Restoring function in exhausted CD8 T cells during chronic viral infection

• Published in: Nature 2006-02, Vol.439 (7077), p.682-687
• Main Authors: Sharpe, Arlene H, Barber, Daniel L, Wherry, E. John, Ahmed, Rafi, Freeman, Gordon J, Allison, James P, Zhu, Baogong, Masopust, David
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD; Antigens, Differentiation - immunology; Antigens, Surface - genetics; Antigens, Surface - metabolism; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; B7-1 Antigen - genetics; B7-1 Antigen - metabolism; B7-H1 Antigen; Biological and medical sciences; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Chronic Disease; Chronic illnesses; CTLA-4 Antigen; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Humanities and Social Sciences; Immune Tolerance - immunology; Immunology; Infections; Lymphocytes; Lymphocytic Choriomeningitis - immunology; Lymphocytic choriomeningitis virus; Lymphocytic choriomeningitis virus - immunology; Lymphocytic choriomeningitis virus - physiology; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Microbiology; multidisciplinary; Peptides - deficiency; Peptides - genetics; Peptides - metabolism; Programmed Cell Death 1 Receptor; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Science; Science (multidisciplinary); Substrate Specificity; T cell receptors; Virology; Virus Diseases - immunology; Viruses
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature04444

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. Boosting antiviral immunity It's common in chronic viral disease for the immune system to grow accustomed to the infection. Normally CD8 T cells retain a ‘memory’ of the viruses they encounter, so they can respond rapidly to a new infection. In a chronic infection the memory cells lose this capacity, but the nature of this ‘exhausted’ state is not well understood. Barber et al . have now found a possible cause in a study of a mouse infection model. The inhibitory immune receptor gene PD-1 is much more active in exhausted than in normal CD8 T cells, and administration of antibodies that block PD-1 action restores function in virus-specific T cells and also reduces virus levels. The discovery of a T-cell exhaustion mechanism suggests a route to immunological strategies for treating chronic viral infections.