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Restoring function in exhausted CD8 T cells during chronic viral infection

Abstract

Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the ‘helpless’ CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.

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Figure 1: PD-1 is highly upregulated by exhausted CD8 T cells during chronic infection.
Figure 2: Blockade of the PD-1/PD-L1 inhibitory pathway increases CD8 T-cell function and enhances the clearance of chronic viral infection.
Figure 3: Restoration of function in ‘helpless’ exhausted CD8 T cells.
Figure 4: Proliferation of exhausted CD8 T cells in both lymphoid and non-lymphoid tissues after anti-PD-L1 treatment.
Figure 5: PD-L1 -/- mice make normal CD8 T-cell responses after LCMV Armstrong infection but succumb to clone 13 infection owing to immunopathology.

References

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

    Article  CAS  Google Scholar 

  2. 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  ADS  Google Scholar 

  3. 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  Google Scholar 

  4. 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  Google Scholar 

  5. 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  Google Scholar 

  6. Pantaleo, G. & Koup, R. A. Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know. Nature Med. 10, 806–810 (2004)

    Article  CAS  Google Scholar 

  7. Letvin, N. L. & Walker, B. D. Immunopathogenesis and immunotherapy in AIDS virus infections. Nature Med. 9, 861–866 (2003)

    Article  CAS  Google Scholar 

  8. Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nature Rev. Immunol. 5, 215–229 (2005)

    Article  CAS  Google Scholar 

  9. 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, 7340–7349 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Ishida, Y., Agata, Y., Shibahara, K. & Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1992)

    Article  CAS  Google Scholar 

  11. Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999)

    Article  CAS  Google Scholar 

  12. Sharpe, A. H. & Freeman, G. J. The B7–CD28 superfamily. Nature Rev. Immunol. 2, 116–126 (2002)

    Article  CAS  Google Scholar 

  13. Chen, L. Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity. Nature Rev. Immunol. 4, 336–347 (2004)

    Article  CAS  Google Scholar 

  14. Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000)

    Article  CAS  Google Scholar 

  15. Dong, H., Zhu, G., Tamada, K. & Chen, L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Med. 5, 1365–1369 (1999)

    Article  CAS  Google Scholar 

  16. Matloubian, M., Concepcion, R. J. & Ahmed, R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J. Virol. 68, 8056–8063 (1994)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bevan, M. J. Helping the CD8+ T-cell response. Nature Rev. Immunol. 4, 595–602 (2004)

    Article  CAS  Google Scholar 

  18. Shin, T. et al. In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses. J. Exp. Med. 201, 1531–1541 (2005)

    Article  CAS  Google Scholar 

  19. Oflazoglu, E. et al. Paradoxical role of programmed death-1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo. Eur. J. Immunol. 34, 3326–3336 (2004)

    Article  CAS  Google Scholar 

  20. Egen, J. G., Kuhns, M. S. & Allison, J. P. CTLA-4: new insights into its biological function and use in tumour immunotherapy. Nature Immunol. 3, 611–618 (2002)

    Article  CAS  Google Scholar 

  21. Probst, H. C., McCoy, K., Okazaki, T., Honjo, T. & van den Broek, M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nature Immunol. 6, 280–286 (2005)

    Article  CAS  Google Scholar 

  22. Tanchot, C. et al. Modifications of CD8+ T cell function during in vivo memory or tolerance induction. Immunity 8, 581–590 (1998)

    Article  CAS  Google Scholar 

  23. Singh, N. J. & Schwartz, R. H. The strength of persistent antigenic stimulation modulates adaptive tolerance in peripheral CD4+ T cells. J. Exp. Med. 198, 1107–1117 (2003)

    Article  CAS  Google Scholar 

  24. Iwai, Y., Terawaki, S., Ikegawa, M., Okazaki, T. & Honjo, T. PD-1 inhibits antiviral immunity at the effector phase in the liver. J. Exp. Med. 198, 39–50 (2003)

    Article  CAS  Google Scholar 

  25. Isogawa, M., Furuichi, Y. & Chisari, F. V. Oscillating CD8+ T cell effector functions after antigen recognition in the liver. Immunity 23, 53–63 (2005)

    Article  CAS  Google Scholar 

  26. Dudley, M. E. & Rosenberg, S. A. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nature Rev. Cancer 3, 666–675 (2003)

    Article  CAS  Google Scholar 

  27. Autran, B., Carcelain, G., Combadiere, B. & Debre, P. Therapeutic vaccines for chronic infections. Science 305, 205–208 (2004)

    Article  CAS  ADS  Google Scholar 

  28. Wherry, E. J., Blattman, J. N. & Ahmed, R. Low CD8 T-cell proliferative potential and high viral load limit the effectiveness of therapeutic vaccination. J. Virol. 79, 8960–8968 (2005)

    Article  CAS  Google Scholar 

  29. Rodig, N. et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur. J. Immunol. 33, 3117–3126 (2003)

    Article  CAS  Google Scholar 

  30. Kaech, S. M., Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111, 837–851 (2002)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Y. Blinder and M. Hulsey for technical assistance, and members of the Ahmed laboratory for helpful discussions. R.A., E.J.W., A.H.S. and G.J.F. were supported by NIH grants and the Gates Grand Challenges in Global Health, and J.P.A. by The Howard Hughes Medical Institute and NIH grants. E.J.W. and D.M. were supported by the Cancer Research Institute.

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Correspondence to Rafi Ahmed.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Breadth of the CD8 T cell response after PD-L1 blockade in chronically infected mice. (PDF 244 kb)

Supplementary Figure 2

Anti-PD-1 mAb enhances virus specific CD8 T cell responses. (PDF 553 kb)

Supplementary Figure 3

Blockade of the CTLA-4 inhibitory pathway has no effect on T cell responses or viral control during chronic LCMV infection. (PDF 205 kb)

Supplementary Figure 4

Sustained increases in virus-specific CD8 T cells after transient PD-L1 blockade during chronic infection. (PDF 237 kb)

Supplementary Methods

Additional descriptions of the methods used in this study. (DOC 28 kb)

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Barber, D., Wherry, E., Masopust, D. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006). https://doi.org/10.1038/nature04444

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