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

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.

[Note: See an explanatory press release on the study by the Wistar Institute, the nonprofit biomedical research institute where lead author E. John Wherry, PhD, is an assistant professor in the Immunology Program – at http://www.wistar.org/news_info/pressreleases/pr_10.18.07.htm]

Source: Immunity. 2007 Oct 17 [E-pub ahead of print] PMID: 17950003, by Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R. Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia; Departments of Pediatric Oncology and Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA [E-mail:
jwherry@wistar.org
ra@microbio.emory.edu ]
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