Skip to main content
SpringerLink
Log in

In Vivo Dynamics of Anti-Viral CD8 T Cell Responses to Different Epitopes

An Evaluation of Bystander Activation in Primary and Secondary Responses to Viral Infection

  • Chapter
Mechanisms of Lymphocyte Activation and Immune Regulation VII

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 452))

Summary

Viral infections induce extensive T cell proliferation in vivo. However, only a small fraction (1–5%) of the activated T cells have been shown to be virus specific leading to the prevailing notion that most of the T cell expansion represents cytokine-mediated bystander activation and/or cross reactive stimulation of non specific cells. To re-examine this issue we quantitated antigen specific CD8 T cells during acute LCMV infection of mice using three sensitive techniques: (i) intracellular cytokine production, (ii) single cell ELISPOT and (iii) direct visualization of antigen specific CD8 T cells by staining with MHC class I tetramers + peptide. In contrast to previous estimates, we found that 50–70% of the activated CD8 T cells were LCMV specific. This represented ≥ 10,000-fold increase (~2 × 107 virus specific cells/spleen) in 8 days with the peak expansion occurring between day 3 and 5 during which period virus specific CD8 T cells had an estimated division time of ~8 hours. Following viral clearance, the number of antigen specific CD8 T cells dropped to 1 × 106 per spleen and were maintained at this level for the life of the mouse. Upon rechallenge with LCMV, memory CD8 T cells rapidly proliferated and again comprised >50% of the total CD8 T cells. In contrast, upon challenge with a heterologous virus such as vaccinia, there was no change in the number of LCMV specific memory CTL, despite a substantial increase in the number of activated CD8 T cells. Taken together, these results show that much of the CD8 T cell expansion seen during viral infection represents antigen specific cells.

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 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight 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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Beverley PC: Is T cell memory maintained by crossreactive stimulation? Immunol. Today 11: 203–5, 1990.

    CAS  Google Scholar 

  2. Cao W, Tykodi SS, Esser MT, Braciale VL, Braciale TJ: Partial activation of CD8+ T cells by a self-derived peptide. Nature 378: 295–8, 1995.

    Article  PubMed  CAS  Google Scholar 

  3. Matzinger P: Immunology. Memories are made of this? Nature 369: 605–6, 1994.

    Article  PubMed  CAS  Google Scholar 

  4. Oldstone MB: Molecular mimicry and autoimmune disease. Cell 50: 819–20, 1987.

    Article  PubMed  CAS  Google Scholar 

  5. Tough DF, Borrow P, Sprent J: Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272: 1947–50, 1996.

    Article  PubMed  CAS  Google Scholar 

  6. Tough DF, Sprent J: Viruses and T cell turnover: evidence for bystander proliferation. Immunol. Rev. 150: 129–42, 1996.

    Article  PubMed  CAS  Google Scholar 

  7. Unutmaz D, Pileri P, Abrignani S: Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J. Exp. Med. 180:1159–64, 1994.

    Article  PubMed  CAS  Google Scholar 

  8. Zal T, Weiss S, Mellor A., Stockinger B: Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function. Proc. Natl. Acad. Sci. USA 93: 9102–7, 1996.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  10. Doherty PC, Allan W, Eichelberger M, Carding SR: Roles of alpha beta and gamma delta T cell subsets in viral immunity. Ann. Rev. Immunol. 10: 123–151, 1992.

    Article  CAS  Google Scholar 

  11. Zinkernagel RM: Immunology taught by viruses. Science 271:173–178, 1996.

    Article  PubMed  CAS  Google Scholar 

  12. Ehl S, Hombach J, Aichele P, HengartnerH, Zinkernagel RM: Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model. J. Exp. Med. 185: 1241–51, 1997.

    Article  PubMed  CAS  Google Scholar 

  13. Zarozinski CC, Welsh RM: Minimal bystander activation of CD8 T cells during the virus-induced polyclonal T cell response. J. Exp. Med. 185: 1629–39, 1997.

    Article  PubMed  CAS  Google Scholar 

  14. Griffin DE: Immune responses during measles virus infection. Curr. Top. Microbiol. Immunol. 191: 117–34, 1995.

    Article  PubMed  CAS  Google Scholar 

  15. Ahmed R, Salmi A, Butler L D, Chiller J M, Oldstone MBA: Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp.Med. 160: 521–40, 1984.

    Article  PubMed  CAS  Google Scholar 

  16. Borrow P, Tishon A, Lee S, Xu J, Grewal IS, Oldstone M B, Flavell RA: CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. J. Exp. Med. 183: 2129–42, 1996.

    Article  PubMed  CAS  Google Scholar 

  17. Byrne JA, Ahmed R, Oldstone MBA: Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus. I. Generation and recognition of virus strains and H-2b mutants. J. Immunol. 133: 433–9, 1984.

    PubMed  CAS  Google Scholar 

  18. Fung-Leung WP, Kundig TM, Zinkernagel RM, Mak T W: Immune response against lymphocytic choriomeningitis virus infection in mice without CD8 expression. J. Exp. Med. 174: 1425–9, 1991.

    Article  PubMed  CAS  Google Scholar 

  19. Gegin C, Lehmann Grube F: Control of acute infection with lymphocytic choriomeningitis virus in mice that cannot present an immunodominant viral cytotoxic T lymphocyte epitope. J. Immunol. 149: 3331–8, 1992.

    PubMed  CAS  Google Scholar 

  20. Kagi D, Ledermann B, Burki K, Zinkernagel R M, Hengartner H: Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Annu. Rev. Immunol. 14:207–32, 1996.

    Article  PubMed  CAS  Google Scholar 

  21. Matloubian M, Kolhekar S R, Somasundaram T, Ahmed R: Molecular determinants of macrophage tropism and viral persistence: importance of single amino acid changes in the polymerase and glycoprotein of lymphocytic choriomeningitis virus. J. Virol. 67: 7340–9, 1993.

    PubMed  CAS  Google Scholar 

  22. McFarland H I, Nahill SR, Maciaszek JW, Welsh R M: CD11b (Mac-1): a marker for CD8+ cytotoxic T cell activation and memory in virus infection. J. Immunol. 149: 1326–33, 1992.

    PubMed  CAS  Google Scholar 

  23. Moskophidis D, Fang L, Gossmann J, Lehmann Grube F: Mechanism of recovery from acute virus infection. IX. Clearance of lymphocytic choriomeningitis (LCM) virus from the feet of mice undergoing LCM virus-specific delayed-type hypersensitivity reaction. J. Gen. Virol. 70: 3305–16, 1989.

    Article  PubMed  Google Scholar 

  24. Moskophidis D, Lechner F, Pircher H, Zinkernagel R M: Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362: 758–61, 1993.

    Article  PubMed  CAS  Google Scholar 

  25. van der Most RG, Sette A, Oseroff C, Alexander J, Murali-Krishna K, Lau LL, Southwood S, Sidney J, Chesnut RW, Matloubian M, Ahmed R: Analysis of cytotoxic T cell responses to dominant and subdominant epitopes during acute and chronic lymphocytic choriomeningitis virus infection. J. Immunol. 157: 5543–54, 1996.

    PubMed  Google Scholar 

  26. Asano MS, and Ahmed R: CD8 T cell memory in B cell-deficient mice. J. Exp. Med. 183: 2165–74, 1996.

    Article  PubMed  CAS  Google Scholar 

  27. Zimmerman C, Brduscha RK, Blaser C, Zinkernagel R M, Pircher H: Visualization, characterization, and turnover of CD8+ memory T cells in virus-infected hosts. J. Exp. Med. 183: 1367–75, 1996.

    Article  PubMed  CAS  Google Scholar 

  28. Lau LL, Jamieson BD, Somasundaram T, Ahmed R: Cytotoxic T-cell memory without antigen. Nature 369: 648–52, 1994.

    Article  PubMed  CAS  Google Scholar 

  29. Nahill SR, Welsh RM: High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte response. J. Exp. Med. 177: 317–27, 1993.

    Article  PubMed  CAS  Google Scholar 

  30. Razvi ES, Welsh R M, McFarland HI: In vivo state of antiviral CTL precursors. Characterization of a cycling cell population containing CTL precursors in immune mice. J. Immunol. 154: 620–32, 1995.

    PubMed  CAS  Google Scholar 

  31. Selin LK, Vergilis K, Welsh RM, Nahill SR: Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. J. Exp. Med. 183: 2489–99, 1996.

    Article  PubMed  CAS  Google Scholar 

  32. van der Most RG, Concepcion R J, Oseroff C, Alexander J, Southwood S, Sidney J, Chesnut RW, Ahmed R, Sette A: Uncovering subdominant cytotoxic T-lymphocyte responses in lymphocytic choriomeningitis virus-infected BALB/c mice. J. Virol. 71:5110–4, 1997.

    PubMed  Google Scholar 

  33. van der Most RG, Murali-Krishna K, Whitton L, Oseroff C, Alexander J, Southwood S, Sidney J, Chesnut RW, Sette A, Ahmed R: Identification of Db and Kb-restricted subdominant cytotoxic T-cell responses in lymphocytic choriomeningitis virus-infected mice. Virology (in press), 1988.

    Google Scholar 

  34. Altman JD, Moss P, Goulder P, Barouch DH, McHeyzer WM, Bell J I, McMichael A J, Davis MM: Pheno-typic analysis of antigen-specific T lymphocytes. Science 274: 94–6, 1996.

    Article  PubMed  CAS  Google Scholar 

  35. Andersson E.C., Christensen.JP, Scheynius A, Marker O, Thomsen AR: Lymphocytic choriomeningitis virus infection is associated with long-standing perturbation of LFA-1 expression on CD8+ T cells. Scand. J. Immunol. 42: 110–8, 1995.

    Article  PubMed  CAS  Google Scholar 

  36. Nagata S, Golstein P: The Fas death factor. Science 267: 1449–56, 1995.

    Article  PubMed  CAS  Google Scholar 

  37. Lalvani A, Brookes R, Hambleton S, Britton WJ, Hill AV, McMichael AJ: Rapid effector function in CD8+ memory T cells. J. Exp. Med. 186: 859–65, 1997.

    Article  PubMed  CAS  Google Scholar 

  38. Callan MF, Steven N, Krausa P, Wilson J D, Moss PA, Gillespie GM, Bell J.I., Rickinson AB, McMichael AJ: Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nat. Med. 2: 906–11, 1996.

    Article  PubMed  CAS  Google Scholar 

  39. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, Farthing C, a Ho DD: Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68: 4650–5, 1994.

    PubMed  CAS  Google Scholar 

  40. Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger J W, Borrow P, Saag MS, Shaw G M, Sekaly R P, and et, a. 1.: Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 370: 463–7, 1994.

    Article  PubMed  CAS  Google Scholar 

  41. Pantaleo G, Soudeyns H, Demarest JF, Vaccarezza M, Graziosi C, Paolucci S, Daucher M, Cohen O J, Denis F, Biddison W E, Sekaly RP, Fauci AS: Evidence for rapid disappearance of initially expanded HIV-specific CD8+ T cell clones during primary HIV infection. Proc. Natl. Acad. Sci. USA 94: 9848–53, 1997.

    Article  PubMed  CAS  Google Scholar 

  42. Cose SC, Jones CM, Wallace ME, Heath WR, Carbone F R: Antigen-specific CD8+ T cell subset distribution in lymph nodes draining the site of herpes simplex virus infection. Eur. J. Immunol. 27: 2310–6, 1997.

    Article  PubMed  CAS  Google Scholar 

  43. Schatz PJ Use of peptide libraries to map the substrate specificity of a peptide-modifying enzyme: a 13 residue consensus peptide specifies biotinylation in Escherichia coli. Biotechnology (NY) 11: 1138–43, 1993.

    Article  CAS  Google Scholar 

  44. Garboczi DN, Hung DT, Wiley DC: HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. Proc. Natl. Acad. Sci. USA 89: 3429–33, 1992.

    Article  PubMed  CAS  Google Scholar 

  45. Taguchi T, McGhee JR, Coffman R L, Beagley K W, Eldridge JH, Takatsu K, Kiyono H: Detection of individual mouse splenic T cells producing IFN-gamma and IL-5 usig the enzyme-linked immunospot (ELIS-POT) assay. J. Immunol. Methods. 128: 65–73, 1990.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, 30322, USA

    Kaja Murali-Krishna, John D. Altman, M. Suresh, David Sourdive, Allan Zajac & Rafi Ahmed

Authors
  1. Kaja Murali-Krishna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John D. Altman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Suresh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Sourdive
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Allan Zajac
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rafi Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rafi Ahmed .

Editor information

Editors and Affiliations

  1. University of California, Irvine, Irvine, California, USA

    Sudhir Gupta

  2. National Institutes of Health, Bethesda, Maryland, USA

    Alan Sher

  3. Emory University, Atlanta, Georgia, USA

    Rafi Ahmed

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer Science+Business Media New York

About this chapter

Cite this chapter

Murali-Krishna, K., Altman, J.D., Suresh, M., Sourdive, D., Zajac, A., Ahmed, R. (1998). In Vivo Dynamics of Anti-Viral CD8 T Cell Responses to Different Epitopes. In: Gupta, S., Sher, A., Ahmed, R. (eds) Mechanisms of Lymphocyte Activation and Immune Regulation VII. Advances in Experimental Medicine and Biology, vol 452. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5355-7_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-5355-7_14

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7443-5

  • Online ISBN: 978-1-4615-5355-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation