Format

Send to

Choose Destination
Immunity. 2017 Dec 19;47(6):1129-1141.e5. doi: 10.1016/j.immuni.2017.11.021. Epub 2017 Dec 12.

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

Author information

1
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.
2
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.
3
Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
4
Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany.
5
Institute of Pathology, University of Würzburg, 97080 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080 Würzburg, Germany.
6
Cellular and Molecular Metabolism, Garvan Institute, Sydney, NSW 2010, Australia.
7
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: kallies@wehi.edu.au.

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.

KEYWORDS:

BATF; CD8(+); IRF4; NAICE; NFAT; NFAT_AP-1_IRF4 composite element; TCF1; chronic infection; differentiation; exhaustion; memory; metabolic function; transcription

PMID:
29246443
DOI:
10.1016/j.immuni.2017.11.021
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center