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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Smith, K.A. Interleukin-2: inception, impact, and implications. Science 240, 1169–1176 (1988).
Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).
Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472–1476 (1995).
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).
Nelson, B.H. IL-2, regulatory T cells, and tolerance. J. Immunol. 172, 3983–3988 (2004).
Malek, T.R. & Bayer, A.L. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4, 665–674 (2004).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Fontenot, J.D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005).
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).
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).
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).
Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Snow, J.W. et al. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J. Immunol. 171, 5042–5050 (2003).
Gentleman, R.C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).
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).
Gentleman, R.C. in Proceedings of COMPSTAT 2004 Symposium (ed. Antoch, J.) 171–180 (Physica Verlag, Heidelberg, 2004).
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.).
The authors declare no competing financial interests.
About this article
Cite this article
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
Pediatric Blood & Cancer (2020)
Innate Activation of IFN-γ—iNOS Axis During Infection With Salmonella Represses the Ability of T Cells to Produce IL-2
Frontiers in Immunology (2020)
Cell Reports (2020)
Cellular & Molecular Immunology (2020)
Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses
Cell Reports (2020)