Beschreibung:
Abstract GATA-3 and T-bet, the key transcription factors of T helper type 1 and type 2 cells, respectively, are specifically upregulated during differentiation of naive Th cells in response to antigen and cytokine signals. GATA-3 expression increases in response to IL-4/STAT6 signaling, whereas T-bet is induced by the IL-12/STAT4 and IFN-y/STAT1 pathways. GATA-3 and T-bet subsequently induce lineage-specific gene expression. Here, we study the regulation of GATA-3 in Th2 cells as well as the interactions between the Th1 and Th2 signaling pathways using time-resolved dose-response experiments and mathematical modeling. We measured the dose response of GATA-3, T-bet and pSTAT1/4/6 to IL-4 and IL-12 in vitro during differentiation and fitted mathematical models to the data. GATA-3 expression was graded and depended on the cytokines’ concentrations. The activation of STAT6 downstream of IL-4 and STAT4 downstream of IL-12 was stronger and longer-lasting with higher cytokine concentrations. We discovered several cross-regulatory mechanisms between the Th1 and Th2 pathways. Furthermore, the different amounts of GATA-3 reached in vitro were stably maintained in vivo for 30 days after transfer into naive mice, suggesting a cell-intrinsic mechanism allowing quantitative memory of GATA-3 expression in resting Th2 cells. Our results provide insight into the molecular mechanisms that underlie the induction and maintenance of Th2 cell differentiation.