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

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. [Display omitted] •TCR signal strength controls IRF4 concentrations and, in turn, Th cell fate choice•Higher expression of IRF4 promotes Teff cell fate at the expense of Tfh cell fate•Higher IRF4 drives access to chromatin embedded with low-affinity IRF4 binding sites•Low-affinity IRF4 binding sites are linked to the regulation of the Teff gene program 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.