The Role of Protein Modifications of T-Bet in Cytokine Production and Differentiation of T Helper Cells

Hindawi Publishing Corporation Journal of Immunology Research Volume 2014, Article ID 589672, 7 pages http://dx.doi.org/10.1155/2014/589672 Review Article The Role of Protein Modifications of T-Bet in Cytokine Production and Differentiation of T Helper Cells Sera Oh and Eun Sook Hwang College of Pharmacy, School of Pharmaceutical Sciences and Global Top 5 Research Program, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, C206 Science Building, Seoul 120-750, Republic of Korea Correspondence should be addressed to Eun Sook Hwang; Received 14 March 2014; Accepted 15 April 2014; Published 13 May 2014 Academic Editor: Mizuko Mamura Copyright © 2014 S. Oh and E. S. Hwang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. T-Bet (T-box protein expressed in T cells, also called as TBX21) was originally cloned as a key transcription factor involved in the commitment of T helper (Th) cells to the Th1 lineage. T-Bet directly activates IFN-𝛾 gene transcription and enhances development of Th1 cells. T-Bet simultaneously modulates IL-2 and Th2 cytokines in an IFN-𝛾-independent manner, resulting in an attenuation of Th2 cell development. Numerous studies have demonstrated that T-bet plays multiple roles in many subtypes of immune cells, including B cell, dendritic cells, natural killer (NK) cells, NK T cells, and innate lymphoid cells. Therefore, T-bet is crucial for the development and coordination of both innate and adaptive immune responses. To fulfill these multiple roles, T-bet undergoes several posttranslational protein modifications, such as phosphorylation at tyrosine, serine, and threonine residues, and ubiquitination at lysine residues, which affect lineage commitment during Th cell differentiation. This review presents a current overview of the progress made in understanding the roles of various types of T-bet protein modifications in the regulation of cytokine production during Th cell differentiation. 1. Introduction T-Bet (T-box protein expressed in T cells, also called TBX21) was firstly described in 2000 in a report examining the effects of T-bet on the differentiation of T helper 1 (Th1) cells [1]. For the past 15 years, many studies have examined the functions of T-bet and have revealed multiple roles for this protein during Th cell differentiation, with a focus on the molecular mechanisms involved, the novel functions of this transcription factor in innate immune cells, and Tbet-mediated modulation of inflammatory diseases [2–9]. It has been clarified that T-bet plays a critical role in the coordination of innate immunity and adaptive immunity and that it fulfills an important function in modulating chronic inflammatory diseases, including asthma and inflammatory bowel disease, by controlling a network of highly conserved genetic programs [10–12]. Thus, optimal regulation of T-bet expression and activity seems to be beneficial for preventing or treating chronic inflammation and autoimmune diseases. Although attempts have been made at identifying the small molecules that control the expression and activity of T-bet that affect the T cell-mediated immune response, little progress has been made on this to date. Given the importance of T-bet in the immune regulation, elucidating the functional mechanisms underlying the multiple roles of T-bet would facilitate the development of novel therapeutic interventions for treating chronic inflammatory and autoimmune diseases. This review summarizes the current state of knowledge about the molecular mechanisms underlying the multiple roles played by T-bet in Th cell development. 2. Structure of T-Bet The T-bet contains an amino-terminus, a T-box domain, and a carboxyl-terminus, which show 82%, 100%, and 79% homology, respectively, between mice (530 amino-acid residue protein) and humans (535 amino-acid residue protein) (Figure 1). The T-box domain, located between residues 135 and 326 in mouse T-bet, is highly conserved in 18 members of the T-box protein (TBX) family [13, 14]. Common features shared by T-box proteins include a capacity for DNA binding through the T-box domain and transcriptional 2 Journal of Immunology Research ub ub ub P ub 1 135 1 136 P Y525 Y265 Y219 T-box Mouse S508 P P P T302 Y304 K313 P Transactivation domain 326 Human 530 T-box 82% identity Position 327 100% identity 535 79% identity Modification Physiological effect Reference Y219/Y265/Y304 c-Abl-mediated phosphorylation Induction of Th1 cell development Suppression of Th2 cell development [28] T302 Phosphorylation Interaction with NFAT Suppression of IL-2 and Th2 cytokines [29] Y304 — Interaction with RUNX1 Inhibition of Th17 cell development [21] K313 Ubiquitination Binding to DNA sequence Control of protein stability [29] S508 GSK-3-mediated phosphorylation Interaction with NF-𝜅B p65 Inhibition of IL-2 [19] Y525 ITK-induced phosphorylation Interaction with GATA-3 Suppression of Th2 cytokines [5] Figure 1: Structure and protein modification of T-bet. Mouse and human T-bet is 100% identical in the T-box domain. Several amino acid residues are conserved in mice and undergo posttranslational modifications, including phosphorylation at serine, threonine, and/or tyrosine residues, and ubiquitination at lysine residues. regulatory activity, which plays a role in controlling the expression of developmental gene in all animal species. The T-box domain is made up of about 180 amino-acid residues and is both sufficient and necessary for binding to the consensus DNA sequence TCACACCT [13–15]. Brachyury (T) was the first T-box protein to be identified and, in dimeric form, interacts with the major and the minor grooves of DNA through hydrophobic interactions and unusual mainchain carbonyl contact with a guanine as a dimer [16]. TBX1 also binds to the DNA sequence as a dimer, whereas TBX2 appears to bind to the same DNA sequence as a monomer [17]. Although TBX1 and TBX2 share 61% identity in the T-box domain, the structure of the DNA-T-box binding complex appears to be different, because of the low homology among the amino- and carboxyl-terminal regions. The T-box domain in T-bet shows 50% homology with the corresponding domain in brachyury (T), TBX1, and TBX2; however, the crystal structure of T-bet bound to the DNA sequence remains to be characterized. 3. Regulation of Th Cell Differentiation by T-Bet 3.1. Stimulation of Th1 Cell Differentiation by T-Bet. T-bet directly binds to the consensus DNA sequence within the IFNG promoter and activates its transcription. The T-betinduced expression of IFNG derives Th precursor cells to differentiate into Th1 effector cells. While exogenous Tbet overexpression in naı̈ve Th cells preferentially increases development of Th1 cells, T-bet deficiency leads to a failure to produce sufficient IFN-𝛾 (...truncated)