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T-bet / Tbx21

Function

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. 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).

Involvement in disease

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.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Post-translational modifications

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).

Tissue specificity

T-cell specific.

Cellular localization

  • Nucleus

Alternative names

  • T-box transcription factor TBX21
  • T-box protein 21
  • T-cell-specific T-box transcription factor T-bet
  • Transcription factor TBLYM
  • TBX21
  • TBET
  • TBLYM

Target type

Proteins

Primary research area

Immunology & Infectious Disease

Other research areas

  • Immuno-oncology

Molecular weight

58328Da