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

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.

journal_name

Immunity

journal_title

Immunity

authors

Krishnamoorthy V,Kannanganat S,Maienschein-Cline M,Cook SL,Chen J,Bahroos N,Sievert E,Corse E,Chong A,Sciammas R

doi

10.1016/j.immuni.2017.09.001

subject

Has Abstract

pub_date

2017-09-19 00:00:00

pages

481-497.e7

issue

3

eissn

1074-7613

issn

1097-4180

pii

S1074-7613(17)30378-3

journal_volume

47

pub_type

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