title: Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Quigley
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
authors.forename: Filippos
authors.initials: F
authors.lastname: Porichis
authors.forename: Catia
authors.initials: C
authors.lastname: Fonseca
authors.forename: Quentin
authors.initials: Q
authors.lastname: Eichbaum
authors.forename: Boris
authors.initials: B
authors.lastname: Julg
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Jesneck
authors.forename: Kathleen
authors.initials: K
authors.lastname: Brosnahan
authors.forename: Sabrina
authors.initials: S
authors.lastname: Imam
authors.forename: Kate
authors.initials: K
authors.lastname: Russell
authors.forename: Ildiko
authors.initials: I
authors.lastname: Toth
authors.forename: Alicja
authors.initials: A
authors.lastname: Piechocka-Trocha
authors.forename: Douglas
authors.initials: D
authors.lastname: Dolfi
authors.forename: Jill
authors.initials: J
authors.lastname: Angelosanto
authors.forename: Alison
authors.initials: A
authors.lastname: Crawford
authors.forename: Haina
authors.initials: H
authors.lastname: Shin
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Kwon
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zupkosky
authors.forename: Loise
authors.initials: L
authors.lastname: Francisco
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ebert
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006678:HIV / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008216:Lymphocytic Choriomeningitis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C099359:BATF protein, human; D050976:Basic-Leucine Zipper Transcription Factors; C431772:Batf protein, mouse; D007376:Interleukin-2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma