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 and Rafi Ahmed ()
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Daniel L. Barber: Emory University School of Medicine
E. John Wherry: The Wistar Institute
David Masopust: Emory University School of Medicine
Baogong Zhu: Harvard Medical School
James P. Allison: Memorial Sloan-Kettering Cancer Center
Arlene H. Sharpe: Harvard Medical School and Brigham and Women's Hospital
Gordon J. Freeman: Harvard Medical School
Rafi Ahmed: Emory University School of Medicine

Nature, 2006, vol. 439, issue 7077, 682-687

Abstract: 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.

Date: 2006
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DOI: 10.1038/nature04444

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