T-bet

Introduction to T-bet Factor

T-box transcription factor TBX21, also known as T-box expressed in T cells (T-bet), is a protein that is firstly described in 2000 as a Th1-specific transcription factor controlling the expression of interferon (IFN-γ, IFNG) by Th1 cells and a master regulator of Th1 cell development and differentiation. As a member of the Tbox family of transcription factors, T-bet contains a Tbox DNA binding domain and an amino-terminus responsible for interactions with other proteins. The Tbox DNA binding domain of T-bet is a sequence with 180 amino-acid residues for the binding to the DNA consensus sequence TCACACCT.

Recent research has revealed that T-bet mediated multiple and critical functions in both innate immune response and adaptive immune response.

• T-bet factor directly binds to the consensus DNA sequence within the IFNG promoter in Th cells, inducing the expression of IFN-γ and leading to the differentiation of Th precursor cells into Th1 cells;
• T-bet remarkably inhibits the production of interleukin-2 via attenuating the activity of nuclear factor κB (NF-κB) p65;
• By inhibiting the expression of GATA-binding protein-3, T-bet suppresses the production of interleukin-4, interleukin-5, and interleukin-13, thereby repressing Th2 cell differentiation;
• T-bet also induces the expression of several chemokines, coordinates with other transcriptional factors to regulate other Th cell lineages.

The T-bet factor is a crucial transcription factor for the development of T lymphocyte, as well as a valuable target for the prevention and treatment of infections, chronic inflammatory disorders, and autoimmune diseases.

Fig.1 T-bet in immunity to pathogens that occupy distinct intracellular niches. (Pritchard, 2019)

T-bet is Critical for IFN-γ Production by γδ T Cell

γδ T cells and αβ T cells are the two subgroups of T lymphocytes based on the T-cell receptor (TCR) structure, among which αβ T cells expressing αβ-TCR account for the majority while γδ T cells carrying γδ-TCR only account for <5%. Although small in number, γδ T cells play a considerable role in tumor immune surveillance, pathogen clearance, and autoimmunity, through expressing a variety of mediators.

Similar to αβ T cells, γδ T cells can be further distinguished two major effector subsets based on the production of cytokines, IFN-γ producing γδ T cells (γδ1 T cells or γδ 27⁺ T cells) and interleukin-17 producing γδ T cells (γδ T17 cells). T-bet expression was detected in murine and human γδ T cells, mainly γδ1 T cells, to induce and promote IFN-γ production. When challenged mice with Herpes virus in vivo or in vitro TCR stimulation, the T-bet transcription factor was indispensable for IFN-γ production by γδ1 T cells in response to infections. And when orally administrated with Listeria monocytogenes, γδ T17 cells and interleukin-17 producing CD4 T cells were significantly increased in mice in T-bet deficiency mice but were suppressed in the wild type mice. This indicated that γδ T cells secret IFN-γ through the induction of T-bet transcription factor, in response to virus infections.

Fig.2 IFN-γ-producing and IL-17-producing CD4 and γδ T cells. (Serre, 2013)

References

1. Pritchard, G.H., et al. The evolving role of T-bet in resistance to infection. Nature Review. Immunology. 2019, 19(6): 398-410.
2. Serre, K., Silva-Santos, B. Molecular mechanisms of differentiation of murine pro-inflammatory γδ T cell subsets. Frontiers in Immunology. 2013, 4: 431.
3. Barros-Martins, J., et al. Effector γδ T Cell Differentiation Relies on Master but Not Auxiliary Th Cell Transcription Factors. The Journal of Immunology. 2016, 196 (9) 3642-3652.