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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Michael Quigley
  • Florencia Pereyra
  • 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 Francisco
  • Gordon J Freeman
  • E John Wherry
  • Daniel E Kaufmann
  • Bruce D Walker
  • Benjamin Ebert
  • W Nicholas Haining
External organisations
  • Harvard University
  • Broad Institute
Research areas and keywords

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