Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF

Michael Quigley, Florencia Pereyra, Björn Nilsson, Filippos Porichis, Catia Fonseca, Quentin Eichbaum, Boris Julg, Jonathan L Jesneck, Kathleen Brosnahan, Sabrina Imam, Kate Russell, Ildiko Toth, Alicja Piechocka-Trocha, Douglas Dolfi, Jill Angelosanto, Alison Crawford, Haina Shin, Douglas S Kwon, Jennifer Zupkosky, Loise FranciscoGordon J Freeman, E John Wherry, Daniel E Kaufmann, Bruce D Walker, Benjamin Ebert, W Nicholas Haining

Research output: Contribution to journalArticlepeer-review

305 Citations (SciVal)

Abstract

CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8(+) T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8(+) T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes--such as BATF--that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.

Original languageEnglish
Pages (from-to)1147-51
Number of pages5
JournalNature Medicine
Volume16
Issue number10
DOIs
Publication statusPublished - 2010 Oct
Externally publishedYes

Keywords

  • Animals
  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • Basic-Leucine Zipper Transcription Factors
  • CD8-Positive T-Lymphocytes
  • Gene Expression Profiling
  • Gene Expression Regulation
  • HIV
  • Humans
  • Interferon-gamma
  • Interleukin-2
  • Lymphocytic Choriomeningitis
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor
  • T-Lymphocytes
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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