Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection
Details
Publication Year 2017-12-19, Volume 47, Issue #6, Page 1129-1141 e5
Journal Title
Immunity
Publication Type
Journal 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.
Publisher
Cell Press
WEHI Research Division(s)
Molecular Immunology; Bioinformatics; Infection And Immunity
PubMed ID
29246443
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-01-15 12:39:55
Last Modified: 2018-02-14 03:59:23
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