Alt. symbols: TBLYM | T-bet

Approved name: T-box transcription factor 21
Alt. names: T-box 21

Location: 17q21.32: 47733236 - 47746122 (+)
Gene type: protein_coding, 2 transcripts.

Scores: LoFtool: 0.067300 | pLI: 0.96324265 | LOEUF: 0.226

HGNC: 11599

NCBI: 30009, RefSeq: NG_012166.1

Ensembl: ENSG00000073861.3

LRG_ | Status: none

OMIM: 604895

Expression | ProteinAtlas

TBX21 encodes T-bet, a T-box-containing transcription factor with multiple roles in the regulation of immune cell development. Studies in mouse have shown that T-bet is a critical regulator of the Th1 differentiation program by inducing the production of IFN-gamma and key Th1 cell migratory factors (PMID: 21685955). Its expression in both dendritic cells and CD4+ T cells is important for Th1 lineage priming and differentiation (PMID: 24113868). T-bet also promotes the differentiation and maturation of NK and CD8+ T cells, as well as the survival of memory B cells and NKT cells. Finally, T-bet is involved in intestinal homeostasis through its roles in regulating IFN-gamma production and other functions of innate lymphoid cells (ILCs).

Biallelic TBX21 loss-of-function has been associated with an autosomal recessive form of Mendelian susceptibility to mycobacterial disease (MSMD) [OMIM: 619630], characterized by the development of disseminated mycobacterial disease following BCG vaccination but no other clinical infectious diseases despite serological evidence of exposure to various viruses and bacteria (PMID: 33296702). The single patient described was homozygous for a TBX21 insertion/deletion (c.466_471delGAGATGinsAGTTTA), re sulting in the substitution of two highly conserved residues (E156S and M157L). The loss of E156 abolished transcriptional activity without affecting protein levels, while loss of M157 preserved transcriptional activity but reduced T-bet protein levels. Together, the 2 changes led to the generation of a mutant protein with no DNA binding ability or transactivation activity and its over-expression could not induce IFN-gamma production in NK or CD4+ T cells. Immunophenotyping showed extremely low numbers of innate and innate-like cell populations - particularly Mycobacterium-reactive NK, iNKT, mucosal-associated invariant T (MAIT), and gamma/delta T cells - and of Mycobacterium-non-reactive classic Th1 lymphocytes, with residual cell populations producing abnormally low levels of IFN-gamma. Moreover, the presence of Mycobacterium-specific, IFN-gamma-producing CD8+ alpha/beta T cells and CD4+ alpha/beta Th1∗ cells appeared unable to compensate for the defect. Finally, T-bet deficiency also led to blood eosinophilia and upper airway inflammation in the same patient via the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4+ alpha/beta T cells (PMID: 34160550). Of note, Akahoshi et al. (2005) identified a promoter polymorphism (c.-1993T>C) linked to increased susceptibility to aspirin-induced asthma as well as to aspirin-independent asthma and nasal polyps [OMIM: 208550] (PMID: 15806396). The authors found that this variant increased the affinity of an unidentified nuclear protein, resulting in increased transcriptional activity and higher expression of the TBX21 gene. They suggested that the concept of allergic inflammation as a homogeneously Th2-driven disease may be too simplistic as IFN-gamma has also been shown to contribute, partly through the activation of eosinophils but also via effects on T cell populations (PMID: 10852746, 11172168, 11466402, 14970180). [Load More]