Pluto Bioinformatics

GSE92272: Read-write integration by the IRF4 gene regulatory module dynamically controls T helper cell fate

Bulk RNA sequencing

Transcriptional regulation of cell fate decisions in the immune system endows cells with specialized function; an iterative process that adapts to the changing landscape of infections. As coordinators of the immune system, T helper cells of the CD4+ lineage possess the ability to differentiate into an array of functional cell states in order to guide the response towards antibody production via the formation of T follicular helper (Tfh) cells or inflammation by the generation of T effector (Teff) cells. TfhTeff cell fate choice is mediated by the BCL6Blimp-1 counter-antagonistic gene regulatory module, polarizing Tfh and Teff cells, respectively. A key question is how T helper cells establish and negotiate BCL6Blimp-1 counter antagonism to control the output of Tfh and Teff cells. We show that the T cell receptor (TCR)-signal induced transcription factor, IRF4, is necessary for the generation of both BCL6-expressing Tfh cells and Blimp-1-expressing Teff cells. Importantly, we show that increasing TCR signal strength augments the amounts of IRF4 expressed as well as Teff cell fate trajectories that occur at the expense of Tfh cells. Using an orthogonal genetic system, based on a tet-inducible allele of Irf4, we demonstrate that increasing IRF4 expression during priming redirected Tfh cell fate choices towards those of Teff. Importantly, promotion of Teff cell fate trajectories by increased IRF4 expression occurred independently of IL-2 signals. At the molecular level, we link greater IRF4 abundance with its recruitment to low affinity DNA binding sites embedded within regulatory elements affiliated with the Teff gene program, including Blimp-1. Together, these results demonstrate that the Irf4 locus functions as the reader of TCR signal strength, in turn, the concentration dependent activity of the IRF4 transcription factor writes T helper cell fate choice. SOURCE: Mark Maienschein-Cline ( - Center for Research Informatics University of Illinois at Chicago

View this experiment on Pluto Bioinformatics