The IRF4 gene regulatory module functions as a read-write integrator to dynamically control T helper cell fate

Abstract

Abstract Transcriptional regulation during CD4+ T cell fate decisions enables their differentiation into distinct states, guiding immune responses towards antibody production via Tfh cells or inflammation by Teff cells. Tfh–Teff 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 fates at the expense of Tfh ones. Importantly, orthogonal induction of IRF4 expression redirected Tfh fate trajectories towards those of Teff and this occurred independently of IL-2 signals. Mechanistically, we linked greater IRF4 abundance with its recruitment towards low affinity binding sites within Teff cis-regulatory elements, including those of Prdm1. We propose that the Irf4 locus functions as the “reader” of TCR signal strength, in turn, concentration-dependent activity of IRF4 “writes” T helper fate choice.