Figure 2: Multiple T-bet functions playing a role in Th cell differentiation. Induction of T-bet expression through activation of STAT1 and STAT4 directly stimulates the transcription of T-box-binding element-containing genes, such as IFNG , IL12RB2 , and CXCR3 , thereby enhancing Th1 cell development. T-Bet undergoes serine phosphorylation at S508 and then downregulates IL-2 production in Th1 cells by recruiting NF- 𝜅 B p65 from the IL2 promoter. Protein levels of T-bet in Th1 cells can be controlled by the ubiquitin-mediated proteasomal degradation pathway. Moreover, T-bet protein undergoes additional posttranslational modifications, for example, phosphorylation at T302 and Y525, which facilitates its suppression of the Th2 cytokine production that is induced by activation of NFAT and