Immunity
Volume 27, Issue 4, 26 October 2007, Pages 670-684
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Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection

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Summary

Chronic viral infections often result in T cell exhaustion. To determine the molecular signature of exhaustion, we compared the gene-expression profiles of dysfunctional lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells from chronic infection to functional LCMV-specific effector and memory CD8+ T cells generated after acute infection. These data showed that exhausted CD8+ T cells: (1) overexpressed several inhibitory receptors, including PD-1, (2) had major changes in T cell receptor and cytokine signaling pathways, (3) displayed altered expression of genes involved in chemotaxis, adhesion, and migration, (4) expressed a distinct set of transcription factors, and (5) had profound metabolic and bioenergetic deficiencies. T cell exhaustion was progressive, and gene-expression profiling indicated that T cell exhaustion and anergy were distinct processes. Thus, functional exhaustion is probably due to both active suppression and passive defects in signaling and metabolism. These results provide a framework for designing rational immunotherapies during chronic infections.

MOLIMMUNO

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3

Present address: Immunology Program, The Wistar Institute, 3601 Spruce Street Room 251, Philadelphia, PA 19104, USA.

4

Present address: Section of Immunobiology, Yale University Medical School, New Haven, CT 06520, USA.

5

Present address: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

6

Present address: Laboratory of Parasitic Diseases, NIH, Building 50, Room 6140, MSC 8003, Bethesda, MD 20892, USA.