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 journalArticlepeer-review

257 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
Pages (from-to)400-412
Number of pages13
JournalImmunity
Volume35
Issue number3
DOIs
Publication statusPublished - 2011 Sep 23

Bibliographical note

Funding Information:
We thank R. Karaffa and S. Durham for FACS sorting at the Emory University School of Medicine Flow Cytometry Core Facility. This work was supported by the National Institutes of Health (NIH) grant 1 P01 AI080192-01 (to R.A. and J.M.B.), grant 2 R37 AI30048-17 (to R.A.), and grant AHMED05GCGH0 (to R.A.), the American Cancer Society (ACS) postdoctoral fellowship PF-09-134-01-MPC (to B.Y.), and the Korea Research Foundation (KRF) grant funded by the Korea government (MEST) No. 2010-0004892 (to S.-J.H.). R.A. and S.-J.H. have patents and receive patent royalties related to the PD-1 pathway.

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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