TY - JOUR
T1 - Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
AU - Wherry, E. John
AU - Ha, Sang Jun
AU - Kaech, Susan M.
AU - Haining, W. Nicholas
AU - Sarkar, Surojit
AU - Kalia, Vandana
AU - Subramaniam, Shruti
AU - Blattman, Joseph N.
AU - Barber, Daniel L.
AU - Ahmed, Rafi
N1 - 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.).
PY - 2007/10/26
Y1 - 2007/10/26
N2 - 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.
AB - 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.
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=35349014587&partnerID=8YFLogxK
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U2 - 10.1016/j.immuni.2007.09.006
DO - 10.1016/j.immuni.2007.09.006
M3 - Article
C2 - 17950003
AN - SCOPUS:35349014587
SN - 1074-7613
VL - 27
SP - 670
EP - 684
JO - Immunity
JF - Immunity
IS - 4
ER -