Skip to main content
SpringerLink
Log in

IL-2 Signaling and CD4+ CD25+ Regulatory T Cells

  • Chapter
  • First Online:
Regulatory T Cells and Clinical Application

  • 697 Accesses

Abstract

Over the last two decades, our understanding of the function of Interleukin-2 (IL-2) has experienced several paradigmatic shifts. Although IL-2 was initially identified as a T cell growth factor, loss of function experiments clearly showed that it rather acts as a gatekeeper of immune homeostasis and tolerance. It is now widely accepted that the major non-redundant function of IL-2 is the maintenance of naturally occurring CD25+ Foxp3+ regulatory T cells (Treg). Importantly, this role as an essential survival factor may blur the interpretation of loss-of-function studies that tried to address other, mutually not exclusive functions of IL-2 in Treg biology, such as development and function. This chapter will summarize our current understanding of how IL-2 signaling may relate to these aspects of immune regulation by Treg.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Taniguchi, T., et al., Structure and expression of a cloned cDNA for human interleukin-2. Nature, 1983, 302(5906):305–10.

    Article  PubMed  CAS  Google Scholar 

  2. Yang-Snyder, J.A. and E.V. Rothenberg, Spontaneous expression of interleukin-2 in vivo in specific tissues of young mice. Dev Immunol, 1998, 5(4):223–45.

    Article  PubMed  CAS  Google Scholar 

  3. Granucci, F., et al., Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat Immunol, 2001, 2(9):882–8.

    Article  PubMed  CAS  Google Scholar 

  4. Sugamura, K., et al., The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu Rev Immunol, 1996, 14: 179–205.

    Article  PubMed  CAS  Google Scholar 

  5. Nelson, B.H. and D.M. Willerford, Biology of the interleukin-2 receptor. Adv Immunol, 1998, 70:1–81.

    Article  PubMed  CAS  Google Scholar 

  6. Eklund, J.W. and T.M. Kuzel, A review of recent findings involving interleukin-2-based cancer therapy. Curr Opin Oncol, 2004, 16(6):542–6.

    Article  PubMed  CAS  Google Scholar 

  7. Pahwa, S. and M. Morales, Interleukin-2 therapy in HIV infection. AIDS Patient Care STDS, 1998, 12(3):187–97.

    Article  PubMed  CAS  Google Scholar 

  8. Waldmann, T.A., The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol, 2006, 6(8):595–601.

    Article  PubMed  CAS  Google Scholar 

  9. Schorle, H., et al., Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature, 1991, 352(6336):621–4.

    Article  PubMed  CAS  Google Scholar 

  10. Willerford, D.M., et al., Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity, 1995, 3(4):521–30.

    Article  PubMed  CAS  Google Scholar 

  11. Suzuki, H., et al., Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain. J Exp Med, 1997, 185(3):499–505.

    Article  PubMed  CAS  Google Scholar 

  12. Sadlack, B., et al., Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell, 1993, 75(2):253–61.

    Article  PubMed  CAS  Google Scholar 

  13. Kramer, S., A. Schimpl, and T. Hunig, Immunopathology of interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene. J Exp Med, 1995, 182(6):1769–76.

    Article  PubMed  CAS  Google Scholar 

  14. Ma, A., et al., T cells, but not B cells, are required for bowel inflammation in interleukin 2-deficient mice. J Exp Med, 1995, 182(5):1567–72.

    Article  PubMed  CAS  Google Scholar 

  15. Van Parijs, L., et al., Functional responses and apoptosis of CD25 (IL-2R alpha)-deficient T cells expressing a transgenic antigen receptor. J Immunol, 1997, 158(8):3738–45.

    PubMed  Google Scholar 

  16. Lenardo, M.J., Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature, 1991, 353(6347):858–61.

    Article  PubMed  CAS  Google Scholar 

  17. Zheng, L., et al., T cell growth cytokines cause the superinduction of molecules mediating antigen-induced T lymphocyte death. J Immunol, 1998, 160(2):763–9.

    PubMed  CAS  Google Scholar 

  18. Refaeli, Y., et al., Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity, 1998, 8(5):615–23.

    Article  PubMed  CAS  Google Scholar 

  19. Suzuki, H., et al., Normal thymic selection, superantigen-induced deletion and Fas-mediated apoptosis of T cells in IL-2 receptor beta chain-deficient mice. Int Immunol, 1997, 9(9): 1367–74.

    Article  PubMed  CAS  Google Scholar 

  20. Leung, D.T., S. Morefield, and D.M. Willerford, Regulation of lymphoid homeostasis by IL-2 receptor signals in vivo. J Immunol, 2000, 164(7):3527–34.

    PubMed  CAS  Google Scholar 

  21. D'Souza, W.N., et al., Essential role for IL-2 in the regulation of antiviral extralymphoid CD8 T cell responses. J Immunol, 2002, 168(11):5566–72.

    PubMed  Google Scholar 

  22. Papiernik, M., et al., Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int Immunol, 1998, 10(4):371–8.

    Article  PubMed  CAS  Google Scholar 

  23. Malek, T.R., et al., CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity, 2002. 17(2):167–78.

    Article  PubMed  CAS  Google Scholar 

  24. Almeida, A.R., et al., Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol, 2002, 169(9):4850–60.

    PubMed  Google Scholar 

  25. Taniguchi, T., et al., IL-2 signaling involves recruitment and activation of multiple protein tyrosine kinases by the IL-2 receptor. Ann N Y Acad Sci, 1995, 766:235–44.

    Article  PubMed  CAS  Google Scholar 

  26. Witthuhn, B.A., et al., Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature, 1994, 370(6485):153–7.

    Article  PubMed  CAS  Google Scholar 

  27. Johnston, J.A., et al., Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature, 1994, 370(6485):151–3.

    Article  PubMed  CAS  Google Scholar 

  28. Van Parijs, L., et al., Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. Immunity, 1999, 11(3):281–8.

    Article  PubMed  Google Scholar 

  29. Gaffen, S.L., et al., Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity. J Biol Chem, 1996, 271(35): 21381–90.

    Article  PubMed  CAS  Google Scholar 

  30. Moriggl, R., et al., Stat5 activation is uniquely associated with cytokine signaling in peripheral T cells. Immunity, 1999, 11(2):225–30.

    Article  PubMed  CAS  Google Scholar 

  31. Lin, J.X. and W.J. Leonard, The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene, 2000, 19(21):2566–76.

    Article  PubMed  CAS  Google Scholar 

  32. Graves, J.D., et al., The growth factor IL-2 activates p21ras proteins in normal human T lymphocytes. J Immunol, 1992, 148(8):2417–22.

    PubMed  CAS  Google Scholar 

  33. Miyazaki, T., et al., Pyk2 is a downstream mediator of the IL-2 receptor-coupled Jak signaling pathway. Genes Dev, 1998, 12(6):770–5.

    Article  PubMed  CAS  Google Scholar 

  34. Friedmann, M.C., et al., Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation. Proc Natl Acad Sci USA, 1996, 93(5):2077–82.

    Article  PubMed  CAS  Google Scholar 

  35. Ravichandran, K.S., et al., Evidence for a role for the phosphotyrosine-binding domain of Shc in interleukin 2 signaling. Proc Natl Acad Sci USA, 1996, 93(11):5275–80.

    Article  PubMed  CAS  Google Scholar 

  36. Blanchard, D.A., et al., Cdk2 associates with MAP kinase in vivo and its nuclear translocation is dependent on MAP kinase activation in IL-2-dependent Kit 225 T lymphocytes. Oncogene, 2000, 19(36):4184–9.

    Article  PubMed  CAS  Google Scholar 

  37. Merida, I., E. Diez, and G.N. Gaulton, IL-2 binding activates a tyrosine-phosphorylated phosphatidylinositol-3-kinase. J Immunol, 1991, 147(7):2202–7.

    PubMed  CAS  Google Scholar 

  38. Augustine, J.A., S.L. Sutor, and R.T. Abraham, Interleukin 2- and polyomavirus middle T antigen-induced modification of phosphatidylinositol 3-kinase activity in activated T lymphocytes. Mol Cell Biol, 1991, 11(9):4431–40.

    PubMed  CAS  Google Scholar 

  39. Kelly, E., et al., IL-2 and related cytokines can promote T cell survival by activating AKT. J Immunol, 2002, 168(2):597–603.

    PubMed  CAS  Google Scholar 

  40. Ahmed, N.N., et al., Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc Natl Acad Sci USA, 1997, 94(8):3627–32.

    Article  PubMed  CAS  Google Scholar 

  41. Jones, R.G., et al., Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo. J Exp Med, 2000, 191(10):1721–34.

    Article  PubMed  CAS  Google Scholar 

  42. Reif, K., B.M. Burgering, and D.A. Cantrell, Phosphatidylinositol 3-kinase links the interleukin-2 receptor to protein kinase B and p70 S6 kinase. J Biol Chem, 1997, 272(22):14426–33.

    Article  PubMed  CAS  Google Scholar 

  43. Brennan, P., et al., Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity, 1997, 7(5):679–89.

    Article  PubMed  CAS  Google Scholar 

  44. Fontenot, J.D., et al., A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol, 2005, 6(11):1142–51.

    Article  PubMed  CAS  Google Scholar 

  45. D'Cruz, L.M. and L. Klein, Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol, 2005, 6(11):1152–9.

    Article  PubMed  Google Scholar 

  46. Setoguchi, R., et al., 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, 2005, 201(5):723–35.

    Article  PubMed  CAS  Google Scholar 

  47. Burchill, M.A., et al., Distinct effects of STAT5 activation on CD4+ and CD8+ T cell homeostasis: development of CD4+CD25+ regulatory T cells versus CD8+ memory T cells. J Immunol, 2003, 171(11):5853–64.

    PubMed  CAS  Google Scholar 

  48. Antov, A., et al., Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol, 2003, 171(7):3435–41.

    PubMed  CAS  Google Scholar 

  49. Bensinger, S.J., et al., Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol, 2004, 172(9):5287–96.

    PubMed  CAS  Google Scholar 

  50. Walker, L.S., et al., Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med, 2003, 198(2):249–58.

    Article  PubMed  CAS  Google Scholar 

  51. Klein, L., K. Khazaie, and H. von Boehmer, In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc Natl Acad Sci USA, 2003, 100(15):8886–91.

    Google Scholar 

  52. Romagnoli, P., D. Hudrisier, and J.P. van Meerwijk, Preferential recognition of self antigens despite normal thymic deletion of CD4(+)CD25(+) regulatory T cells. J Immunol, 2002, 168(4):1644–8.

    Google Scholar 

  53. Hsieh, C.S., et al., Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity, 2004, 21(2):267–77.

    Article  PubMed  CAS  Google Scholar 

  54. Yu, A. and T.R. Malek, Selective availability of IL-2 is a major determinant controlling the production of CD4+CD25+Foxp3+ T regulatory cells. J Immunol, 2006, 177(8):5115–21.

    PubMed  CAS  Google Scholar 

  55. Cheng, L.E., et al., Enhanced signaling through the IL-2 receptor in CD8+ T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8+ T cells rather than promotion of cell death. Proc Natl Acad Sci USA, 2002, 99(5): 3001–6.

    Article  PubMed  CAS  Google Scholar 

  56. Fontenot, J.D., M.A. Gavin, and A.Y. Rudensky, Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol, 2003, 4(4):330–6.

    Article  PubMed  CAS  Google Scholar 

  57. Hori, S., T. Nomura, and S. Sakaguchi, Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003, 299(5609):1057–61.

    Article  PubMed  CAS  Google Scholar 

  58. Wu, Y., et al., FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell, 2006, 126(2):375–87.

    Article  PubMed  CAS  Google Scholar 

  59. Nakamura, K., A. Kitani, and W. Strober, Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med, 2001, 194(5):629–44.

    Article  PubMed  CAS  Google Scholar 

  60. Piccirillo, C.A., et al., CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med, 2002, 196(2):237–46.

    Article  PubMed  CAS  Google Scholar 

  61. de la Rosa, M., et al., Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol, 2004, 34(9):2480–8.

    Article  PubMed  Google Scholar 

  62. Thornton, A.M. and E.M. Shevach, CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med, 1998, 188(2):287–96.

    Article  PubMed  CAS  Google Scholar 

  63. Thornton, A.M., et al., Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol, 2004, 172(11):6519–23.

    PubMed  CAS  Google Scholar 

  64. Barthlott, T., G. Kassiotis, and B. Stockinger, T cell regulation as a side effect of homeostasis and competition. J Exp Med, 2003, 197(4):451–60.

    Article  PubMed  CAS  Google Scholar 

  65. Furtado, G.C., et al., Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med, 2002, 196(6):851–7.

    Article  PubMed  CAS  Google Scholar 

  66. Liang, S., et al., Conversion of CD4+ CD25- cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med, 2005, 201(1):127–37.

    Article  PubMed  CAS  Google Scholar 

  67. Thorstenson, K.M. and A. Khoruts, Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J Immunol, 2001, 167(1):188–95.

    PubMed  CAS  Google Scholar 

  68. Mahnke, K., et al., Induction of CD4+/CD25+ regulatory T cells by targting of antigens to immature dendritic cells. Blood, 2003, 101(12):4862–9.

    Article  PubMed  CAS  Google Scholar 

  69. Chen, W., et al., Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med, 2003, 198(12):1875–86.

    Article  PubMed  CAS  Google Scholar 

  70. Kretschmer, K., et al., Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer. Immunol Rev, 2006, 212:163–9.

    Article  PubMed  CAS  Google Scholar 

  71. Kretschmer, K., et al., Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol, 2005, 6(12):1219–27.

    Article  PubMed  CAS  Google Scholar 

  72. Knoechel, B., et al., Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med, 2005, 202(10):1375–86.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Immunology, Ludwig-Maximilians-University Munich, Goethestrasse 31, Germany

    Ludger Klein

Authors
  1. Louise M. D’Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ludger Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ludger Klein .

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2008 Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    D’Cruz, L.M., Klein, L. (2008). IL-2 Signaling and CD4+ CD25+ Regulatory T Cells. In: Jiang, S. (eds) Regulatory T Cells and Clinical Application. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77909-6_5

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation