Schematic of the NFAT interaction partners in Th1 cells. Differentiation is initiated by the activation of the TCR and costimulatory signals, as well as the Th1-determining factors IFN-γ and/or IL-27, which induce via the IFNGR and the IL-27R the activation of STAT1. STAT1, in combination with NFAT, AP-1, NF-κB, and the Notch3/RBPJ/MAML1 signaling pathway, binds to the Tbx21 promoter and subsequently induces the transcription of the master transcription factor of Th1 cells, T-bet. T-bet induces the production of IFN-γ and the activation of the transcription factors Hlx and Runx3. IL-2 helps to induce STAT5 via the IL-2R, which additionally triggers IFN-γ production. The termination of TCR signaling allows the up-regulation of Il12Rβ2. Therefore, IL-12 can additionally activate STAT4, which together with STAT1, Hlx, Runx3, T-bet, AP-1, and NFAT, further induces IFN-γ transcription. In parallel, NFAT, together with STAT4 and NF-κB, binds to the promoter of the twist1 gene.