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T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion

Nature Immunology volume 14, pages 603–610 (2013)Cite this article

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Abstract

During chronic infection, pathogen-specific CD8+ T cells upregulate expression of molecules such as the inhibitory surface receptor PD-1, have diminished cytokine production and are thought to undergo terminal differentiation into exhausted cells. Here we found that T cells with memory-like properties were generated during chronic infection. After transfer into naive mice, these cells robustly proliferated and controlled a viral infection. The reexpanded T cell populations continued to have the exhausted phenotype they acquired during the chronic infection. Thus, the cells underwent a form of differentiation that was stably transmitted to daughter cells. We therefore propose that during persistent infection, effector T cells stably differentiate into a state that is optimized to limit viral replication without causing overwhelming immunological pathology.

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Figure 1: CD8+ T cells able to undergo secondary population expansion are present in mice infected with LCMV-c13.
Figure 2: Proliferation of PD-1hi T cells.
Figure 3: Functional effector CD8+ T cells can be recovered from mice infected with LCMV-c13.
Figure 4: The phenotype acquired during infection with LCMV-c13 is passed to daughter cells.
Figure 5: Reexpanded T cell populations retain high PD-1 expression.
Figure 6: LCMV-c13–primed CD8+ T cells maintain their phenotype after long-term antigen withdrawal.
Figure 7: Similar expression of effector molecules among PD-1+ or PD-1− melan-A- and EBV-specific human CD8+ T cells.

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References

  1. McDermott, A.B. & Koup, R.A. CD8+ T cells in preventing HIV infection and disease. AIDS 26, 1281–1292 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Rehermann, B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J. Clin. Invest. 119, 1745–1754 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ahmed, R., Salmi, A., Butler, L.D., Chiller, J.M. & Oldstone, M.B. 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, 521–540 (1984).

    Article  CAS  PubMed  Google Scholar 

  4. Klenerman, P. & Hill, A. T cells and viral persistence: lessons from diverse infections. Nat. Immunol. 6, 873–879 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. McMichael, A.J., Borrow, P., Tomaras, G.D., Goonetilleke, N. & Haynes, B.F. The immune response during acute HIV-1 infection: clues for vaccine development. Nat. Rev. Immunol. 10, 11–23 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Gallimore, A. et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J. Exp. Med. 187, 1383–1393 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zajac, A.J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wherry, E.J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. 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, 758–761 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Paley, M.A. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338, 1220–1225 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Day, C.L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Blackburn, S.D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Barber, D.L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Wherry, E.J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Bowen, D.G. & Walker, C.M. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436, 946–952 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Pichenot, M., Deuffic-Burban, S., Cuzin, L. & Yazdanpanah, Y. Efficacy of new antiretroviral drugs in treatment-experienced HIV-infected patients: a systematic review and meta-analysis of recent randomized controlled trials. HIV Med. 13, 148–155 (2012).

    CAS  PubMed  Google Scholar 

  17. Jin, X. et al. Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189, 991–998 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schmitz, J.E. et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Velu, V. et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206–210 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Vezys, V. et al. Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J. Exp. Med. 203, 2263–2269 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wherry, E.J., Barber, D.L., Kaech, S.M., Blattman, J.N. & Ahmed, R. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl. Acad. Sci. USA 101, 16004–16009 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shin, H. & Wherry, E.J. CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol. 19, 408–415 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Shin, H., Blackburn, S.D., Blattman, J.N. & Wherry, E.J. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med. 204, 941–949 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wherry, E.J., Blattman, J.N., Murali-Krishna, K., van der Most, R. & Ahmed, R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911–4927 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dillon, S.R., Jameson, S.C. & Fink, P.J. Vβ5+ T cell receptors skew toward OVA+H-2Kb recognition. J. Immunol. 152, 1790–1801 (1994).

    CAS  PubMed  Google Scholar 

  26. Miller, N.E., Bonczyk, J.R., Nakayama, Y. & Suresh, M. Role of thymic output in regulating CD8 T-cell homeostasis during acute and chronic viral infection. J. Virol. 79, 9419–9429 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brandle, D. et al. Involvement of both T cell receptor Vα and Vβ variable region domains and α chain junctional region in viral antigen recognition. Eur. J. Immunol. 21, 2195–2202 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Richter, K., Brocker, T. & Oxenius, A. Antigen amount dictates CD8+ T-cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell. Eur. J. Immunol. 42, 2290–2304 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Mueller, S.N. & Ahmed, R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 106, 8623–8628 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Geginat, J., Lanzavecchia, A. & Sallusto, F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 101, 4260–4266 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. 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  PubMed  Google Scholar 

  32. 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  PubMed  PubMed Central  Google Scholar 

  33. Duraiswamy, J. et al. Phenotype, function, and gene expression profiles of programmed death-1hi CD8 T cells in healthy human adults. J. Immunol. 186, 4200–4212 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Baumgaertner, P. et al. Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int. J. cancer cancer 130, 2607–2617 (2012).

    Article  CAS  Google Scholar 

  35. Arens, R. & Schoenberger, S.P. Plasticity in programming of effector and memory CD8 T-cell formation. Immunol. Rev. 235, 190–205 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cui, W. & Kaech, S.M. Generation of effector CD8+ T cells and their conversion to memory T cells. Immunol. Rev. 236, 151–166 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lefrancois, L. & Masopust, D. The road not taken: memory T cell fate 'decisions'. Nat. Immunol. 10, 369–370 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nolz, J.C. & Harty, J.T. Protective capacity of memory CD8+ T cells is dictated by antigen exposure history and nature of the infection. Immunity 34, 781–793 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Williams, M.A. & Bevan, M.J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Snyder, C.M. et al. Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity 29, 650–659 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Blackburn, S.D., Shin, H., Freeman, G.J. & Wherry, E.J. Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. Proc. Natl. Acad. Sci. USA 105, 15016–15021 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pellegrini, M. et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144, 601–613 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Sharpe, A.H., Wherry, E.J., Ahmed, R. & Freeman, G.J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8, 239–245 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198–1202 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Speiser, D.E. et al. Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen. Proc. Natl. Acad. Sci. USA 105, 3849–3854 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Frebel, H. et al. Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice. J. Exp. Med. 209, 2485–2499 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pircher, H. et al. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature 346, 629–633 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. Battegay, M. et al. Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates. J. Virol. Methods 33, 191–198 (1991).

    Article  CAS  PubMed  Google Scholar 

  49. Speiser, D.E. et al. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J. Clin. Invest. 115, 739–746 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank S. Enouz, S. Oberle and M. Prlic for discussions and critical review of the manuscript; A. Oxenius (Institute of Microbiology, Swiss Federal Institute of Technology Zürich) for P14αβ mice; P. Fink (University of Washington, Seattle) for Vβ5 mice; and A. Wilson and H.R. MacDonald (Ludwig Center for Cancer Research, University of Lausanne) for antibodies specific to CD45.2 (clone 104) and CD45.1 (clone A20). Supported by the Swiss Vaccine Research Institute (D.Z.) and the Swiss National Science Foundation (CRSII3_141879 to D.Z. and D.E.S.).

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Authors and Affiliations

  1. Swiss Vaccine Research Institute, Epalinges, Switzerland

    Daniel T Utzschneider, Lucie Carrié & Dietmar Zehn

  2. Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland

    Daniel T Utzschneider, Lucie Carrié & Dietmar Zehn

  3. Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland

    Amandine Legat, Silvia A Fuertes Marraco, Immanuel Luescher & Daniel E Speiser

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Contributions

D.T.U. and D.Z. initiated and designed the study; D.T.U. did all mouse experiments with the assistance of L.C. in the laboratory of D.Z.; I.L. provided expertise, support and reagents for tetramer analysis; A.L. and S.A.F.M. did experiments with human samples under the supervision of D.E.S.; D.T.U. and D.Z. analyzed data from mouse experiments; A.L., S.A.F.M. and D.E.S. analyzed data from human experiments; D.T.U. and D.Z. wrote the manuscript; and A.L., S.A.F.M., I.L .and D.E.S. provided advice and suggestions for the manuscript.

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Correspondence to Dietmar Zehn.

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I.L. is the founder of TCMetrix, which provided the mouse and human tetramers used.

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Utzschneider, D., Legat, A., Fuertes Marraco, S. et al. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat Immunol 14, 603–610 (2013). https://doi.org/10.1038/ni.2606

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