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Introduction

TBX21 or T-bet is a transcription factor, more precisely a T-box proteins. The DNA binding domain of T-bet has a dimer structure composes of two identical chains ( / ) with a total molecular weight of 76,37 kDA. This binding domain allows it to bind itself to the DNA on promotor or regulator area. The particularity of this T-box protein is that is able to . Moreover, it is able to link two areas of the same DNA molecules which are far from each other and thus create a chromatin loop. The main function of this transcription factor is to direct TH1 cells differentiation from naive CD4+ cells. Nevertheless, the action field of T-bet is larger than classical T-box protein.

Structure and structural interactions

Primary Structure

schema of primary structure of T-bet protein from Mus musculus

The DNA binding domain of T-bet from Mus musculus for a monomer is located between the residues and .

Secondary structure and interactions

The secondary structure of the protein allows it to bind with the DNA : The T-box domain consists of several repeats of and is involved in both dimerization and DNA binding. The crystal structure of the α-helices of the T-box domain bound to DNA strongly suggests that the amino group of is associated with the phosphate of a DNA base via hydrogen-bond interaction. Thanks to some post-translational modifications of the protein’s residues, the transcription factor TBX21 can bind with DNA and some proteins. Firstly, the ubiquitination of the residue allows TBX21 to bind with the DNA sequence. Lys-313 was lately found as a key site required for T-bet to interact with the IFN-γ gene promoter and to assure phosphorylation at Thr-302. Secondly, the phosphorylation of some residues allows TBX21 to interact with several proteins : the phosphorylation of allows TBX21 to interact with NFAT[[1]], the one of allows TBX21 to interact with RUNX1[[2]], the one of allows the interaction with NF-кB p65[[3]] and finaly the one of Y525 allows the interaction with GATA-3.

Some roles of TBX21

Regulation of Th cells differentiation by TBX21

The transcription factor T-bet directs Th1 cell differentiation. The molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood but several hypotheses have already been made of the mechanism of action of T-bet. We know that T-bet initiates Th1 lineage development from naive Thp cells by activating Th1 genetics and repressing the opposing Th2 programs. Th1 cells stimulate cellular immune response while Th2 stimulates humoral immune response and induces antibody production.

Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the formation of the super elongation complex (SEC). Th1 genes are occupied by RNA polymerase II in Thp cells, while T-bet-mediated recruitment of P-TEFb [[4]] and mediator [[5]]and activates transcriptional elongation giving place to an increased differentiation of Thp into Th1.

T-bet can also regulates Th1 cell differentiation by directly initiating gamma interferon (IFN-γ[[6]]) transcription and by suppressing Th2-specific transcription factor GATA-3 [[7]]. The T-bet induced expression of IFN-γ derives Th precursor cells to differentiate into Th1 effector cells. This stimulation of IFN-γ can takes place thanks to the action of a nuclear tyrosine kinase, c-Abl. C-Abl induces phosphorylation of T-bet at tyrosine residues , , and . C-Abl phosphorylates the tyrosine residues within the T-box domain, which is the DNA-binding domain of T-bet. This phosphorylation leads to conformational changes of the T-box domain to facilitate the DNA-binding activity of T-bet and appears to play a crucial role in the IFN-γ promoter-binding activity of T-bet.

Recently, many studies have reported that T-bet also modulates other Th cell lineages, including Th17, Treg, and follicular Th (TFH) cells, in coordination with many transcription factors, such as the retinoic acid-related orphan receptor-𝛾t (ROR𝛾t)[[8]], runt-related transcription factor 3 (RUNX3)[[9]], and B-cell lymphoma-6 (BCL6)[[10]].These findings suggest that T-bet is a transcription factor that is critical for fine-tuning Th cell development.

TBX21 as an antiasthmatic regulator

Asthma remains one of the commonest chronic inflammatory diseases and has a major impact on the life of sufferers. It is associated with allergy mediated by IgE antibodies[[11]].T-bet was found associated with many immune-mediated diseases such as asthma.

In asthmatic airways, Th2 cells are activated and release several cytokines that regulate IgE production and inflammatory cell recruitment, such as eosinophils. Th2 cells and GATA-3 play an important role in allergic inflammation and asthma, and induce IgE production. The asthmatic patients present high levels of total IgE. On the contrary, the T-bet gene expression and Th1 pattern, along with the IFN- γ production, are usually associated with non-allergic asthmatics and healthy subjects.

In T-bet structure, ubiquitination takes place at . It has an impact on the stability of the protein and leads to the degradation of the protein by the proteosome. Some research found the role of deubiquitinases involved in T-bet stability and function. As a deubiquitinase, USP10 belongs to the ubiquitin-specificprotease family of cysteine proteases. Cysteine 424 site on USP10[[12]] is crucial for its hydrolase activity. Results have shown that USP10 could interact with T-bet and stabilize it via interaction between Lysine 313 (K313) of T-bet and Cysteine 424 of USP10. Deubiquitination inhibits its degradation by the proteosome and enhance the secretion of IFN- γ.

Researchers believe that the USP10-dependent T-bet deubiquitination and stabilization can regulate antigen induced immune disorder especially in Th1 specific inflammation. Thus, appropriate decreasing USP10 level may contribute to the T-bet degradation and inflammation attenuation.

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References

1 Mehta, D. S., Wurster, A. L., Weinmann, A. S., & Grusby, M. J. (2005). NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 2016–2021. https://doi.org/10.1073/pnas.0409512102

2 Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet Eun Jung Jang, Hye Ryeon Park, Jeong-Ho Hong, Eun Sook Hwang The Journal of Immunology June 1, 2013, 190 (11) 5764-5770; DOI: 10.4049/jimmunol.1203403

3 Oh, S., & Hwang, E. S. (2014). The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. Journal of immunology research, 2014, 589672. https://doi.org/10.1155/2014/589672

4 Pan, L., Chen, Z., Wang, L., Chen, C., Li, D., Wan, H., Li, B., & Shi, G. (2014). Deubiquitination and stabilization of T-bet by USP10. Biochemical and biophysical research communications, 449(3), 289–294. https://doi.org/10.1016/j.bbrc.2014.05.037

5 Wang, P., Wang, Y., Xie, L., Xiao, M., Wu, J., Xu, L., Bai, Q., Hao, Y., Huang, Q., Chen, X., He, R., Li, B., Yang, S., Chen, Y., Wu, Y., & Ye, L. (2019). The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection. Frontiers in immunology, 10, 606. https://doi.org/10.3389/fimmu.2019.00606

6 Hertweck, A., Evans, C. M., Eskandarpour, M., Lau, J. C., Oleinika, K., Jackson, I., Kelly, A., Ambrose, J., Adamson, P., Cousins, D. J., Lavender, P., Calder, V. L., Lord, G. M., & Jenner, R. G. (2016). T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell reports, 15(12), 2756–2770. https://doi.org/10.1016/j.celrep.2016.05.054

7 Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature immunology, 10(6), 595–602. https://doi.org/10.1038/ni.1731

8 Lazarevic, V., Chen, X., Shim, J. H., Hwang, E. S., Jang, E., Bolm, A. N., Oukka, M., Kuchroo, V. K., & Glimcher, L. H. (2011). T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature immunology, 12(1), 96–104. https://doi.org/10.1038/ni.1969

9 Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 100(6), 655–669. https://doi.org/10.1016/s0092-8674(00)80702-3

10 Robinson, D. S., & Lloyd, C. M. (2002). Asthma: T-bet--a master controller?. Current biology : CB, 12(9), R322–R324. https://doi.org/10.1016/s0960-9822(02)00830-8

11 Jenner, R. G., Townsend, M. J., Jackson, I., Sun, K., Bouwman, R. D., Young, R. A., Glimcher, L. H., & Lord, G. M. (2009). The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17876–17881. https://doi.org/10.1073/pnas.0909357106