Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection

Joseph N. Blattman, E. John Wherry, Sang-Jun Ha, Robbert G. Van Der Most, Rafi Ahmed

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

During some persistent viral infections, virus-specific T-cell responses wane due to the antigen-specific deletion or functional inactivation (i.e., exhaustion) of responding CD8 T cells. T-cell exhaustion often correlates with high viral load and is associated with the expression of the inhibitory receptor PD-1. In other infections, functional T cells are observed despite high levels of pathogen persistence. The reasons for these different T-cell fates during chronic viral infections are not clear. Here, we tracked the fate of virus-specific CD8 T cells in lymphocytic choriomeningitis virus (LCMV)-infected mice during viral clearance, the persistence of wild-type virus, or the selection and persistence of a viral variant that abrogates the presentation of a single epitope. Viral clearance results in PD-1lo functional virus-specific CD8 T cells, while the persistence of wild-type LCMV results in high PD-1 levels and T-cell exhaustion. However, following the emergence of a GP35V→A variant virus that abrogates the presentation of the GP33 epitope, GP33-specific CD8 T cells remained functional, continued to show low levels of PD-1, and reexpressed CD127, a marker of memory T-cell differentiation. In the same animals and under identical environmental conditions, CD8 T cells recognizing nonmutated viral epitopes became physically deleted or were PD-1hi and nonfunctional. Thus, the upregulation of PD-1 and the functional inactivation of virus-specific T cells during chronic viral infection is dependent upon continued epitope recognition. These data suggest that optimal strategies for vaccination should induce high-magnitude broadly specific T-cell responses that prevent cytotoxic T-lymphocyte escape and highlight the need to evaluate the function of vaccine-induced T cells in the context of antigens presented during virus persistence.

Original languageEnglish
Pages (from-to)4386-4394
Number of pages9
JournalJournal of Virology
Volume83
Issue number9
DOIs
Publication statusPublished - 2009 May 1

Fingerprint

epitopes
Epitopes
T-lymphocytes
T-Lymphocytes
Infection
infection
viruses
Viruses
Virus Diseases
Lymphocytic choriomeningitis virus
Programmed Cell Death 1 Receptor
inactivation
Virus Inactivation
antigens
Antigens
cytotoxic T-lymphocytes
Cytotoxic T-Lymphocytes
viral load
Viral Load
cell differentiation

All Science Journal Classification (ASJC) codes

  • Immunology
  • Virology

Cite this

Blattman, Joseph N. ; Wherry, E. John ; Ha, Sang-Jun ; Van Der Most, Robbert G. ; Ahmed, Rafi. / Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection. In: Journal of Virology. 2009 ; Vol. 83, No. 9. pp. 4386-4394.
@article{c2647a6eff214830b6f8f3f6557fc43d,
title = "Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection",
abstract = "During some persistent viral infections, virus-specific T-cell responses wane due to the antigen-specific deletion or functional inactivation (i.e., exhaustion) of responding CD8 T cells. T-cell exhaustion often correlates with high viral load and is associated with the expression of the inhibitory receptor PD-1. In other infections, functional T cells are observed despite high levels of pathogen persistence. The reasons for these different T-cell fates during chronic viral infections are not clear. Here, we tracked the fate of virus-specific CD8 T cells in lymphocytic choriomeningitis virus (LCMV)-infected mice during viral clearance, the persistence of wild-type virus, or the selection and persistence of a viral variant that abrogates the presentation of a single epitope. Viral clearance results in PD-1lo functional virus-specific CD8 T cells, while the persistence of wild-type LCMV results in high PD-1 levels and T-cell exhaustion. However, following the emergence of a GP35V→A variant virus that abrogates the presentation of the GP33 epitope, GP33-specific CD8 T cells remained functional, continued to show low levels of PD-1, and reexpressed CD127, a marker of memory T-cell differentiation. In the same animals and under identical environmental conditions, CD8 T cells recognizing nonmutated viral epitopes became physically deleted or were PD-1hi and nonfunctional. Thus, the upregulation of PD-1 and the functional inactivation of virus-specific T cells during chronic viral infection is dependent upon continued epitope recognition. These data suggest that optimal strategies for vaccination should induce high-magnitude broadly specific T-cell responses that prevent cytotoxic T-lymphocyte escape and highlight the need to evaluate the function of vaccine-induced T cells in the context of antigens presented during virus persistence.",
author = "Blattman, {Joseph N.} and Wherry, {E. John} and Sang-Jun Ha and {Van Der Most}, {Robbert G.} and Rafi Ahmed",
year = "2009",
month = "5",
day = "1",
doi = "10.1128/JVI.02524-08",
language = "English",
volume = "83",
pages = "4386--4394",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "9",

}

Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection. / Blattman, Joseph N.; Wherry, E. John; Ha, Sang-Jun; Van Der Most, Robbert G.; Ahmed, Rafi.

In: Journal of Virology, Vol. 83, No. 9, 01.05.2009, p. 4386-4394.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection

AU - Blattman, Joseph N.

AU - Wherry, E. John

AU - Ha, Sang-Jun

AU - Van Der Most, Robbert G.

AU - Ahmed, Rafi

PY - 2009/5/1

Y1 - 2009/5/1

N2 - During some persistent viral infections, virus-specific T-cell responses wane due to the antigen-specific deletion or functional inactivation (i.e., exhaustion) of responding CD8 T cells. T-cell exhaustion often correlates with high viral load and is associated with the expression of the inhibitory receptor PD-1. In other infections, functional T cells are observed despite high levels of pathogen persistence. The reasons for these different T-cell fates during chronic viral infections are not clear. Here, we tracked the fate of virus-specific CD8 T cells in lymphocytic choriomeningitis virus (LCMV)-infected mice during viral clearance, the persistence of wild-type virus, or the selection and persistence of a viral variant that abrogates the presentation of a single epitope. Viral clearance results in PD-1lo functional virus-specific CD8 T cells, while the persistence of wild-type LCMV results in high PD-1 levels and T-cell exhaustion. However, following the emergence of a GP35V→A variant virus that abrogates the presentation of the GP33 epitope, GP33-specific CD8 T cells remained functional, continued to show low levels of PD-1, and reexpressed CD127, a marker of memory T-cell differentiation. In the same animals and under identical environmental conditions, CD8 T cells recognizing nonmutated viral epitopes became physically deleted or were PD-1hi and nonfunctional. Thus, the upregulation of PD-1 and the functional inactivation of virus-specific T cells during chronic viral infection is dependent upon continued epitope recognition. These data suggest that optimal strategies for vaccination should induce high-magnitude broadly specific T-cell responses that prevent cytotoxic T-lymphocyte escape and highlight the need to evaluate the function of vaccine-induced T cells in the context of antigens presented during virus persistence.

AB - During some persistent viral infections, virus-specific T-cell responses wane due to the antigen-specific deletion or functional inactivation (i.e., exhaustion) of responding CD8 T cells. T-cell exhaustion often correlates with high viral load and is associated with the expression of the inhibitory receptor PD-1. In other infections, functional T cells are observed despite high levels of pathogen persistence. The reasons for these different T-cell fates during chronic viral infections are not clear. Here, we tracked the fate of virus-specific CD8 T cells in lymphocytic choriomeningitis virus (LCMV)-infected mice during viral clearance, the persistence of wild-type virus, or the selection and persistence of a viral variant that abrogates the presentation of a single epitope. Viral clearance results in PD-1lo functional virus-specific CD8 T cells, while the persistence of wild-type LCMV results in high PD-1 levels and T-cell exhaustion. However, following the emergence of a GP35V→A variant virus that abrogates the presentation of the GP33 epitope, GP33-specific CD8 T cells remained functional, continued to show low levels of PD-1, and reexpressed CD127, a marker of memory T-cell differentiation. In the same animals and under identical environmental conditions, CD8 T cells recognizing nonmutated viral epitopes became physically deleted or were PD-1hi and nonfunctional. Thus, the upregulation of PD-1 and the functional inactivation of virus-specific T cells during chronic viral infection is dependent upon continued epitope recognition. These data suggest that optimal strategies for vaccination should induce high-magnitude broadly specific T-cell responses that prevent cytotoxic T-lymphocyte escape and highlight the need to evaluate the function of vaccine-induced T cells in the context of antigens presented during virus persistence.

UR - http://www.scopus.com/inward/record.url?scp=66149123225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149123225&partnerID=8YFLogxK

U2 - 10.1128/JVI.02524-08

DO - 10.1128/JVI.02524-08

M3 - Article

C2 - 19211743

AN - SCOPUS:66149123225

VL - 83

SP - 4386

EP - 4394

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 9

ER -