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.
['Krishnamoorthy|Veena|V|', 'Kannanganat|Sunil|S|', 'Maienschein-Cline|Mark|M|', 'Cook|Sarah L|SL|', 'Chen|Jianjun|J|', 'Bahroos|Neil|N|', 'Sievert|Evelyn|E|', 'Corse|Emily|E|', 'Chong|Anita|A|', 'Sciammas|Roger|R|']
D000818:Animals D000941:Antigens D001665:Binding Sites D002454:Cell Differentiation D002460:Cell Line D005260:Female D020869:Gene Expression Profiling D005786:Gene Expression Regulation D053263:Gene Regulatory Networks D006801:Humans D007114:Immunization D050835:Interferon Regulatory Factors D007376:Interleukin-2 D008297:Male D051379:Mice D018345:Mice, Knockout D059372:Nucleotide Motifs D011485:Protein Binding D011948:Receptors, Antigen, T-Cell D015398:Signal Transduction D006377:T-Lymphocytes, Helper-Inducer
Irf4 transcription factors Bcl6 Blimp-1 CD4 T cell differentiation T cell receptor T effector cells T follicular helper cells antibody responses