T regulatory cell development during the neonatal period. J. Exp. Med. 201, 769–777 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Furtado, G.C., Curotto de Lafaille, M.A., Kutchukhidze, N. & Lafaille, J.J. Interleukin 2 signaling is required for CD4+ regulatory T cell function. J. Exp. Med. 196, 851–857 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Almeida, A.R., Legrand, N., Papiernik, M. & Freitas, A.A. Homeostasis of peripheral CD4+ T cells: IL-2Rα and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J. Immunol. 169, 4850–4860 (2002).

    Article  PubMed  Google Scholar 

  12. Curotto de Lafaille, M.A., Lino, A.C., Kutchukhidze, N. & Lafaille, J.J. CD25-T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J. Immunol. 173, 7259–7268 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic maintenance of natural Foxp3+CD25+CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723–735 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. de la Rosa, M., Rutz, S., Dorninger, H. & Scheffold, A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2480–2488 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Thornton, A.M., Donovan, E.E., Piccirillo, C.A. & Shevach, E.M. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J. Immunol. 172, 6519–6523 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Fontenot, J.D. & Rudensky, A.Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 6, 331–337 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Fontenot, J.D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Godfrey, V.L., Wilkinson, J.E. & Russell, L.B. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am. J. Pathol. 138, 1379–1387 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Brunkow, M.E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gondek, D.C., Lu, L.F., Quezada, S.A., Sakaguchi, S. & Noelle, R.J. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 174, 1783–1786 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Grossman, W.J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Paust, S., Lu, L., McCarty, N. & Cantor, H. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc. Natl. Acad. Sci. USA 101, 10398–10403 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brusko, T.M., Wasserfall, C.H., Agarwal, A., Kapturczak, M.H. & Atkinson, M.A. An integral role for heme oxygenase-1 and carbon monoxide in maintaining peripheral tolerance by CD4+CD25+ regulatory T cells. J. Immunol. 174, 5181–5186 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Chan, C.W. et al. Soluble fibrinogen-like protein 2/fibroleukin exhibits immunosuppressive properties: suppressing T cell proliferation and inhibiting maturation of bone marrow-derived dendritic cells. J. Immunol. 170, 4036–4044 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Asseman, C., Mauze, S., Leach, M.W., Coffman, R.L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Malek, T.R., Porter, B.O., Codias, E.K., Scibelli, P. & Yu, A. Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors. J. Immunol. 164, 2905–2914 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Almeida, A.R., Rocha, B., Freitas, A.A. & Tanchot, C. Homeostasis of T cell numbers: from thymus production to peripheral compartmentalization and the indexation of regulatory T cells. Semin. Immunol. 17, 239–249 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Piccirillo, C.A. et al. CD4+CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness. J. Exp. Med. 196, 237–246 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fahlen, L. et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Marie, J.C., Letterio, J.J., Gavin, M. & Rudensky, A.Y. TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 1061–1067 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Alexander, W.S. & Hilton, D.J. The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu. Rev. Immunol. 22, 503–529 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Antov, A., Yang, L., Vig, M., Baltimore, D. & Van Parijs, L. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J. Immunol. 171, 3435–3441 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Snow, J.W. et al. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J. Immunol. 171, 5042–5050 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Gentleman, R.C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wu, Z., Irizarry, R., Gentleman, R.C., Murillo, F.M. & Spencer, F. A model based background adjustment for oligonucleotide expression arrays. Working Paper 1 (Johns Hopkins University, Department of Biostatistics Working Papers, http://www.bepress.com/jhubiostat/paper1, 2004).

  40. Gentleman, R.C. in Proceedings of COMPSTAT 2004 Symposium (ed. Antoch, J.) 171–180 (Physica Verlag, Heidelberg, 2004).

    Book  Google Scholar 

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Acknowledgements

We thank all members of the Rudensky lab for advice and discussions; and K. Forbush, L. Hsing, Y. Liang and L. Karpik for technical expertise and mouse colony management. Supported by National Institutes of Health (R01AI034206 to A.Y.R.) and Howard Hughes Medical Institute (A.Y.R.).

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Correspondence to Jason D Fontenot or Alexander Y Rudensky.

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Supplementary information

Supplementary Fig. 1

Il2−/− and Il2ra−/− mice develop a less severe lymphoproliferative autoimmune syndrome than Foxp3 mice. (PDF 485 kb)

Supplementary Fig. 2

IL-2 neutralization reduces the percentage of Foxp3+ Treg cells and reduces amounts of CD25 and Foxp3 in Foxp3+ Treg cells. (PDF 623 kb)

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Fontenot, J., Rasmussen, J., Gavin, M. et al. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6, 1142–1151 (2005). https://doi.org/10.1038/ni1263

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