Restoring function in exhausted CD8 T cells during chronic viral infection Journal Article


Authors: Barber, D. L.; Wherry, E. J.; Masopust, D.; Zhu, B.; Allison, J. P.; Sharpe, A. H.; Freeman, G. J.; Ahmed, R.
Article Title: 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. © 2006 Nature Publishing Group.
Keywords: controlled study; unclassified drug; nonhuman; cd8 antigen; cell proliferation; cd8-positive t-lymphocytes; proteins; mouse; animals; mice; cell function; genes; gene expression; animal experiment; animal model; protein; apoptosis regulatory proteins; animalia; chronic disease; gene expression regulation; cytokine; immune tolerance; membrane glycoproteins; substrate specificity; peptides; molecular structure; upregulation; virus infection; virus load; antibodies; antigens, cd; cytotoxic t lymphocyte antigen 4; cytokine release; medicine; virus diseases; antigens, differentiation; antigens, surface; protein antibody; memory t lymphocyte; cells; antigens, cd80; lymphocytic choriomeningitis; lymphocytic choriomeningitis virus; viruses; medical problems; cd8 t cells; chronic viral infection; lymphocytic choriomeningitis virus (lcmv); t-cell dysfunction; programmed death 1 protein; programmed death ligand 1 antibody
Journal Title: Nature
Volume: 439
Issue: 7077
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2006-02-09
Start Page: 682
End Page: 687
Language: English
DOI: 10.1038/nature04444
PUBMED: 16382236
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 886" - "Export Date: 4 June 2012" - "CODEN: NATUA" - "Source: Scopus"
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  1. James P Allison
    129 Allison