TBX21 gene

The TBX21 gene (TBX21 stands for: T-Box Transcription Factor 21) is a protein-coding gene localized on chromsome 17q21.32. This gene belongs to a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors that are involved in the regulation of developmental processes. This gene is the human ortholog of the mouse Tbx21/Tbet gene. An important paralog of this gene is EOMES.

Studies in mice show that the encoded Tbx21 protein(T-Bet) is a Th1 cell-specific transcription factor that regulates the expression of the characteristic Th1 cytokine interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFN-gamma expression in Th1 and natural killer cells, suggesting a role for this gene in the development of the Th1 lineage from naïve Th progenitor cells.

Diseases associated with TBX21 include asthma, nasal polyps, aspirin intolerance and immunodeficiency 88. Related pathways include IL27-mediated signaling events and IL12-mediated signaling events.

T-bet is a "lineage-defining" transcription factor that initiates the development of the Th1 lineage from naïve Th progenitor cells by both activating Th1 gene programs and repressing the opposing Th2 and Th17 gene programs (Szabo SJ et al. 2000). Activates transcription of a number of genes important for Th1 cell function, including those encoding IFN-gamma and the chemokine receptor CXCR3. Causes permissive chromatin accessibility and CpG methylation in IFNG (Yang R et al. 2020).

Partially activates the IFNG and CXCR3 genes through the recruitment of chromatin remodeling complexes, whereby these complexes serve to establish a more permissive chromatin state that favors transcriptional activation. Can also activate Th1 genes via recruitment of the Mediator complex and P-TEFb (consisting of CDK9 and CCNT1/Cyclin-T1) in the form of the superelongation complex (SEC) to super-enhancers and associated genes in activated Th1 cells (Hertweck A et al. 2016). Inhibits Th17 cell lineage commitment by blocking RUNX1-mediated transactivation of the Th17 cell-specific transcriptional regulator RORC. Inhibits Th2 cell lineage formation by suppressing the production of Th2 cytokines, such as IL-4, IL-5 and IL-13, via suppression of the transcriptional regulators GATA3 and NFATC2. Protects Th1 cells from amplifying an aberrant type I IFN response in an IFN-gamma-rich microenvironment by acting as a repressor of type I IFN transcription factors and type I IFN-stimulated genes. Acts as a regulator of antiviral B cell responses; controls chronic viral infections by promoting antiviral antibody isotype switching and by regulating a broad antiviral gene expression program. Required for the proper development of natural killer (NK) cells and mucosal-associated invariant T (MAIT) cells (Yang R et al. 2020).

1. Domeier PP et al. (2016) IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. J Exp Med 213:715-732.
2. Elbendary A et al. (2016) Expression of T-bet and GATA-3 in early mycosis fungoides and spongiotic dermatitis. J Am Acad Dermatol 74:1012-1014.
3. Hertweck A et al. (2016) T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell Rep 15:2756-2770
4. Hosokawa H et al. (2016) Akt1-mediated Gata3 phosphorylation controls the repression of IFNγ in memory-type Th2 cells. Nat Commun 7:11289.
5. Szabo SJ et al. (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100: 655-669.
6. Yang R et al. (2020) Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria. Cell 183:1826-1847