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Restoring function in exhausted CD8 T cells during chronic viral infection

Nature volume 439, pages 682–687 (2006)Cite this article

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.

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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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Authors and Affiliations

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

    Daniel L. Barber, David Masopust & Rafi Ahmed

  2. Immunology Program, The Wistar Institute, Pennsylvania, 19104, Philadelphia, USA

    E. John Wherry

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Massachusetts, 02115, Boston, USA

    Baogong Zhu & Gordon J. Freeman

  4. Department of Medicine, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    James P. Allison

  5. Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Massachusetts, 02115, Boston, USA

    Arlene H. Sharpe

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Correspondence to Rafi Ahmed.

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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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