TBX21
Description
The TBX21 (T-box transcription factor 21) is a protein-coding gene located on chromosome 17.
TBX21, also known as T-bet, is a protein encoded by the TBX21 gene in humans. While traditionally considered a master regulator of type 1 immune response, recent findings demonstrate its involvement in the development of diverse immune cell subsets and the maintenance of mucosal homeostasis. TBX21 is a member of the T-box family of transcription factors, known for their role in regulating developmental processes. It is the human ortholog of the mouse Tbx21/Tbet gene. Studies in mice have shown that TBX21 is a Th1 cell-specific transcription factor that controls the expression of IFN-gamma, a key Th1 cytokine. Expression of the human TBX21 gene also correlates with IFNg expression in Th1 and natural killer cells, suggesting its involvement in initiating Th1 lineage development from naive Th precursor cells. TBX21 is not constitutively expressed in naive Th cells but can be induced through two independent signaling pathways: IFNg-STAT1 and IL-12-STAT4 pathways. Both pathways must cooperate to achieve a stable Th1 phenotype.
TBX21, also known as T-bet, is a lineage-defining transcription factor that initiates Th1 lineage development from naive Th precursor cells. It achieves this by activating Th1 genetic programs and repressing the opposing Th2 and Th17 genetic programs. TBX21 activates transcription of genes crucial for Th1 cell function, including those encoding IFN-gamma and the chemokine receptor CXCR3. It induces permissive chromatin accessibility and CpG methylation in IFNG. TBX21 activates IFNG and CXCR3 genes by recruiting chromatin remodeling complexes, such as KDM6B, a SMARCA4-containing SWI/SNF complex, and an H3K4me2-methyltransferase complex, to their promoters. These complexes establish a more permissive chromatin state conducive to transcriptional activation. Additionally, TBX21 can activate Th1 genes by recruiting the Mediator complex and P-TEFb to super-enhancers and associated genes in activated Th1 cells. TBX21 inhibits Th17 cell lineage commitment by blocking RUNX1-mediated transactivation of the Th17 cell-specific transcriptional regulator RORC. It inhibits Th2 cell lineage commitment by suppressing the production of Th2 cytokines, such as IL-4, IL-5, and IL-13, through repression of transcriptional regulators GATA3 and NFATC2. TBX21 protects Th1 cells from amplifying aberrant type-I IFN response by acting as a repressor of type-I IFN transcription factors and type-I IFN-stimulated genes. It serves as a regulator of antiviral B-cell responses, controlling chronic viral infection by promoting the antiviral antibody IgG2a isotype switching and regulating a broad antiviral gene expression program. TBX21 is required for the correct development of natural killer (NK) and mucosal-associated invariant T (MAIT) cells.
TBX21 is also known as IMD88, T-PET, T-bet, TBET, TBLYM.
