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.
Wherry
E John
EJ
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
Ha
Sang-Jun
SJ
Kaech
Susan M
SM
Haining
W Nicholas
WN
Sarkar
Surojit
S
Kalia
Vandana
V
Subramaniam
Shruti
S
Blattman
Joseph N
JN
Barber
Daniel L
DL
Ahmed
Rafi
R
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*