Antigen-independent memory CD8 T cells do not develop during chronic viral infection

E. John Wherry, Daniel L. Barber, Susan M. Kaech, Joseph Blattman, Rafi Ahmed

Research output: Contribution to journalArticle

355 Citations (Scopus)

Abstract

Memory T cells can persist for extended periods in the absence of antigen, and long-term T cell immunity is often seen after acute infections. Paradoxically, there have been observations suggesting that T cell memory may be antigen-dependent during chronic infections. To elucidate the underlying mechanisms we have compared memory CD8 T cell differentiation during an acute versus chronic infection by using the mouse model of infection with lymphocytic choriomeningitis virus. We found that during a chronic infection virus-specific CD8 T cells failed to acquire the cardinal memory T cell property of long-term antigen-independent persistence. These chronically stimulated CD8 T cells were unable to undergo homeostatic proliferation, responded poorly to IL-7 and IL-15, and expressed reduced levels of the IL-7 and IL-15 receptors, thus providing a possible mechanism for the inability of these cells to persist long term in the absence of antigen. In striking contrast, virus-specific memory CD8 T cells that developed after an acute lymphocytic choriomeningitis virus infection could persist without antigen, were capable of self-renewal because of homeostatic proliferation, responded efficiently to IL-7 and IL-15, and expressed high levels of receptors for these two cytokines. Thus, memory CD8 T cells generated after acute infections are likely to have a competitive advantage over CD8 T cells that develop during chronic infections. These findings raise concerns about using vaccines that may persist and also suggest that there may be limitations and challenges in designing effective immunological interventions for the treatment of chronic infections and tumors.

Original languageEnglish (US)
Pages (from-to)16004-16009
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number45
DOIs
StatePublished - Nov 9 2004
Externally publishedYes

Fingerprint

Virus Diseases
T-Lymphocytes
Antigens
Interleukin-7
Infection
Lymphocytic choriomeningitis virus
Interleukin-15
Interleukin-15 Receptors
Cytokine Receptors
Cell Differentiation
Immunity
Vaccines
Viruses

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Antigen-independent memory CD8 T cells do not develop during chronic viral infection. / Wherry, E. John; Barber, Daniel L.; Kaech, Susan M.; Blattman, Joseph; Ahmed, Rafi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 45, 09.11.2004, p. 16004-16009.

Research output: Contribution to journalArticle

@article{79d87c81d4f84bcc93c28e09d47cda5e,
title = "Antigen-independent memory CD8 T cells do not develop during chronic viral infection",
abstract = "Memory T cells can persist for extended periods in the absence of antigen, and long-term T cell immunity is often seen after acute infections. Paradoxically, there have been observations suggesting that T cell memory may be antigen-dependent during chronic infections. To elucidate the underlying mechanisms we have compared memory CD8 T cell differentiation during an acute versus chronic infection by using the mouse model of infection with lymphocytic choriomeningitis virus. We found that during a chronic infection virus-specific CD8 T cells failed to acquire the cardinal memory T cell property of long-term antigen-independent persistence. These chronically stimulated CD8 T cells were unable to undergo homeostatic proliferation, responded poorly to IL-7 and IL-15, and expressed reduced levels of the IL-7 and IL-15 receptors, thus providing a possible mechanism for the inability of these cells to persist long term in the absence of antigen. In striking contrast, virus-specific memory CD8 T cells that developed after an acute lymphocytic choriomeningitis virus infection could persist without antigen, were capable of self-renewal because of homeostatic proliferation, responded efficiently to IL-7 and IL-15, and expressed high levels of receptors for these two cytokines. Thus, memory CD8 T cells generated after acute infections are likely to have a competitive advantage over CD8 T cells that develop during chronic infections. These findings raise concerns about using vaccines that may persist and also suggest that there may be limitations and challenges in designing effective immunological interventions for the treatment of chronic infections and tumors.",
author = "Wherry, {E. John} and Barber, {Daniel L.} and Kaech, {Susan M.} and Joseph Blattman and Rafi Ahmed",
year = "2004",
month = "11",
day = "9",
doi = "10.1073/pnas.0407192101",
language = "English (US)",
volume = "101",
pages = "16004--16009",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "45",

}

TY - JOUR

T1 - Antigen-independent memory CD8 T cells do not develop during chronic viral infection

AU - Wherry, E. John

AU - Barber, Daniel L.

AU - Kaech, Susan M.

AU - Blattman, Joseph

AU - Ahmed, Rafi

PY - 2004/11/9

Y1 - 2004/11/9

N2 - Memory T cells can persist for extended periods in the absence of antigen, and long-term T cell immunity is often seen after acute infections. Paradoxically, there have been observations suggesting that T cell memory may be antigen-dependent during chronic infections. To elucidate the underlying mechanisms we have compared memory CD8 T cell differentiation during an acute versus chronic infection by using the mouse model of infection with lymphocytic choriomeningitis virus. We found that during a chronic infection virus-specific CD8 T cells failed to acquire the cardinal memory T cell property of long-term antigen-independent persistence. These chronically stimulated CD8 T cells were unable to undergo homeostatic proliferation, responded poorly to IL-7 and IL-15, and expressed reduced levels of the IL-7 and IL-15 receptors, thus providing a possible mechanism for the inability of these cells to persist long term in the absence of antigen. In striking contrast, virus-specific memory CD8 T cells that developed after an acute lymphocytic choriomeningitis virus infection could persist without antigen, were capable of self-renewal because of homeostatic proliferation, responded efficiently to IL-7 and IL-15, and expressed high levels of receptors for these two cytokines. Thus, memory CD8 T cells generated after acute infections are likely to have a competitive advantage over CD8 T cells that develop during chronic infections. These findings raise concerns about using vaccines that may persist and also suggest that there may be limitations and challenges in designing effective immunological interventions for the treatment of chronic infections and tumors.

AB - Memory T cells can persist for extended periods in the absence of antigen, and long-term T cell immunity is often seen after acute infections. Paradoxically, there have been observations suggesting that T cell memory may be antigen-dependent during chronic infections. To elucidate the underlying mechanisms we have compared memory CD8 T cell differentiation during an acute versus chronic infection by using the mouse model of infection with lymphocytic choriomeningitis virus. We found that during a chronic infection virus-specific CD8 T cells failed to acquire the cardinal memory T cell property of long-term antigen-independent persistence. These chronically stimulated CD8 T cells were unable to undergo homeostatic proliferation, responded poorly to IL-7 and IL-15, and expressed reduced levels of the IL-7 and IL-15 receptors, thus providing a possible mechanism for the inability of these cells to persist long term in the absence of antigen. In striking contrast, virus-specific memory CD8 T cells that developed after an acute lymphocytic choriomeningitis virus infection could persist without antigen, were capable of self-renewal because of homeostatic proliferation, responded efficiently to IL-7 and IL-15, and expressed high levels of receptors for these two cytokines. Thus, memory CD8 T cells generated after acute infections are likely to have a competitive advantage over CD8 T cells that develop during chronic infections. These findings raise concerns about using vaccines that may persist and also suggest that there may be limitations and challenges in designing effective immunological interventions for the treatment of chronic infections and tumors.

UR - http://www.scopus.com/inward/record.url?scp=8644268831&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=8644268831&partnerID=8YFLogxK

U2 - 10.1073/pnas.0407192101

DO - 10.1073/pnas.0407192101

M3 - Article

VL - 101

SP - 16004

EP - 16009

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 45

ER -