TBX21

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human ortholog of mouse Tbx21/Tbet gene. Studies in mouse show that Tbx21 protein is a Th1 cell-specific transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFNG expression in Th1 and natural killer cells, suggesting a role for this gene in initiating Th1 lineage development from naive Th precursor cells.

T-Box 21

Lineage-defining transcription factor which initiates Th1 lineage development from naive Th precursor cells both by activating Th1 genetic programs and by repressing the opposing Th2 and Th17 genetic programs (PubMed:10761931).
Activates transcription of a set of genes important for Th1 cell function, including those encoding IFN-gamma and the chemokine receptor CXCR3. Induces permissive chromatin accessibilty and CpG methylation in IFNG (PubMed:33296702).
Activates IFNG and CXCR3 genes in part by recruiting chromatin remodeling complexes including KDM6B, a SMARCA4-containing SWI/SNF-complex, and an H3K4me2-methyltransferase complex to their promoters and all of these complexes serve to establish a more permissive chromatin state conducive with transcriptional activation (By similarity).
Can activate Th1 genes also via recruitment of Mediator complex and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1) in the form of the super elongation complex (SEC) to super-enhancers and associated genes in activated Th1 cells (PubMed:27292648).
Inhibits the Th17 cell lineage commitment by blocking RUNX1-mediated transactivation of Th17 cell-specific transcriptinal regulator RORC. Inhibits the Th2 cell lineage commitment by suppressing the production of Th2 cytokines, such as IL-4, IL-5, and IL- 13, via repression of transcriptional regulators GATA3 and NFATC2. Protects Th1 cells from amplifying aberrant type-I IFN response in an IFN-gamma abundant 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 infection by promoting the antiviral antibody IgG2a isotype switching and via regulation of a broad antiviral gene expression program (By similarity).
Required for the correct development of natural killer (NK) and mucosal-associated invariant T (MAIT) cells (PubMed:33296702).

Biological Process cell fate specificationIBA:GO_Central1 Publication
Biological Process cellular response to organic substanceIEA:Ensembl
Biological Process lymphocyte migrationIDA:UniProtKB1 Publication
Biological Process negative regulation of DNA-templated transcriptionISS:UniProtKB
Biological Process negative regulation of interleukin-2 productionISS:UniProtKB
Biological Process negative regulation of T-helper 17 cell differentiationISS:UniProtKB
Biological Process negative regulation of T-helper 17 cell lineage commitmentISS:UniProtKB
Biological Process negative regulation of T-helper 2 cell cytokine productionISS:UniProtKB
Biological Process negative regulation of transcription by RNA polymerase IIIDA:NTNU_SB1 Publication
Biological Process positive regulation of DNA-templated transcriptionIDA:UniProtKB1 Publication
Biological Process positive regulation of isotype switching to IgG isotypesIEA:Ensembl
Biological Process positive regulation of T-helper 1 cell cytokine productionISS:UniProtKB
Biological Process positive regulation of transcription by RNA polymerase IIISS:UniProtKB
Biological Process proteasome-mediated ubiquitin-dependent protein catabolic processISS:UniProtKB
Biological Process regulation of T cell differentiationISS:UniProtKB
Biological Process regulation of transcription by RNA polymerase IIIBA:GO_Central1 Publication
Biological Process response to virusIEP:UniProtKB1 Publication
Biological Process T-helper 1 cell lineage commitmentISS:UniProtKB

Nucleus

Asthma, with nasal polyps and aspirin intolerance (ANPAI):
A condition consisting of asthma, aspirin sensitivity and nasal polyposis. Nasal polyposis is due to chronic inflammation of the paranasal sinus mucosa, leading to protrusion of edematous polyps into the nasal cavities.
Immunodeficiency 88 (IMD88):
An autosomal recessive disorder characterized by the development of disseminated mycobacterial disease following vaccination with BCG. Clinical features included fever, lymphadenopathy, and cutaneous eruption.

Phosphorylations at Ser-53, Tyr-77, Ser-225 and Ser-513 are regulated by mTORC1. Phosphorylation at Tyr-530 is essential for its interaction GATA3. Phosphorylation at Tyr-220, Tyr-266 and Tyr-305 enhances its transcriptional activator activity. Phosphorylation at Thr-303 is required for its interaction with NFATC2.
Ubiquitinated at Lys-314, leading to its degradation by the proteasome. Ubiquitination is essential for controlling protein stability, binding to the T-box-binding element of the IFN-gamma promoter, and for interaction with NFATC2 through induction of phosphorylation at Thr-303 (By similarity).
Deubiquitinated by USP10 leading to its stabilization (PubMed:24845384).