Tbet

T-bet, also known as TBX21, is a transcription factor of the T-box family that controls gene expression programs in the immune system. It is a nuclear protein encoded by the TBX21 gene in humans and is conserved across vertebrates.

In adaptive immunity, T-bet is the master regulator of T helper 1 (Th1) cell differentiation. It promotes the expression of IFN-γ and supports the development and function of cytotoxic CD8+ T cells. T-bet also contributes to the activity of natural killer (NK) cells and innate lymphoid cell type 1 (ILC1), guiding their cytotoxic and cytokine profiles. By antagonizing alternative lineages, particularly Th2 and Th17, T-bet helps shape the balance of immune responses.

T-bet expression is induced by signals such as interleukin-12 and IFN-γ, acting through STAT4 and STAT1 signaling pathways and T cell receptor engagement. As a transcription factor, it binds to specific DNA motifs via its conserved T-box domain, recruiting chromatin remodelers to regulate target genes. Its activity is modulated by interactions with other transcription factors, including GATA3, which it can oppose to influence lineage decisions.

Clinical and research relevance includes associations with autoimmune and infectious diseases, where altered T-bet levels can affect disease severity and immune control. In experimental models, loss of T-bet impairs Th1 responses and resistance to intracellular pathogens, while overexpression can drive excessive IFN-γ production and inflammation. TBX21 and T-bet continue to be studied for their roles in immune regulation and as potential therapeutic targets.

Overall, T-bet is a central regulator of cellular immunity, coordinating transcriptional programs that enable effective Th1 responses, cytotoxic function, and coordinated innate and adaptive immune activity.