| T-bet (TBX21) belongs to the T-box family of transcription factors defined by a conserved DNA-binding T-box domain that recognizes specific T-element sequences on target gene promoters. The protein features an N-terminal transactivation domain, central T-box for DNA interaction and protein dimerization, and C-terminal regulatory regions that recruit corepressors or coactivators. T-bet activates transcription of Ifng by direct binding to its promoter and upstream enhancer regions, while simultaneously repressing Il4, Il5, and Il13 through interference with GATA3 binding and recruitment of HDAC3-containing corepressor complexes. Expression initiates rapidly in naïve CD4+ T cells upon TCR stimulation and IL-12 signaling via STAT4 and STAT1 phosphorylation, which bind T-bet promoter to drive its transcription and autoactivation loop. T-bet cooperates with Runx3 to silence Cd4 expression during Th1 differentiation and induces eomesodermin (Eomes) in CD8+ T cells for granzyme B and perforin expression. In NK cells, T-bet sustains Ifng production and maturation alongside Eomes in a hierarchical manner. T-bet directly antagonizes Th17 differentiation by sequestering Runx1 from Rorc promoter and promoting Blimp1-mediated Il17 repression. Post-translational sumoylation at lysine residues within the T-box enhances DNA binding affinity, while tyrosine phosphorylation by Itk fine-tunes Th1/Th17 balance. During B cell responses, T-bet drives IgG class switching to IgG2a/c subtypes via direct activation of Sγ2a switch regions. Dysregulation through polymorphisms associates with autoimmune disorders, including multiple sclerosis and type 1 diabetes, via excessive Th1 responses. |
Lane 1: NK-92
