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

Publication ,  Journal Article
Krishnamoorthy, V; Kannanganat, S; Maienschein-Cline, M; Cook, SL; Chen, J; Bahroos, N; Sievert, E; Corse, E; Chong, A; Sciammas, R
Published in: Immunity
September 2017

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.

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Published In

Immunity

DOI

EISSN

1097-4180

ISSN

1074-7613

Publication Date

September 2017

Volume

47

Issue

3

Start / End Page

481 / 497.e7

Related Subject Headings

  • T-Lymphocytes, Helper-Inducer
  • Signal Transduction
  • Receptors, Antigen, T-Cell
  • Protein Binding
  • Nucleotide Motifs
  • Mice, Knockout
  • Mice
  • Male
  • Interleukin-2
  • Interferon Regulatory Factors
 

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Krishnamoorthy, V., Kannanganat, S., Maienschein-Cline, M., Cook, S. L., Chen, J., Bahroos, N., … 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
Krishnamoorthy, Veena, Sunil Kannanganat, Mark Maienschein-Cline, Sarah L. Cook, Jianjun Chen, Neil Bahroos, Evelyn Sievert, Emily Corse, Anita Chong, and Roger Sciammas. “The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate.Immunity 47, no. 3 (September 2017): 481-497.e7. https://doi.org/10.1016/j.immuni.2017.09.001.
Krishnamoorthy V, Kannanganat S, Maienschein-Cline M, Cook SL, Chen J, Bahroos N, et al. The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate. Immunity. 2017 Sep;47(3):481-497.e7.
Krishnamoorthy, Veena, et al. “The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate.Immunity, vol. 47, no. 3, Sept. 2017, pp. 481-497.e7. Epmc, doi:10.1016/j.immuni.2017.09.001.
Krishnamoorthy V, Kannanganat S, Maienschein-Cline M, Cook SL, Chen J, Bahroos N, Sievert E, Corse E, Chong A, Sciammas R. The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate. Immunity. 2017 Sep;47(3):481-497.e7.
Journal cover image

Published In

Immunity

DOI

EISSN

1097-4180

ISSN

1074-7613

Publication Date

September 2017

Volume

47

Issue

3

Start / End Page

481 / 497.e7

Related Subject Headings

  • T-Lymphocytes, Helper-Inducer
  • Signal Transduction
  • Receptors, Antigen, T-Cell
  • Protein Binding
  • Nucleotide Motifs
  • Mice, Knockout
  • Mice
  • Male
  • Interleukin-2
  • Interferon Regulatory Factors