[PDF][PDF] Molecular signature of CD8+ T cell exhaustion during chronic viral infection

EJ Wherry, SJ Ha, SM Kaech, WN Haining, S Sarkar… - Immunity, 2007 - cell.com
Immunity, 2007cell.com
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 …
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.
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