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Abstract
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.