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

Research output: Contribution to journalArticleResearchpeer-review

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1129-1141
Number of pages13
JournalImmunity
Volume47
Issue number6
DOIs
Publication statusPublished - 19 Dec 2017
Externally publishedYes

Keywords

  • BATF
  • CD8
  • chronic infection
  • differentiation
  • exhaustion
  • IRF4
  • memory
  • metabolic function
  • NAICE
  • NFAT
  • NFAT_AP-1_IRF4 composite element
  • TCF1
  • transcription

Cite this

Man, Kevin ; Gabriel, Sarah S. ; Liao, Yang ; Gloury, Renee ; Preston, Simon ; Henstridge, Darren C. ; Pellegrini, Marc ; Zehn, Dietmar ; Berberich-Siebelt, Friederike ; Febbraio, Mark A. ; Shi, Wei ; Kallies, Axel. / Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection. In: Immunity. 2017 ; Vol. 47, No. 6. pp. 1129-1141.
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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.",
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author = "Kevin Man and Gabriel, {Sarah S.} and Yang Liao and Renee Gloury and Simon Preston and Henstridge, {Darren C.} and Marc Pellegrini and Dietmar Zehn and Friederike Berberich-Siebelt and Febbraio, {Mark A.} and Wei Shi and Axel Kallies",
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Man, K, Gabriel, SS, Liao, Y, Gloury, R, Preston, S, Henstridge, DC, Pellegrini, M, Zehn, D, Berberich-Siebelt, F, Febbraio, MA, Shi, W & 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. https://doi.org/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. / Man, Kevin; Gabriel, Sarah S.; Liao, Yang; Gloury, Renee; Preston, Simon; Henstridge, Darren C.; Pellegrini, Marc; Zehn, Dietmar; Berberich-Siebelt, Friederike; Febbraio, Mark A.; Shi, Wei; Kallies, Axel.

In: Immunity, Vol. 47, No. 6, 19.12.2017, p. 1129-1141.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection

AU - Man, Kevin

AU - Gabriel, Sarah S.

AU - Liao, Yang

AU - Gloury, Renee

AU - Preston, Simon

AU - Henstridge, Darren C.

AU - Pellegrini, Marc

AU - Zehn, Dietmar

AU - Berberich-Siebelt, Friederike

AU - Febbraio, Mark A.

AU - Shi, Wei

AU - Kallies, Axel

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KW - exhaustion

KW - IRF4

KW - memory

KW - metabolic function

KW - NAICE

KW - NFAT

KW - NFAT_AP-1_IRF4 composite element

KW - TCF1

KW - transcription

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