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

Kevin Man; Sarah S Gabriel; Yang Liao; Renee Gloury; Simon Preston; Darren C Henstridge; Marc Pellegrini; Dietmar Zehn; Friederike Berberich-Siebelt; Mark A Febbraio; Wei Shi; Axel Kallies

doi:10.1016/j.immuni.2017.11.021

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

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

Authors

Affiliations

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.

PMID: 29246443
DOI: 10.1016/j.immuni.2017.11.021

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic-Leucine Zipper Transcription Factors / genetics
Basic-Leucine Zipper Transcription Factors / immunology
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / virology
Cell Differentiation
Gene Expression Regulation
HEK293 Cells
Hepatocyte Nuclear Factor 1-alpha / genetics
Hepatocyte Nuclear Factor 1-alpha / immunology
Humans
Immunologic Memory*
Interferon Regulatory Factors / deficiency
Interferon Regulatory Factors / genetics
Interferon Regulatory Factors / immunology*
Lymphocyte Activation
Lymphocyte Depletion
Lymphocytic Choriomeningitis / genetics
Lymphocytic Choriomeningitis / immunology*
Lymphocytic Choriomeningitis / virology
Lymphocytic choriomeningitis virus / growth & development
Lymphocytic choriomeningitis virus / immunology*
Mice
Mice, Knockout
NFATC Transcription Factors / genetics
NFATC Transcription Factors / immunology
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / immunology*
Signal Transduction

Substances

Basic-Leucine Zipper Transcription Factors
Batf protein, mouse
Hepatocyte Nuclear Factor 1-alpha
Hnf1a protein, mouse
Interferon Regulatory Factors
NFATC Transcription Factors
Nfatc1 protein, mouse
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Receptors, Antigen, T-Cell
interferon regulatory factor-4