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

Immunity. 2017 Dec 19;47(6):1129-1141.e5. doi: 10.1016/j.immuni.2017.11.021. Epub 2017 Dec 12.

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.

Keywords: BATF; CD8(+); IRF4; NAICE; NFAT; NFAT_AP-1_IRF4 composite element; TCF1; chronic infection; differentiation; exhaustion; memory; metabolic function; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation
  • Gene Expression Regulation
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / immunology
  • Humans
  • Immunologic Memory*
  • Interferon Regulatory Factors / deficiency
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / immunology*
  • Lymphocyte Activation
  • Lymphocyte Depletion
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / growth & development
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Mice, Knockout
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / immunology
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Batf protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Interferon Regulatory Factors
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell
  • interferon regulatory factor-4