title: Molecular signature of CD8+ T cell exhaustion during chronic viral infection.
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.
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road Room G211, Atlanta, GA 30322, USA. jwherry@wistar.org
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
authors.forename: Surojit
authors.initials: S
authors.lastname: Sarkar
authors.forename: Vandana
authors.initials: V
authors.lastname: Kalia
authors.forename: Shruti
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Blattman
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002908:Chronic Disease; D017635:Clonal Anergy; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology*; D020869:Gene Expression Profiling; D007156:Immunologic Memory / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014777:Virus Diseases / Q000276:immunology*