The Ikaros Zinc Finger Transcription Factor Eos As a Candidate Regulator of TH2 Differentiation and Function.

Abstract Although CD4+ T helper 2 (TH2) cells normally defend against parasitic infection, they play a central role in the pathogenesis of allergic asthma. Therefore, understanding the molecular mechanisms governing TH2 differentiation and function is a top priority for improving asthma outcomes. One pathway of interest for controlling TH2-mediated disease is IL-2/STAT5 signaling, which is essential for TH2 polarization yet boasts a complex regulatory network that is incompletely understood. Here, we identify the Ikaros zinc finger (IkZF) transcription factor Eos as a candidate regulator of IL-2/STAT5 signaling underlying TH2 differentiation and function. To start, we show that Eos gene and protein expression is increased in TH2 cells relative to CD4+ T cell subsets that are negatively regulated by IL-2/STAT5 signaling, such as TH17 and TFH cells. Given these findings, we sought to define the functional effects of Eos in TH2 cells using in vitro and in vivo murine house dust mite asthma models. Intriguingly, Eos deficiency in vitro and in vivo results in reduced expression of key TH2 transcription factors (Gata3, Blimp-1), effector cytokines (IL-4, IL-13), and differentiation receptors (IL-2Rα, IL-2Rβ, IL-4Rα). Mechanistically, our data reveal that Eos interacts with and increases the activity of STAT5, suggesting that Eos enhances TH2 differentiation and effector function through direct STAT5 regulation. These findings in proinflammatory TH2 cells are of high significance, as Eos, to date, has largely been associated with the immunosuppressive functions of TREG cells. Taken together, our data reveal a novel mechanism by which Eos positively regulates IL-2/STAT5 signaling to promote TH2 differentiation and function. Work supported by grants from the NIH (R01AI134972) and The Ohio State University (Susan Huntington Dean’s Distinguished University Fellowship).