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

• DOI: 10.1016/j.immuni.2007.11.006
• Publication Date: 2007-12-01T08:25:38Z
• Authors: 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
• Keywords: Immunology; Molecular Sequence Data; Gene Expression; CD8-Positive T-Lymphocytes; Lymphocyte Activation; Mice; 03 medical and health sciences; 0302 clinical medicine; Immunology and Allergy; Animals; Lymphocytic choriomeningitis virus; MOLIMMUNO; Oligonucleotide Array Sequence Analysis; Clonal Anergy; Gene Expression Profiling; Cell Differentiation; Flow Cytometry; 3. Good health; Mice, Inbred C57BL; Infectious Diseases; Phenotype; Virus Diseases; Chronic Disease; Female; Immunologic Memory

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.