IkZF and STAT factor regulatory modules as drivers of TH1 and TFH cell differentiation decisions

Abstract CD4+ T helper cells are capable of differentiating into subsets that regulate distinct aspects of the immune response. The differentiation of these populations is driven by subset-specific cytokine signals and downstream transcription factor networks that are responsible for promoting the unique gene expression programs of each cell type. It is well-established that cytokine signals are propagated by Signal Transducer and Activator of Transcription (STAT) factors. Recently, we demonstrated that STAT3 and Aiolos, a member of the Ikaros Zinc Finger (IkZF) family, form a novel transcriptional complex that directly induces expression of the T follicular helper (TFH) cell lineage defining factor, Bcl-6. Interestingly, we have also found that a second IkZF factor Eos interacts with STAT5 and forms an opposing complex in T helper 1 (TH1) cells that promotes expression of the Bcl-6 antagonist, Blimp-1. However, whether additional IkZF/STAT complexes function downstream of other cytokine signals in these cell populations is unclear. Here, we report that in vitro-generated TH1 and TFH1-like cells similarly express Ikaros concurrent with increased STAT4 activation downstream of IL-12 signaling. Using co-immunoprecipitation analyses, we were also able to detect interactions between Ikaros and STAT4. Furthermore, as with the other IkZF/STAT complexes, we find that interactions between Ikaros and STAT4 were dependent upon the IkZF C-terminal ZF domain, suggesting that this is a conserved regulatory feature of IkZF/STAT complex formation. Current efforts are now aimed at identifying whether mechanistic interplay between the Ikaros/STAT4 complex and the other IkZF/STAT factors may ultimately dictate TH1 or TFH cell fate and function.