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Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections

Nature Medicine volume 8, pages 379–385 (2002)Cite this article

Abstract

The viruses HIV-1, Epstein–Barr virus (EBV), cytomegalovirus (CMV) and hepatitis C virus (HCV) are characterized by the establishment of lifelong infection in the human host, where their replication is thought to be tightly controlled by virus-specific CD8+ T cells. Here we present detailed studies of the differentiation phenotype of these cells, which can be separated into three distinct subsets based on expression of the costimulatory receptors CD28 and CD27. Whereas CD8+ T cells specific for HIV, EBV and HCV exhibit similar characteristics during primary infection, there are significant enrichments at different stages of cellular differentiation in the chronic phase of persistent infection according to the viral specificity, which suggests that distinct memory T-cell populations are established in different virus infections. These findings challenge the current definitions of memory and effector subsets in humans, and suggest that ascribing effector and memory functions to subsets with different differentiation phenotypes is no longer appropriate.

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Figure 1: Characterization of virus-specific CD8+ T cells during primary infection.
Figure 2: CD28/CD27 expression on virus-specific CD8+ T cells during chronic infection.
Figure 3: Multicolor staining on virus-specific CD8+ T cells from a single donor.
Figure 4: Dissection of the CD8+ T-cell population using intracellular and extracellular markers.
Figure 5: Functional characterization of the intermediate-differentiated CD8+ subset.

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References

  1. Koup, R.A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).

    CAS  PubMed Central  Google Scholar 

  2. Callan, M.F. et al. Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nature Med. 2, 906–911 (1996).

    Article  CAS  Google Scholar 

  3. Wills, M.R. et al. The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J. Virol. 70, 7569–7579 (1996).

    CAS  PubMed Central  Google Scholar 

  4. Lechner, F. et al. CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. Eur. J. Immunol. 30, 2479–2487 (2000).

    Article  CAS  Google Scholar 

  5. Appay, V. et al. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med. 192, 63–75 (2000).

    Article  CAS  Google Scholar 

  6. Gillespie, G.M. et al. Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors. J. Virol. 74, 8140–8150 (2000).

    Article  CAS  Google Scholar 

  7. Hislop, A.D. et al. EBV-specific CD8+ T cell memory: relationships between epitope specificity, cell phenotype, and immediate effector function. J. Immunol. 167, 2019–2029 (2001).

    Article  CAS  Google Scholar 

  8. Lechner, F. et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191, 1499–1512 (2000).

    Article  CAS  Google Scholar 

  9. Effros, R.B. et al. Shortened telomeres in the expanded CD28−CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS 10, F17–22 (1996).

    Article  CAS  Google Scholar 

  10. Posnett, D.N., Edinger, J.W., Manavalan, J.S., Irwin, C. & Marodon, G. Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones. Int. Immunol. 11, 229–241 (1999).

    Article  CAS  Google Scholar 

  11. Borthwick, N.J., Lowdell, M., Salmon, M. & Akbar, A.N. Loss of CD28 expression on CD8(+) T cells is induced by IL-2 receptor γ chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. Int. Immunol. 12, 1005–1013 (2000).

    Article  CAS  Google Scholar 

  12. Hamann, D. et al. Evidence that human CD8+CD45RA+CD27− cells are induced by antigen and evolve through extensive rounds of division. Int. Immunol. 11, 1027–1033 (1999).

    Article  CAS  Google Scholar 

  13. Roos, M.T. et al. Changes in the composition of circulating CD8+ T cell subsets during acute Epstein–Barr and human immunodeficiency virus infections in humans. J. Infect. Dis. 182, 451–458 (2000).

    Article  CAS  Google Scholar 

  14. Globerson, A. & Effros, R.B. Ageing of lymphocytes and lymphocytes in the aged. Immunol. Today 21, 515–521 (2000).

    Article  CAS  Google Scholar 

  15. De Rosa, S.C., Herzenberg, L.A. & Roederer, M. 11-color, 13-parameter flow cytometry: identification of human naive T cells by phenotype, function, and T-cell receptor diversity. Nature Med. 7, 245–248 (2001).

    Article  CAS  Google Scholar 

  16. Ahmed, R. & Gray, D. Immunological memory and protective immunity: Understanding their relation. Science 272, 54–60 (1996).

    Article  CAS  Google Scholar 

  17. Doherty, P.C. & Christensen, J.P. Accessing complexity: The dynamics of virus-specific T cell responses. Annu. Rev. Immunol. 18, 561–592 (2000).

    Article  CAS  Google Scholar 

  18. Bevan, M.J. & Fink, P.J. The CD8 response on autopilot. Nature Immunol. 2, 381–382 (2001).

    Article  CAS  Google Scholar 

  19. Hu, H. et al. CD4(+) T cell effectors can become memory cells with high efficiency and without further division. Nature Immunol. 2, 705–710 (2001).

    Article  CAS  Google Scholar 

  20. Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 (1997).

    Article  CAS  Google Scholar 

  21. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  Google Scholar 

  22. Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).

    Article  CAS  Google Scholar 

  23. Strasser, A., O'Connor, L. & Dixit, V.M. Apoptosis signaling. Annu. Rev. Biochem. 69, 217–245 (2000).

    Article  CAS  Google Scholar 

  24. Lenschow, D.J., Walunas, T.L. & Bluestone, J.A. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14, 233–258 (1996).

    Article  CAS  Google Scholar 

  25. Hendriks, J. et al. CD27 is required for generation and long-term maintenance of T cell immunity. Nature Immunol. 1, 433–439 (2000).

    Article  CAS  Google Scholar 

  26. Ferbas, J. et al. Virus burden in long-term survivors of human immunodeficiency virus (HIV) infection is a determinant of anti-HIV CD8+ lymphocyte activity. J. Infect. Dis. 172, 329–339 (1995).

    Article  CAS  Google Scholar 

  27. Medley, Q.G. et al. Characterization of GMP-17, a granule membrane protein that moves to the plasma membrane of natural killer cells following target cell recognition. Proc. Natl. Acad. Sci. USA 93, 685–689 (1996).

    Article  CAS  Google Scholar 

  28. Campbell, J.J. et al. 6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the MIP-3β receptor CCR7. J. Cell Biol 141, 1053–1059 (1998).

    Article  CAS  Google Scholar 

  29. Campbell, J.J. et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381–384 (1998).

    Article  CAS  Google Scholar 

  30. Chen, G. et al. CD8 T cells specific for human immunodeficiency virus, Epstein–Barr virus, and cytomegalovirus lack molecules for homing to lymphoid sites of infection. Blood 98, 156–164 (2001).

    Article  CAS  Google Scholar 

  31. Baars, P.A. et al. Cytolytic mechanisms and expression of activation-regulating receptors on effector-type CD8+CD45RA+CD27− human T cells. J. Immunol. 165, 1910–1917 (2000).

    Article  CAS  Google Scholar 

  32. Callan, M.F. et al. CD8(+) T-cell selection, function, and death in the primary immune response in vivo. J. Clin. Invest. 106, 1251–1261 (2000).

    Article  CAS  Google Scholar 

  33. Mueller, Y.M. et al. Increased CD95/Fas-induced apoptosis of HIV-specific CD8(+) T cells. Immunity 15, 871–882 (2001).

    Article  CAS  Google Scholar 

  34. Ridge, J.P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).

    Article  CAS  Google Scholar 

  35. Kalams, S.A. & Walker, B.D. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J. Exp. Med. 188, 2199–2204 (1998).

    Article  CAS  Google Scholar 

  36. Andrews, D.M., Andoniou, C.E., Granucci, F., Ricciardi-Castagnoli, P. & Degli-Esposti, M.A. Infection of dendritic cells by murine cytomegalovirus induces functional paralysis. Nature Immunol. 22, 22 (2001).

    Google Scholar 

  37. Grayson, J.M., Zajac, A.J., Altman, J.D. & Ahmed, R. Cutting edge: Increased expression of Bcl–2 in antigen-specific memory CD8+ T cells. J. Immunol. 164, 3950–3954 (2000).

    Article  CAS  Google Scholar 

  38. Homann, D., Teyton, L. & Oldstone, M.B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nature Med. 7, 913–919 (2001).

    Article  CAS  Google Scholar 

  39. Kostense, S. et al. High viral burden in the presence of major HIV-specific CD8(+) T cell expansions: Evidence for impaired CTL effector function. Eur. J. Immunol. 31, 677–686 (2001).

    Article  CAS  Google Scholar 

  40. Easterbrook, P.J. Long-term non-progression in HIV infection: Definitions and epidemiological issues. J. Infect. 38, 71–73 (1999).

    Article  CAS  Google Scholar 

  41. Bunce, M. et al. Phototyping: Comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens 46, 355–367 (1995).

    Article  CAS  Google Scholar 

  42. Altman, J.D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996); erratum: 280, 1821 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Lucas for help; J. Collier and R. Chapman for blood samples from the Oxford clinic; T. Rostron for HLA typing; B. Walker, G. Lauer, E. Barnes and G. Dusheiko for collaboration; and the staff and patients of the clinics that provided blood samples, particularly the Caldecot Centre at King's College Hospital, the VA Research Center for AIDS and HIV Infection and the UCSD Center for AIDS Research. This work was supported by the Medical Research Council of the UK, the Wellcome Trust, the EU (QLK2-CT-1999-00356), Elizabeth Glaser Pediatric AIDS Foundation and the NIH. S.L.R.-J. is an MRC Senior Fellow and holds an Elizabeth Glaser scientist award.

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Authors and Affiliations

  1. MRC Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK

    Victor Appay, P. Rod Dunbar, Margaret Callan, Geraldine M.A. Gillespie, Laura Papagno, Graham S. Ogg, Abigail King, Mariolina Salio, Vincenzo Cerundolo, Andrew J. McMichael & Sarah L. Rowland-Jones

  2. Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford, UK

    Paul Klenerman & Franziska Lechner

  3. University of California San Diego, La Jolla, California, USA

    Celsa A. Spina, Susan Little, Diane V. Havlir & Douglas D. Richman

  4. San Diego VA Research Center for AIDS and HIV Infection, San Diego, California, USA

    Celsa A. Spina, Susan Little & Douglas D. Richman

  5. Institute for Immunology, Munchen, Germany

    Norbert Gruener & Gerd Pape

  6. Department of HIV/GUM, The Guy's, Kings' and St Thomas' School of Medicine, Weston Education Centre, London, UK

    Anele Waters & Philippa Easterbrook

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Correspondence to Victor Appay.

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Appay, V., Dunbar, P., Callan, M. et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8, 379–385 (2002). https://doi.org/10.1038/nm0402-379

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