Restoring Function in Exhausted CD8 T Cells During Chronic Viral Infection

Nature. 2006 Feb 9;439(7077):682-7. doi: 10.1038/nature04444. Epub 2005 Dec 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CTLA-4 Antigen
  • Cell Proliferation
  • Chronic Disease
  • Gene Expression Regulation
  • Immune Tolerance / immunology
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic choriomeningitis virus / immunology
  • Lymphocytic choriomeningitis virus / physiology
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Peptides / deficiency
  • Peptides / genetics
  • Peptides / metabolism
  • Programmed Cell Death 1 Receptor
  • Substrate Specificity
  • Virus Diseases / immunology*

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Cd274 protein, mouse
  • Ctla4 protein, mouse
  • Membrane Glycoproteins
  • Pdcd1 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Receptor