The Ikaros zinc finger (IkZF) transcription factor Eos is a known regulator of CD4+ regulatory T cell (TREG) populations. However, its role in the differentiation of other CD4+ T cell subsets is unknown. Here, we find that Eos deficiency results in both compromised TH1 cell differentiation and reduced production of the TH1 effector cytokine IFN-γ. Historically, IkZF factors have been associated with changes in gene expression via the alteration of chromatin structure. However, ATAC-seq analysis indicated that there were minimal changes in chromatin accessibility between wild type and Eos-deficient cells cultured under TH1-polarizing conditions. Rather, we find that IL-2 signaling promotes the STAT5-dependent induction of Eos expression, and that Eos both interacts with STAT5 and supports tyrosine phosphorylation-mediated STAT5 activation. Consequently, STAT5 enrichment is reduced at TH1 target genes in the absence of Eos. Thus, modulation of STAT5 signaling represents a novel mechanism by which Eos positively regulates the TH1 gene program. Given the important role for IL-2/STAT5 signaling in the differentiation of TH2, TH9, and TREG cell subsets, it will be of interest to determine whether this mechanism is conserved across additional CD4+ T cell populations.
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.
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