IL-4 and IL-13 guide early thymic progenitors to mature towards dendritic cells

Recently we reported that IL-4 and IL-13 signaling in murine early thymic progenitors (ETPs) expressing the heteroreceptor (HR) comprising IL-4 receptor alpha (IL-4Rα) and IL-13 receptor alpha 1 (IL-13Rα1) activate STAT6 and inhibit ETP maturation potential towards T cells. In this study we asked whether IL-4 and IL-13 signaling through the HR mobilizes other STAT molecules to shape ETP fate decision. The findings indicate that HR + ETPs undergoing cytokine signaling display increased STAT1, but not STAT3, phosphorylation in addition to STAT6 activation. In parallel, the ETPs had a STAT1-dependent heightened expression of IRF-8, a transcription factor essential for development of CD8α + dendritic cells (DCs). Interestingly, STAT1 phosphorylation and IRF-8 upregulation which were independent of STAT6 activation guided ETP maturation towards myeloid cells with a CD8α + DC phenotype. Furthermore, these CD8α + DCs display a thymic resident phenotype as they did not express SIRPα, a molecule presumed to be involved in cell migration. These findings suggest that IL-4 and IL-13 cytokine-induced HR signaling provides a double-edged sword that simultaneously blocks T cell lineage potential but advances myeloid maturation which could impact T cell selection and central tolerance.