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Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection.

Abstract During chronic stimulation, CD8+ T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, down-modulation of effector function, and metabolic impairments. T cell exhaustion protects from excessive immunopathology but limits clearance of virus-infected or tumor cells. We transcriptionally profiled antigen-specific T cells from mice infected with lymphocytic choriomeningitis virus strains that cause acute or chronic disease. T cell exhaustion during chronic infection was driven by high amounts of T cell receptor (TCR)-induced transcription factors IRF4, BATF, and NFATc1. These regulators promoted expression of inhibitory receptors, including PD-1, and mediated impaired cellular metabolism. Furthermore, they repressed the expression of TCF1, a transcription factor required for memory T cell differentiation. Reducing IRF4 expression restored the functional and metabolic properties of antigen-specific T cells and promoted memory-like T cell development. These findings indicate that IRF4 functions as a central node in a TCR-responsive transcriptional circuit that establishes and sustains T cell exhaustion during chronic infection.
PMID
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Authors

Mayor MeshTerms

Immunologic Memory

Keywords

BATF

CD8(+)

IRF4

NAICE

NFAT

NFAT_AP-1_IRF4 composite element

TCF1

chronic infection

differentiation

exhaustion

memory

metabolic function

transcription

Journal Title immunity
Publication Year Start




PMID- 29246443
OWN - NLM
STAT- MEDLINE
DCOM- 20171226
LR  - 20171226
IS  - 1097-4180 (Electronic)
IS  - 1074-7613 (Linking)
VI  - 47
IP  - 6
DP  - 2017 Dec 19
TI  - Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the
      Development of Memory-like T Cells during Chronic Infection.
PG  - 1129-1141.e5
LID - S1074-7613(17)30522-8 [pii]
LID - 10.1016/j.immuni.2017.11.021 [doi]
AB  - During chronic stimulation, CD8(+) T cells acquire an exhausted phenotype
      characterized by expression of inhibitory receptors, down-modulation of effector 
      function, and metabolic impairments. T cell exhaustion protects from excessive
      immunopathology but limits clearance of virus-infected or tumor cells. We
      transcriptionally profiled antigen-specific T cells from mice infected with
      lymphocytic choriomeningitis virus strains that cause acute or chronic disease. T
      cell exhaustion during chronic infection was driven by high amounts of T cell
      receptor (TCR)-induced transcription factors IRF4, BATF, and NFATc1. These
      regulators promoted expression of inhibitory receptors, including PD-1, and
      mediated impaired cellular metabolism. Furthermore, they repressed the expression
      of TCF1, a transcription factor required for memory T cell differentiation.
      Reducing IRF4 expression restored the functional and metabolic properties of
      antigen-specific T cells and promoted memory-like T cell development. These
      findings indicate that IRF4 functions as a central node in a TCR-responsive
      transcriptional circuit that establishes and sustains T cell exhaustion during
      chronic infection.
CI  - Crown Copyright (c) 2017. Published by Elsevier Inc. All rights reserved.
FAU - Man, Kevin
AU  - Man K
AD  - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
      Parkville, VIC 3052, Australia; The Department of Medical Biology, University of 
      Melbourne, Parkville, VIC 3010, Australia.
FAU - Gabriel, Sarah S
AU  - Gabriel SS
AD  - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
      Parkville, VIC 3052, Australia; Department of Microbiology and Immunology, The
      University of Melbourne, Parkville, VIC 3010, Australia; The Peter Doherty
      Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC
      3000, Australia.
FAU - Liao, Yang
AU  - Liao Y
AD  - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
      Parkville, VIC 3052, Australia; The Department of Medical Biology, University of 
      Melbourne, Parkville, VIC 3010, Australia.
FAU - Gloury, Renee
AU  - Gloury R
AD  - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
      Parkville, VIC 3052, Australia; Department of Microbiology and Immunology, The
      University of Melbourne, Parkville, VIC 3010, Australia; The Peter Doherty
      Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC
      3000, Australia.
FAU - Preston, Simon
AU  - Preston S
AD  - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
      Parkville, VIC 3052, Australia; The Department of Medical Biology, University of 
      Melbourne, Parkville, VIC 3010, Australia.
FAU - Henstridge, Darren C
AU  - Henstridge DC
AD  - Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
FAU - Pellegrini, Marc
AU  - Pellegrini M
AD  - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
      Parkville, VIC 3052, Australia; The Department of Medical Biology, University of 
      Melbourne, Parkville, VIC 3010, Australia.
FAU - Zehn, Dietmar
AU  - Zehn D
AD  - Division of Animal Physiology and Immunology, School of Life Sciences
      Weihenstephan, Technical University of Munich, 85354 Freising, Germany.
FAU - Berberich-Siebelt, Friederike
AU  - Berberich-Siebelt F
AD  - Institute of Pathology, University of Wurzburg, 97080 Wurzburg, Germany;
      Comprehensive Cancer Center Mainfranken, University of Wurzburg, 97080 Wurzburg, 
      Germany.
FAU - Febbraio, Mark A
AU  - Febbraio MA
AD  - Cellular and Molecular Metabolism, Garvan Institute, Sydney, NSW 2010, Australia.
FAU - Shi, Wei
AU  - Shi W
AD  - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
      Parkville, VIC 3052, Australia; The Department of Medical Biology, University of 
      Melbourne, Parkville, VIC 3010, Australia.
FAU - Kallies, Axel
AU  - Kallies A
AD  - The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade,
      Parkville, VIC 3052, Australia; Department of Microbiology and Immunology, The
      University of Melbourne, Parkville, VIC 3010, Australia; The Peter Doherty
      Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC
      3000, Australia. Electronic address: [email protected]
LA  - eng
PT  - Journal Article
DEP - 20171212
PL  - United States
TA  - Immunity
JT  - Immunity
JID - 9432918
RN  - 0 (Basic-Leucine Zipper Transcription Factors)
RN  - 0 (Batf protein, mouse)
RN  - 0 (Hepatocyte Nuclear Factor 1-alpha)
RN  - 0 (Hnf1a protein, mouse)
RN  - 0 (Interferon Regulatory Factors)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (Nfatc1 protein, mouse)
RN  - 0 (Pdcd1 protein, mouse)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (interferon regulatory factor-4)
SB  - IM
MH  - Animals
MH  - Basic-Leucine Zipper Transcription Factors/genetics/immunology
MH  - CD8-Positive T-Lymphocytes/*immunology/virology
MH  - Cell Differentiation
MH  - Gene Expression Regulation
MH  - HEK293 Cells
MH  - Hepatocyte Nuclear Factor 1-alpha/genetics/immunology
MH  - Humans
MH  - *Immunologic Memory
MH  - Interferon Regulatory Factors/deficiency/genetics/*immunology
MH  - Lymphocyte Activation
MH  - Lymphocyte Depletion
MH  - Lymphocytic Choriomeningitis/genetics/*immunology/virology
MH  - Lymphocytic choriomeningitis virus/growth & development/*immunology
MH  - Mice
MH  - Mice, Knockout
MH  - NFATC Transcription Factors/genetics/immunology
MH  - Programmed Cell Death 1 Receptor/genetics/immunology
MH  - Receptors, Antigen, T-Cell/genetics/*immunology
MH  - Signal Transduction
OTO - NOTNLM
OT  - BATF
OT  - CD8(+)
OT  - IRF4
OT  - NAICE
OT  - NFAT
OT  - NFAT_AP-1_IRF4 composite element
OT  - TCF1
OT  - chronic infection
OT  - differentiation
OT  - exhaustion
OT  - memory
OT  - metabolic function
OT  - transcription
EDAT- 2017/12/17 06:00
MHDA- 2017/12/27 06:00
CRDT- 2017/12/17 06:00
PHST- 2016/08/19 00:00 [received]
PHST- 2017/08/08 00:00 [revised]
PHST- 2017/11/28 00:00 [accepted]
PHST- 2017/12/17 06:00 [pubmed]
PHST- 2017/12/27 06:00 [medline]
PHST- 2017/12/17 06:00 [entrez]
AID - S1074-7613(17)30522-8 [pii]
AID - 10.1016/j.immuni.2017.11.021 [doi]
PST - ppublish
SO  - Immunity. 2017 Dec 19;47(6):1129-1141.e5. doi: 10.1016/j.immuni.2017.11.021. Epub
      2017 Dec 12.