Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation

Immunity. 2013 Nov 14;39(5):833-45. doi: 10.1016/j.immuni.2013.10.007. Epub 2013 Nov 7.

Abstract

Upon infection, CD8(+) T cells undergo a stepwise process of early activation, expansion, and differentiation into effector cells. How these phases are transcriptionally regulated is incompletely defined. Here, we report that interferon regulatory factor 4 (IRF4), dispensable for early CD8(+) T cell activation, was vital for sustaining the expansion and effector differentiation of CD8(+) T cells. Mechanistically, IRF4 promoted the expression and function of Blimp1 and T-bet, two transcription factors required for CD8(+) T cell effector differentiation, and simultaneously repressed genes that mediate cell cycle arrest and apoptosis. Selective ablation of Irf4 in peripheral CD8(+) T cells impaired antiviral CD8(+) T cell responses, viral clearance, and CD8(+) T cell-mediated host recovery from influenza infection. IRF4 expression was regulated by T cell receptor (TCR) signaling strength via mammalian target of rapamycin (mTOR). Our data reveal that IRF4 translates differential strength of TCR signaling into different quantitative and qualitative CD8(+) T cell responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Bcl-2-Like Protein 11
  • CD8-Positive T-Lymphocytes / cytology*
  • Cell Differentiation
  • Cells, Cultured / cytology
  • Coculture Techniques
  • Cyclin-Dependent Kinase Inhibitor Proteins / antagonists & inhibitors
  • Dendritic Cells / immunology
  • Gene Expression Regulation
  • Interferon Regulatory Factors / deficiency
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / immunology
  • Interferon Regulatory Factors / physiology*
  • Lymphocyte Activation
  • Membrane Proteins / antagonists & inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / virology
  • Positive Regulatory Domain I-Binding Factor 1
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Receptors, Antigen, T-Cell / immunology
  • Specific Pathogen-Free Organisms
  • T-Box Domain Proteins / biosynthesis
  • T-Box Domain Proteins / genetics
  • TOR Serine-Threonine Kinases / physiology
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Viral Plaque Assay

Substances

  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Cyclin-Dependent Kinase Inhibitor Proteins
  • Interferon Regulatory Factors
  • Membrane Proteins
  • Prdm1 protein, mouse
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factors
  • interferon regulatory factor-4
  • Positive Regulatory Domain I-Binding Factor 1
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse