Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T Cells

Ben Youngblood, Kenneth J. Oestreich, Sang Jun Ha, Jaikumar Duraiswamy, Rama S. Akondy, Erin E. West, Zhengyu Wei, Peiyuan Lu, James W. Austin, James L. Riley, Jeremy M. Boss, Rafi Ahmed

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

Functionally exhausted T cells have high expression of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. By using human and murine systems of acute and chronic viral infections, we analyzed epigenetic regulation of PD-1 expression during CD8+ T cell differentiation. During acute infection, naive to effector CD8+ T cell differentiation was accompanied by a transient loss of DNA methylation of the Pdcd1 locus that was directly coupled to the duration and strength of T cell receptor signaling. Further differentiation into functional memory cells coincided with Pdcd1 remethylation, providing an adapted program for regulation of PD-1 expression. In contrast, the Pdcd1 regulatory region was completely demethylated in exhausted CD8+ T cells and remained unmethylated even when virus titers decreased. This lack of DNA remethylation leaves the Pdcd1 locus poised for rapid expression, potentially providing a signal for premature termination of antiviral functions.

Original languageEnglish (US)
Pages (from-to)400-412
Number of pages13
JournalImmunity
Volume35
Issue number3
DOIs
StatePublished - Sep 23 2011
Externally publishedYes

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CD8 Antigens
Virus Diseases
T-Lymphocytes
Programmed Cell Death 1 Receptor
Cell Differentiation
Nucleic Acid Regulatory Sequences
DNA Methylation
T-Cell Antigen Receptor
Viral Load
Epigenomics
Antiviral Agents
DNA
Infection
Neoplasms

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Cite this

Youngblood, B., Oestreich, K. J., Ha, S. J., Duraiswamy, J., Akondy, R. S., West, E. E., ... Ahmed, R. (2011). Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T Cells. Immunity, 35(3), 400-412. https://doi.org/10.1016/j.immuni.2011.06.015

Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T Cells. / Youngblood, Ben; Oestreich, Kenneth J.; Ha, Sang Jun; Duraiswamy, Jaikumar; Akondy, Rama S.; West, Erin E.; Wei, Zhengyu; Lu, Peiyuan; Austin, James W.; Riley, James L.; Boss, Jeremy M.; Ahmed, Rafi.

In: Immunity, Vol. 35, No. 3, 23.09.2011, p. 400-412.

Research output: Contribution to journalArticle

Youngblood, B, Oestreich, KJ, Ha, SJ, Duraiswamy, J, Akondy, RS, West, EE, Wei, Z, Lu, P, Austin, JW, Riley, JL, Boss, JM & Ahmed, R 2011, 'Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T Cells', Immunity, vol. 35, no. 3, pp. 400-412. https://doi.org/10.1016/j.immuni.2011.06.015
Youngblood, Ben ; Oestreich, Kenneth J. ; Ha, Sang Jun ; Duraiswamy, Jaikumar ; Akondy, Rama S. ; West, Erin E. ; Wei, Zhengyu ; Lu, Peiyuan ; Austin, James W. ; Riley, James L. ; Boss, Jeremy M. ; Ahmed, Rafi. / Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T Cells. In: Immunity. 2011 ; Vol. 35, No. 3. pp. 400-412.
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