Restoring function in exhausted CD8 T cells during chronic viral infection

Daniel L. Barber, E. John Wherry, David Masopust, Baogong Zhu, James P. Allison, Arlene H. Sharpe, Gordon J. Freeman, Rafi Ahmed

Research output: Contribution to journalArticlepeer-review

3004 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)682-687
Number of pages6
JournalNature
Volume439
Issue number7077
DOIs
StatePublished - Feb 9 2006

Bibliographical note

Funding Information:
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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