Skip to main content
SpringerLink
Log in
Book cover

Memory T Cells pp 28–41Cite as

The Role of Interleukin-2 in Memory CD8 Cell Differentiation

  • Chapter

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 684))

Abstract

The current literature on the role of interleukin (IL)-2 in memory CD8+ T-cell differentiation indicates a significant contribution of IL-2 during primary and also secondary expansion of CD8+ T cells. IL-2 seems to be responsible for optimal expansion and generation of effector functions following primary antigenic challenge. As the magnitude of T-cell expansion determines the numbers of memory CD8+ T cells surviving after pathogen elimination, these events influence memory cell generation. Moreover, during the contraction phase of an immune response where most antigen-specific CD8+ T cells disappear by apoptosis, IL-2 signals are able to rescue CD8+ T cells from cell death and provide a durable increase in memory CD8+ T-cell counts. At the memory stage, CD8+ T-cell frequencies can be boosted by administration of exogenous IL-2. Significantly, only CD8+ T cells that have received IL-2 signals during initial priming are able to mediate efficient secondary expansion following renewed antigenic challenge. Thus, IL-2 signals during different phases of an immune response are key in optimizing CD8+ T-cell functions, thereby affecting both primary and secondary responses of these T cells.

This is a preview of subscription content, 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   189.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
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

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat Rev Immunol 2005; 5:772–82.

    Article  CAS  PubMed  Google Scholar 

  2. von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med 2000; 343:1020–34.

    Article  Google Scholar 

  3. Tough DF, Sprent J. Turnover of naive-and memory-phenotype T-cells. J Exp Med 1994; 179:1127–35.

    Article  CAS  PubMed  Google Scholar 

  4. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392:245–52.

    Article  CAS  PubMed  Google Scholar 

  5. Sprent J, Tough DF. T-cell death and memory. Science 2001; 293:245–8.

    Article  CAS  PubMed  Google Scholar 

  6. Haring JS, Badovinac VP, Harty JT. Inflaming the CD8+ T-cell response. Immunity 2006; 25:19–29.

    Article  CAS  PubMed  Google Scholar 

  7. Ahmed R, Gray D. Immunological memory and protective immunity: understanding their relation. Science 1996; 272:54–60.

    Article  CAS  PubMed  Google Scholar 

  8. Sprent J, Surh CD. T-cell memory. Annu Rev Immunol 2002; 20:551–79.

    Article  CAS  PubMed  Google Scholar 

  9. Boyman O, Purton JF, Surh CD et al. Cytokines and T-cell homeostasis. Curr Opin Immunol 2007; 19:320–6.

    Article  CAS  PubMed  Google Scholar 

  10. Surh CD, Boyman O, Purton JF et al. Homeostasis of memory T-cells. Immunol Rev 2006; 211:154–63.

    Article  CAS  PubMed  Google Scholar 

  11. Schluns KS, Kieper WC, Jameson SC et al. Interleukin-7 mediates the homeostasis of naive and memory CD8 T-cells in vivo. Nat Immunol 2000; 1:426–32.

    Article  CAS  PubMed  Google Scholar 

  12. Tan JT, Dudl E, LeRoy E et al. IL-7 is critical for homeostatic proliferation and survival of naive T-cells. Proc Natl Acad Sci USA 2001; 98:8732–7.

    Article  CAS  PubMed  Google Scholar 

  13. Murali-Krishna K, Lau LL, Sambhara S et al. Persistence of memory CD8 T-cells in MHC class I-deficient mice. Science 1999; 286:1377–81.

    Article  CAS  PubMed  Google Scholar 

  14. Judge AD, Zhang X, Fujii H et al. Interleukin 15 controls both proliferation and survival of a subset of memory-phenotype CD8(+) T-cells. J Exp Med 2002; 196:935–46.

    Article  CAS  PubMed  Google Scholar 

  15. Becker TC, Wherry EJ, Boone D et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T-cells. J Exp Med 2002; 195:1541–8.

    Article  CAS  PubMed  Google Scholar 

  16. Swain SL, Hu H, Huston G. Class II-independent generation of CD4 memory T-cells from effectors. Science 1999; 286:1381–3.

    Article  CAS  PubMed  Google Scholar 

  17. Kondrack RM, Harbertson J, Tan JT et al. Interleukin 7 regulates the survival and generation of memory CD4 cells. J Exp Med 2003; 198:1797–806.

    Article  CAS  PubMed  Google Scholar 

  18. Lenz DC, Kurz SK, Lemmens E et al. IL-7 regulates basal homeostatic proliferation of antiviral CD4+T cell memory. Proc Natl Acad Sci USA 2004; 101:9357–62.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang X, Sun S, Hwang I et al. Potent and selective stimulation of memory-phenotype CD8+ T-cells in vivo by IL-15. Immunity 1998; 8:591–9.

    Article  CAS  PubMed  Google Scholar 

  20. Purton JF, Tan JT, Rubinstein MP et al. Antiviral CD4+ memory T-cells are IL-15 dependent. J Exp Med 2007; 204:951–61.

    Article  CAS  PubMed  Google Scholar 

  21. Boyman O, Cho JH, Tan JT et al. A major histocompatibility complex class I-dependent subset of memory phenotype CD8+ cells. J Exp Med 2006; 203:1817–25.

    Article  CAS  PubMed  Google Scholar 

  22. Malek TR. The biology of interleukin-2. Annu Rev Immunol 2008; 26:453–79.

    Article  CAS  PubMed  Google Scholar 

  23. Swain SL. Lymphokines and the immune response: the central role of interleukin-2. Curr Opin Immunol 1991; 3:304–10.

    Article  CAS  PubMed  Google Scholar 

  24. Paul WE, Seder RA. Lymphocyte responses and cytokines. Cell 1994; 76:241–51.

    Article  CAS  PubMed  Google Scholar 

  25. Setoguchi R, Hori S, Takahashi T 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; 201:723–35.

    Article  CAS  PubMed  Google Scholar 

  26. Granucci F, Vizzardelli C, Pavelka N et al. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat Immunol 2001; 2:882–8.

    Article  CAS  PubMed  Google Scholar 

  27. Yui MA, Hernandez-Hoyos G, Rothenberg EV. A new regulatory region of the IL-2 locus that confers position-independent transgene expression. J Immunol 2001; 166:1730–9.

    CAS  PubMed  Google Scholar 

  28. Yui MA, Sharp LL, Havran WL et al. Preferential activation of an IL-2 regulatory sequence transgene in TCR gamma delta and NKT cells: subset-specific differences in IL-2 regulation. J Immunol 2004; 172:4691–9.

    CAS  PubMed  Google Scholar 

  29. Jiang S, Game DS, Davies D et al. Activated CD1d-restricted natural killer T-cells secrete IL-2: innate help for CD4+CD25+ regulatory T-cells? Eur J Immunol 2005; 35:1193–200.

    Article  CAS  PubMed  Google Scholar 

  30. Smith KA. Interleukin-2: inception, impact and implications. Science 1988; 240:1169–76.

    Article  CAS  PubMed  Google Scholar 

  31. Minami Y, Kono T, Miyazaki T et al. The IL-2 receptor complex: its structure, function and target genes. Annu Rev Immunol 1993; 11:245–68.

    Article  CAS  PubMed  Google Scholar 

  32. Leonard WJ. Type I cytokines and interferons and their receptors. In: Paul, WE ed. Fundamental Immunology. Philadelphia, PA, 19106 USA: Lippincott Williams & Wilkins, 2003: 701–747.

    Google Scholar 

  33. Waldmann TA. The multi-subunit interleukin-2 receptor. Annu Rev Biochem 1989; 58:875–911.

    Article  CAS  PubMed  Google Scholar 

  34. Sakaguchi S, Sakaguchi N, Asano M et al. Immunologic self-tolerance maintained by activated T-cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155:1151–64.

    CAS  PubMed  Google Scholar 

  35. Hou S, Hyland L, Ryan KW et al. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature 1994; 369:652–4.

    Article  CAS  PubMed  Google Scholar 

  36. Kundig TM, Schorle H, Bachmann MF et al. Immune responses in interleukin-2-deficient mice. Science 1993; 262:1059–61.

    Article  CAS  PubMed  Google Scholar 

  37. Bachmann MF, Schorle H, Kuhn R et al. Antiviral immune responses in mice deficient for both interleukin-2 and interleukin-4. J Virol 1995; 69:4842–6.

    CAS  PubMed  Google Scholar 

  38. Cousens LP, Orange JS, Biron CA. Endogenous IL-2 contributes to T-cell expansion and IFN-gamma production during lymphocytic choriomeningitis virus infection. J Immunol 1995; 155:5690–9.

    CAS  PubMed  Google Scholar 

  39. Su HC, Cousens LP, Fast LD et al. CD4+ and CD8+ T-cell interactions in IFN-gamma and IL-4 responses to viral infections: requirements for IL-2. J Immunol 1998; 160:5007–17.

    CAS  PubMed  Google Scholar 

  40. Steiger J, Nickerson PW, Steurer W et al. IL-2 knockout recipient mice reject islet cell allografts. J Immunol 1995; 155:489–98.

    CAS  PubMed  Google Scholar 

  41. Dai Z, Konieczny BT, Baddoura FK et al. Impaired alloantigen-mediated T-cell apoptosis and failure to induce long-term allograft survival in IL-2-deficient mice. J Immunol 1998; 161:1659–63.

    CAS  PubMed  Google Scholar 

  42. D’Souza WN, Schluns KS, Masopust D et al. Essential role for IL-2 in the regulation of antiviral extralymphoid CD8 T-cell responses. J Immunol 2002; 168:5566–72.

    PubMed  Google Scholar 

  43. D’Souza WN, Lefrancois L. IL-2 is not required for the initiation of CD8 T-cell cycling but sustains expansion. J Immunol 2003; 171:5727–35.

    PubMed  Google Scholar 

  44. Wong P, Pamer EG. Disparate in vitro and in vivo requirements for IL-2 during antigen-independent CD8 T-cell expansion. J Immunol 2004; 172:2171–6.

    CAS  PubMed  Google Scholar 

  45. Boyman O, Kovar M, Rubinstein MP et al. Selective stimulation of T-cell subsets with antibody-cytokine immune complexes. Science 2006; 311:1924–7.

    Article  CAS  PubMed  Google Scholar 

  46. Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T-cells. Nature 2006; 441:890–3.

    Article  CAS  PubMed  Google Scholar 

  47. Cheng LE, Greenberg PD. Selective delivery of augmented IL-2 receptor signals to responding CD8+ T-cells increases the size of the acute antiviral response and of the resulting memory T-cell pool. J Immunol 2002; 169:4990–7.

    PubMed  Google Scholar 

  48. Li XC, Demirci G, Ferrari-Lacraz S et al. IL-15 and IL-2: a matter of life and death for T-cells in vivo. Nat Med 2001; 7:114–8.

    Article  CAS  PubMed  Google Scholar 

  49. Blattman JN, Grayson JM, Wherry EJ et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat Med 2003; 9:540–7.

    Article  CAS  PubMed  Google Scholar 

  50. Nutt SL, Fairfax KA, Kallies A. BLIMP1 guides the fate of effector B-and T-cells. Nat Rev Immunol 2007; 7:923–7.

    Article  CAS  PubMed  Google Scholar 

  51. Lenardo MJ. Interleukin-2 programs mouse alpha beta T-lymphocytes for apoptosis. Nature 1991; 353:858–61.

    Article  CAS  PubMed  Google Scholar 

  52. Van Parijs L, Abbas AK. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 1998; 280:243–8.

    Article  PubMed  Google Scholar 

  53. Sadlack B, Merz H, Schorle H et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993; 75:253–61.

    Article  CAS  PubMed  Google Scholar 

  54. Willerford DM, Chen J, Ferry JA et al. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995; 3:521–30.

    Article  CAS  PubMed  Google Scholar 

  55. Suzuki H, Kundig TM, Furlonger C et al. Deregulated T-cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 1995; 268:1472–6.

    Article  CAS  PubMed  Google Scholar 

  56. Bachmann MF, Wolint P, Walton S et al. Differential role of IL-2R signaling for CD8+ T-cell responses in acute and chronic viral infections. Eur J Immunol 2007; 37:1502–12.

    Article  CAS  PubMed  Google Scholar 

  57. Yu A, Zhou J, Marten N et al. Efficient induction of primary and secondary T-cell-dependent immune responses in vivo in the absence of functional IL-2 and IL-15 receptors. J Immunol 2003; 170:236–42.

    CAS  PubMed  Google Scholar 

  58. Jin H, Gong D, Adeegbe D et al. Quantitative assessment concerning the contribution of IL-2Rbeta for superantigen-mediated T-cell responses in vivo. Int Immunol 2006; 18:565–72.

    Article  CAS  PubMed  Google Scholar 

  59. Teague RM, Tempero RM, Thomas S et al. Proliferation and differentiation of CD8+ T-cells in the absence of IL-2/15 receptor beta-chain expression or STAT5 activation. J Immunol 2004; 173:3131–9.

    CAS  PubMed  Google Scholar 

  60. Dai Z, Konieczny BT, Lakkis FG. The dual role of IL-2 in the generation and maintenance of CD8+ memory T-cells. J Immunol 2000; 165:3031–6.

    CAS  PubMed  Google Scholar 

  61. Kuroda K, Yagi J, Imanishi K et al. Implantation of IL-2-containing osmotic pump prolongs the survival of superantigen-reactive T-cells expanded in mice injected with bacterial superantigen. J Immunol 1996; 157:1422–31.

    CAS  PubMed  Google Scholar 

  62. Sprent J, Schaefer M, Gao EK et al. Role of T-cell subsets in lethal graft-versus-host disease (GVHD) directed to class I versus class II H-2 differences. I. L3T4+ cells can either augment or retard GVHD elicited by Lyt-2+ cells in class I different hosts. J Exp Med 1988; 167:556–69.

    Article  CAS  PubMed  Google Scholar 

  63. Sykes M, Romick ML, Hoyles KA et al. In vivo administration of interleukin 2 plus T-cell-depleted syngeneic marrow prevents graft-versus-host disease mortality and permits alloengraftment. J Exp Med 1990; 171:645–58.

    Article  CAS  PubMed  Google Scholar 

  64. Cho JH, Boyman O, Kim HO et al. An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2. J Exp Med 2007; 204:1787–801.

    Article  CAS  PubMed  Google Scholar 

  65. Kamimura D, Bevan MJ. Naive CD8+ T-cells differentiate into protective memory-like cells after IL-2 anti IL-2 complex treatment in vivo. J Exp Med 2007; 204:1803–12.

    Article  CAS  PubMed  Google Scholar 

  66. Mostbock S, Lutsiak ME, Milenic DE et al. IL-2/anti-IL-2 antibody complex enhances vaccine-mediated antigen-specific CD8(+) T-cell responses and increases the ratio of effector/memory CD8(+) T-cells to regulatory T-cells. J Immunol 2008; 180:5118–29.

    CAS  PubMed  Google Scholar 

  67. Kaech SM, Tan JT, Wherry EJ et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T-cells that give rise to long-lived memory cells. Nat Immunol 2003; 4:1191–8.

    Article  CAS  PubMed  Google Scholar 

  68. Shedlock DJ, Shen H. Requirement for CD4 T-cell help in generating functional CD8 T-cell memory. Science 2003; 300:337–9.

    Article  CAS  PubMed  Google Scholar 

  69. Sun JC, Bevan MJ. Defective CD8 T-cell memory following acute infection without CD4 T-cell help. Science 2003; 300:339–42.

    Article  CAS  PubMed  Google Scholar 

  70. Sun JC, Williams MA, Bevan MJ. CD4+ T-cells are required for the maintenance, not programming, of memory CD8+ T-cells after acute infection. Nat Immunol 2004; 5:927–33.

    Article  CAS  PubMed  Google Scholar 

  71. D’Souza WN, Lefrancois L. Frontline: An in-depth evaluation of the production of IL-2 by antigen-specific CD8 T-cells in vivo. Eur J Immunol 2004; 34:2977–85.

    Article  PubMed  CAS  Google Scholar 

  72. Wherry EJ, Barber DL, Kaech SM et al. Antigen-independent memory CD8 T-cells do not develop during chronic viral infection. Proc Natl Acad Sci USA 2004; 101:16004–9.

    Article  CAS  PubMed  Google Scholar 

  73. Kaech SM, Hemby S, Kersh E et al. Molecular and functional profiling of memory CD8 T-cell differentiation. Cell 2002; 111:837–51.

    Article  CAS  PubMed  Google Scholar 

  74. Furtado GC, de Lafaille MAC, Kutchukhidze N et al. Interleukin 2 Signaling Is Required for CD4+ Regulatory T-Cell Function. J Exp Med 2002; 196:851–857.

    Article  CAS  PubMed  Google Scholar 

  75. Fontenot JD, Rasmussen JP, Gavin MA et al. A function for interleukin 2 in Foxp3-expressing regulatory T-cells. Nat Immunol 2005; 6:1142–51.

    Article  CAS  PubMed  Google Scholar 

  76. Hori S, Nomura T, Sakaguchi S. Control of regulatory T-cell development by the transcription factor Foxp3. Science 2003; 299:1057–61.

    Article  CAS  PubMed  Google Scholar 

  77. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T-cells. Nat Immunol 2003; 4:330–6.

    Article  CAS  PubMed  Google Scholar 

  78. Ramsdell F, Ziegler SF. Transcription factors in autoimmunity. Curr Opin Immunol 2003; 15:718–24.

    Article  CAS  PubMed  Google Scholar 

  79. Murakami M, Sakamoto A, Bender J et al. CD25+CD4+ T-cells contribute to the control of memory CD8+ T-cells. Proc Natl Acad Sci USA 2002; 99:8832–7.

    Article  CAS  PubMed  Google Scholar 

  80. Kursar M, Bonhagen K, Fensterle J et al. Regulatory CD4+CD25+ T-cells restrict memory CD8+ T-cell responses. J Exp Med 2002; 196:1585–92.

    Article  CAS  PubMed  Google Scholar 

  81. Suvas S, Kumaraguru U, Pack CD et al. CD4+CD25+ T-cells regulate virus-specific primary and memory CD8+ T-cell responses. J Exp Med 2003; 198:889–901.

    Article  CAS  PubMed  Google Scholar 

  82. Sharma R, Zheng L, Deshmukh US et al. A regulatory T-cell-dependent novel function of CD25 (IL-2Ralpha) controlling memory CD8(+) T-cell homeostasis. J Immunol 2007; 178:1251–5.

    CAS  PubMed  Google Scholar 

  83. Pandiyan P, Zheng L, Ishihara S et al. CD4+CD25+Foxp3+ regulatory T-cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T-cells. Nat Immunol 2007; 8:1353–62.

    Article  CAS  PubMed  Google Scholar 

  84. Sakaguchi S. Naturally arising CD4+ regulatory T-cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22:531–562.

    Article  CAS  PubMed  Google Scholar 

  85. Shevach EM, McHugh RS, Piccirillo CA et al. Control of T-cell activation by CD4+ CD25+ suppressor T-cells. Immunol Rev 2001; 182:58–67.

    Article  CAS  PubMed  Google Scholar 

  86. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T-cell development and the forkhead family transcription factor Foxp3. Nat Immunol 2005; 6:331–7.

    Article  CAS  PubMed  Google Scholar 

  87. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004; 4:665–74.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Immunology and Allergy, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, CH-1011, Lausanne, Switzerland

    Onur Boyman, Jae-Ho Cho & Jonathan Sprent

Authors
  1. Onur Boyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jae-Ho Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan Sprent
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Onur Boyman .

Editor information

Editors and Affiliations

  1. The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, California, USA

    Maurizio Zanetti MD (Professor of Medicine) (Professor of Medicine)

  2. Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA

    Stephen P. Schoenberger PhD (member in the Laboratory of Cellular Immunology) (member in the Laboratory of Cellular Immunology)

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Boyman, O., Cho, JH., Sprent, J. (2010). The Role of Interleukin-2 in Memory CD8 Cell Differentiation. In: Zanetti, M., Schoenberger, S.P. (eds) Memory T Cells. Advances in Experimental Medicine and Biology, vol 684. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6451-9_3

Download citation

Publish with us

Policies and ethics

Search

Navigation