Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.
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.
Quigley
Michael
M
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Pereyra
Florencia
F
Nilsson
Björn
B
Porichis
Filippos
F
Fonseca
Catia
C
Eichbaum
Quentin
Q
Julg
Boris
B
Jesneck
Jonathan L
JL
Brosnahan
Kathleen
K
Imam
Sabrina
S
Russell
Kate
K
Toth
Ildiko
I
Piechocka-Trocha
Alicja
A
Dolfi
Douglas
D
Angelosanto
Jill
J
Crawford
Alison
A
Shin
Haina
H
Kwon
Douglas S
DS
Zupkosky
Jennifer
J
Francisco
Loise
L
Freeman
Gordon J
GJ
Wherry
E John
EJ
Kaufmann
Daniel E
DE
Walker
Bruce D
BD
Ebert
Benjamin
B
Haining
W Nicholas
WN
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*
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