Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection

E. John Wherry, Sang Jun Ha, Susan M. Kaech, W. Nicholas Haining, Surojit Sarkar, Vandana Kalia, Shruti Subramaniam, Joseph N. Blattman, Daniel L. Barber, Rafi Ahmed

Research output: Contribution to journalArticlepeer-review

1204 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)670-684
Number of pages15
Issue number4
Publication statusPublished - 2007 Oct 26

Bibliographical note

Funding Information:
We thank P. Mahar, S. Jenkins, Y. Blinder, and B. Konieczny for technical assistance and R. Karaffa and M. Hulsey for FACS sorting. This work was supported by the National Institutes of Health (NIH) (grant AI30048 to R.A. and AI071309 to E.J.W.) and the Foundation for NIH and Bill and Melinda Gates foundation (to R.A.), Elizabeth Glaser Pediatric AIDS Foundation Scholar Awards (to S.S. and V.K.), and a Cancer Research Institute postdoctoral fellowship (to E.J.W.).

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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