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

86 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

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