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Transcription factor IRF4 Promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection

Citation

Man, K and Gabriel, SS and Liao, Y and Gloury, R and Preston, S and Henstridge, DC and Pellegrini, M and Zehn, D and Berberich-Siebelt, F and Febbraio, MA and Shi, W and Kallies, A, Transcription factor IRF4 Promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection, Immunity, 47, (6) pp. 1129-1141. ISSN 1074-7613 (2017) [Refereed Article]

Copyright Statement

Copyright 2017 Crown Copyright

DOI: 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. During chronic stimulation, CD8+ T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, loss of effector function, and metabolic impairments. Man et al. have identified a transcriptional module consisting of the TCR-induced transcription factors IRF4, BATF, and NFATc1 that drives T cell exhaustion and impairs memory T cell development. © 2017

Item Details

Item Type:Refereed Article
Keywords:BATF, CD8+, chronic infection, differentiation, exhaustion, IRF4, memory, metabolic function, NAICE, NFAT, NFAT AP-1 IRF4 composite element, TCF1, transcription, transcription factor, animal cell
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Cell Metabolism
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Immune System and Allergy
UTAS Author:Henstridge, DC (Mr Darren Henstridge)
ID Code:133374
Year Published:2017
Web of Science® Times Cited:48
Deposited By:Health Sciences
Deposited On:2019-06-24
Last Modified:2019-07-23
Downloads:0

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