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

Man, K, Gabriel, SS, Liao, Y, Gloury, R, Preston, S, Henstridge, DC ORCID: 0000-0003-4988-767X, Pellegrini, M, Zehn, D, Berberich-Siebelt, F, Febbraio, MA, Shi, W and Kallies, A 2017 , 'Transcription factor IRF4 Promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection' , Immunity, vol. 47, no. 6 , pp. 1129-1141 , doi: 10.1016/j.immuni.2017.11.021.

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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 Type: Article
Authors/Creators: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
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
Journal or Publication Title: Immunity
Publisher: Cell Press
ISSN: 1074-7613
DOI / ID Number: 10.1016/j.immuni.2017.11.021
Copyright Information:

Copyright 2017 Crown Copyright

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