The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate

Veena Krishnamoorthy, Sunil Kannanganat, Mark Maienschein-Cline, Sarah L. Cook, Jianjun Chen, Neil Bahroos, Evelyn Sievert, Emily Corse, Anita Chong, Roger Sciammas

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Transcriptional regulation during CD4+ T cell fate decisions enables their differentiation into distinct states, guiding immune responses toward antibody production via Tfh cells or inflammation by Teff cells. Tfh-Teff cell fate commitment is regulated by mutual antagonism between the transcription factors Bcl6 and Blimp-1. Here we examined how T cell receptor (TCR) signals establish and arbitrate Bcl6-Blimp-1 counter-antagonism. We found that the TCR-signal-induced transcription factor Irf4 is essential for the differentiation of Bcl6-expressing Tfh and Blimp-1-expressing Teff cells. Increased TCR signaling raised Irf4 amounts and promoted Teff cell fates at the expense of Tfh ones. Importantly, orthogonal induction of Irf4 expression redirected Tfh cell fate trajectories toward those of Teff. Mechanistically, we linked greater Irf4 abundance with its recruitment toward low-affinity binding sites within Teff cell cis-regulatory elements, including those of Prdm1. We propose that the Irf4 locus functions as the “reader” of TCR signal strength, and in turn, concentration-dependent activity of Irf4 “writes” T helper fate choice. Krishnamoorthy et al. show that the Irf4 locus “senses” the intensity of T cell receptor signaling to scale expression of Irf4. Differential binding of IRF4 to divergent DNA sequences is controlled by the amounts of IRF4 expressed and coordinates alternate T helper cell fate choice. Thus, IRF4 expression links TCR signal strength to T helper cell fate determination.

Original languageEnglish (US)
Pages (from-to)481-497.e7
JournalImmunity
Volume47
Issue number3
DOIs
StatePublished - Sep 19 2017

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Keywords

  • antibody responses
  • Bcl6
  • Blimp-1
  • CD4 T cell differentiation
  • Irf4
  • T cell receptor
  • T effector cells
  • T follicular helper cells
  • transcription factors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Krishnamoorthy, V., Kannanganat, S., Maienschein-Cline, M., Cook, S. L., Chen, J., Bahroos, N., Sievert, E., Corse, E., Chong, A., & Sciammas, R. (2017). The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate. Immunity, 47(3), 481-497.e7. https://doi.org/10.1016/j.immuni.2017.09.001