Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection - PubMed (original) (raw)
. 2017 Dec 19;47(6):1129-1141.e5.
doi: 10.1016/j.immuni.2017.11.021. Epub 2017 Dec 12.
Sarah S Gabriel 2, Yang Liao 1, Renee Gloury 2, Simon Preston 1, Darren C Henstridge 3, Marc Pellegrini 1, Dietmar Zehn 4, Friederike Berberich-Siebelt 5, Mark A Febbraio 6, Wei Shi 1, Axel Kallies 7
Affiliations
- PMID: 29246443
- DOI: 10.1016/j.immuni.2017.11.021
Free article
Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection
Kevin Man et al. Immunity. 2017.
Free article
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.
Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.
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