@article {542496,
	title = {Restoring function in exhausted CD8 T cells during chronic viral infection.},
	journal = {Nature},
	volume = {439},
	number = {7077},
	year = {2006},
	month = {2006 Feb 9},
	pages = {682-7},
	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 {\textquoteright}helpless{\textquoteright} 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.},
	keywords = {Animals, Antigens, CD, Antigens, CD274, Antigens, CD80, Antigens, Differentiation, Antigens, Surface, Apoptosis Regulatory Proteins, CD8-Positive T-Lymphocytes, Cell Proliferation, Chronic Disease, CTLA-4 Antigen, Gene Expression Regulation, Immune Tolerance, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Membrane Glycoproteins, Mice, Peptides, Programmed Cell Death 1 Receptor, Substrate Specificity, Virus Diseases},
	issn = {1476-4687},
	doi = {10.1038/nature04444},
	author = {Barber, Daniel L and Wherry, E John and Masopust, David and Zhu, Baogong and Allison, James P and Sharpe, Arlene H and Freeman, Gordon J and Ahmed, Rafi}
}
