Cooperative activities between STAT3 and Ikaros Zinc Finger transcription factors regulate Bcl-6 expression in CD4+ T helper cells

Abstract

Abstract CD4+ T cell subtype specialization depends upon unique lineage-defining transcription factors that direct T helper cell development by both activating cell-specific gene expression programs and repressing alternative T helper cell fates. One such example is the transcriptional repressor Bcl-6, required for the development of T follicular helper (TFH) cell populations. Here, we identify the Ikaros zinc finger (IkZF) transcription factors Ikaros and Aiolos as novel regulators of Bcl-6 expression. We find that increased expression of Bcl-6 in T helper cells is associated with enhanced enrichment of Aiolos and Ikaros at the Bcl6 promoter. Additionally, we demonstrate that signal transducer and activator of transcription 3 (STAT3) physically interacts with Aiolos, suggesting a cooperative role for these factors in the activation of Bcl-6 expression. Mechanistically, the association of Ikaros, Aiolos, and STAT3 with the Bcl6 promoter was accompanied by chromatin remodeling events consistent with gene activation including increased histone acetylation. Importantly, expression of Aiolos and Ikaros was elevated in in vivo generated TFH cell populations compared to other IkZF family members. Collectively, these data describe a novel regulatory mechanism wherein STAT3 and the IkZF transcription factors Ikaros and Aiolos cooperate to regulate Bcl-6 expression. Elucidating the complex network of signals and factors that regulate Bcl-6 expression may enhance the potential to design more efficacious vaccines and develop novel immunotherapeutic approaches due to the wide-ranging importance of this transcriptional regulator.