Next Article in Journal
A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections
Previous Article in Journal
Normal and Dysregulated Sphingolipid Metabolism: Contributions to Podocyte Injury and Beyond
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 13
Issue 11
10.3390/cells13110891
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

BACH2: The Future of Induced T-Regulatory Cell Therapies

by
Daniel Zwick
1,*,
Mai Tram Vo
2,
Young Jun Shim
3,
Helena Reijonen
4 and
Jeong-su Do
4,*
1
Frederick National Laboratory, Frederick, MD 21701, USA
2
School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
3
Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
4
Department of Immunology and Theranostics, City of Hope, Duarte, CA 91010, USA
*
Authors to whom correspondence should be addressed.
Cells 2024, 13(11), 891; https://doi.org/10.3390/cells13110891
Submission received: 16 April 2024 / Revised: 17 May 2024 / Accepted: 20 May 2024 / Published: 22 May 2024
(This article belongs to the Section Cellular Immunology)
Browse Figures
Review Reports Versions Notes

Abstract

:
BACH2 (BTB Domain and CNC Homolog 2) is a transcription factor that serves as a central regulator of immune cell differentiation and function, particularly in T and B lymphocytes. A picture is emerging that BACH2 may function as a master regulator of cell fate that is exquisitely sensitive to cell activation status. In particular, BACH2 plays a key role in stabilizing the phenotype and suppressive function of transforming growth factor-beta (TGF-β)-derived human forkhead box protein P3 (FOXP3)+ inducible regulatory T cells (iTregs), a cell type that holds great clinical potential as a cell therapeutic for diverse inflammatory conditions. As such, BACH2 potentially could be targeted to overcome the instability of the iTreg phenotype and suppressive function that has hampered their clinical application. In this review, we focus on the role of BACH2 in T cell fate and iTreg function and stability. We suggest approaches to modulate BACH2 function that may lead to more stable and efficacious Treg cell therapies.

1. Introduction

BACH2 is a highly conserved transcriptional repressor that controls the maturation and differentiation of T and B lymphocytes [1,2,3]. Originally, BACH2 was identified as an important molecule in B cell development. However, it was subsequently discovered that BACH2 is highly expressed in CD4 and CD8 T cells and plays a significant role in T cell differentiation to Th1 [4,5] and Th2 cells [6] and in stabilizing regulatory T cell (Treg)-mediated homeostasis.
The identification of a role for BACH2 in Treg cells may have important implications for therapeutic applications of Tregs. Tregs can be classified as thymus-derived natural FOXP3+ CD4 Treg cells (nTreg) and FOXP3+ inducible Treg cells (iTregs). nTregs are critical for the maintenance of immune homeostasis [7,8]. FOXP3+ iTregs can be generated ex vivo in the presence of IL-2 and TGF-β, exhibiting similar suppressive activity to that of nTreg [9,10]. As FOXP3+ iTregs can be readily expanded in large quantities from naïve T cells ex vivo, they have potentially enormous clinical application in autoimmune disorders and graft-versus-host disease [11]. However, the unstable phenotype and function of iTregs and their conversion to pathogenic T cells in an inflammatory environment remain major obstacles to their clinical application [11,12].
Targeting BACH2 function is a potential approach to stabilize the iTreg phenotype. Several studies have elucidated a key role for BACH2 in iTreg differentiation and function. Although the role of BACH2 in T cells has received much attention [4,13,14], the factors that regulate BACH2 expression in the development of mature CD4+ T-cells, as well as the mechanisms that establish a Treg-specific transcriptional program, have only recently been elucidated. This review provides an overview of the molecular mechanisms of BACH2 function and their relevance to autoimmune and inflammatory conditions. Furthermore, we highlight recent findings regarding the role of BACH2 in iTregs, with special attention to the clinical significance of BACH2 in generating stable iTregs.

2. BACH2 Structure

The structure of the BACH family of transcription factors has been reviewed in detail previously [15]. The BACH family consists of a basic region leucine zipper (bZip) containing transcription factors that form heterodimeric complexes with Maf proteins to repress gene expression (Figure 1). Maf proteins bind to palindromic DNA sequences termed Maf recognition elements (MAREs). BACH2 also contains an N-terminal BTB domain that mediates protein–protein interactions and a C-terminal nuclear export sequence (NES). Through experimental mutagenesis, the sites of post-translational modification have been identified, including serine phosphosites and lysine residues that undergo SUMO2 conjugation. Disease-associated mutations have been identified and linked to specific defects in BACH2 protein stability and function (Figure 1). In addition, single nucleotide polymorphisms (SNPs) that have been noted to affect protein stability have been identified. Associations with autoimmune diseases have been reported with BACH2 (See Table 1).
Much of our knowledge of the molecular mechanisms of BACH2 regulation comes from studies in B cells. BACH2 localization is regulated by a nuclear export sequence at the C terminus and a nuclear localization sequence in the bZip domain. PI3K signaling leads to BACH2 phosphorylation and promotes its cytoplasmic localization (see Figure 2). Oxidative stress inhibits the function of the cytoplasmic localization sequence and induces nuclear accumulation of BACH2 [36]. BACH2 is phosphorylated at several residues, yet only a single site appears to play a key role in controlling its nuclear localization [37].

3. BACH2 Cell Type-Specific Roles

3.1. BACH2 in T-Cell Differentiation

BACH2 plays a critical role in controlling T-cell differentiation pathways and can serve as a potent repressor of T cell polarization and functional responses (reviewed in [4]). Numerous studies have demonstrated that BACH2 can act at the transcriptional level to inhibit T-cell differentiation programs. BACH2 can integrate cytokine signals to inhibit STAT3-mediated CXCR5 expression and modulate the balance between Th17 and Tfh cell differentiation [38]. BACH2 regulates CD8 T-cell differentiation, and BACH2 deletion in naïve CD8 T cells results in changes in chromatin architecture that resemble effector and memory T cells [39,40].

3.2. BACH2 in iTregs: Regulation of FOXP3 Expression and iTreg Stability in Humans

BACH2 has been implicated in the stabilization of FOXP3 iTregs. The role of BACH2 in iTregs has important implications for iTreg-based cell therapeutics. Although iTregs can be readily induced in large quantities, the instability of FOXP3 expression in iTregs, both during ex vivo expansion and upon transfer to a pro-inflammatory environment, remains a critical obstacle to their clinical implementation. Thus, BACH2 could potentially be targeted for the generation of more stable iTreg-cell-based therapeutics.
Prior work has shown BACH2 regulates transcription downstream of the TCR to control Treg cell differentiation and homeostasis [41]. Murine gene deletion studies have revealed that BACH2 is a critical transcription factor for iTreg function [5,42] and represses genes associated with effector T-cell differentiation [5]. In addition, Tregs derived from mice lacking BACH2 exhibit a reduced number and diminished capacity to control T-cell-mediated colitis [5,42]. BACH2 plays a critical role in stabilizing Treg suppressor function by inhibiting T effector differentiation programs [5,6].
BACH2 is implicated in the unique gene expression profile of umbilical cord blood (UCB)-versus adult peripheral blood (AB)-derived naive CD4+ T cells [43]. The inhibition of BACH2 suppresses interleukin-2 (IL-2) expression in UCB CD4+CD45RA+ T cells [44]. However, BACH2 has been identified as an important regulator in the formation and function of CD4+ T cell lineages across various diseases [13]. It seems its role is dynamic in the status of CD4 T cells. The differential expression of BACH2 in CD4 T cells from UCB versus AB controls IL-2 production in CD4 T cells [44], regulates IL-2 receptor signaling in Tregs [45], and plays a key role in regulating Treg functions [46]. Intriguingly, UCB iTregs exhibit more robust, sustained FOXP3 expression and enhanced stability compared with AB iTregs. Mechanistically, BACH2 regulates human UCB iTreg development via direct transcriptional activity at the FOXP3 promoter [47], and BACH2 binds the FOXP3 promoter region in differentiated UCB but not AB iTregs. These studies revealed that BACH2 regulates the transcriptional mechanisms controlling FOXP3 expression in UCB iTregs, and differential expression and regulation of BACH2 could account for enhanced FOXP3 stability in UCB iTregs. Therefore, it is of interest to identify the mechanisms controlling BACH2 expression and the regulation of FOXP3 expression.
Recent insights into the mechanisms of BACH2-mediated transcriptional control of iTreg stability come from the analysis of transcription factor binding sites. Nuclear factor of activated T cells (NFAT) proteins are activated by calcium signaling pathways upon T-cell receptor (TCR) stimulation. Once activated, NFAT translocates into the nucleus, where it binds to specific DNA sequences, known as NFAT response elements, in the promoter regions of target genes [48]. FOXP3 expression and the iTreg suppressor phenotype depend on interactions with the NFAT transcription factor [49]. In FOXP3+ Treg cells, NFAT contributes to the expression of genes involved in Treg cell development and function, including FOXP3 itself. The BACH2 consensus binding sequence overlaps with that of NFAT (Figure 3). Thus, one intriguing possibility is that BACH2 competes with NFAT for the same binding sites in iTregs to regulate iTreg transcriptional stabilization. Also, FOXP3 interacts with BACH2 in a co-immunoprecipitation binding assay [47]. Because BACH2 expression is higher in UCB than AB iTregs, BACH2 regulation of FOXP3 and competition with NFAT could contribute to the differential stability of UCB and AB iTregs. In analogy to this proposed mechanism, it has been found that BACH2 modulates CD8 T-cell differentiation by regulating AP-1 binding to enhancer regions of TCR-regulated genes [3]. AP-1 is a dimeric transcription factor composed of proteins from the Jun (c-Jun, JunB, JunD) and Fos (c-Fos, FosB, Fra-1, Fra-2) families [50]. AP-1 activity is regulated by various signaling pathways, including those activated downstream of TCR engagement [51]. In addition, BACH2 represses the AP-1-driven expression of IL-2 in CD4 T cells [52]. Thus, it is of interest to determine whether an analogous mechanism of BACH2/NFAT competition is involved in the regulation of iTreg stability. In addition to competition for transcription factor binding sites, it has been identified that BACH2 can regulate NFAT expression. In particular, reduced BACH2 expression was correlated with aberrant NFAT expression in T cells derived from chronic myelogenous leukemia patients [53].

3.3. BACH2 in T-Cell Exhaustion

A prior comprehensive review suggested that BACH2 may be a key regulator of exhaustion [4]. Additional reports support this notion. For instance, recently, BACH2 was identified as a key regulator of exhaustion in precursor T cells in chronic viral infection [41,54] and has also been implicated in Treg quiescence [55]. In addition, BACH2 plays a critical role in stabilizing Treg naive phenotypes [5,6] and suppressing the expression of genes associated with T-cell exhaustion [39].

4. Molecular Mechanisms That Regulate BACH2

4.1. BACH2 Regulation by MicroRNAs (miRs)

Accumulating studies have highlighted the diverse mechanisms regulating BACH2 function (Figure 4). miRs are small, non-coding RNAs that bind to specific sequences in the mRNA molecules of target genes, leading to mRNA degradation or translational repression [56]. miRs play a crucial role in the regulation of BACH2 expression. miRs have been implicated in the unique transcriptional regulatory mechanisms in UCB CD4 T cells [57,58], including the regulation of BACH2 expression specifically. Interestingly, in each case, miR-mediated downregulation of BACH2 was associated with enhanced susceptibility of different cell types to apoptosis [59]. One study identified that miR 16-5p and miR 145-p promote apoptosis of human gingival epithelial cells via the downregulation of BACH2 [60]. Other miR studies have supported the critical role of BACH2 in immune cell differentiation and function. For instance, miR 148a targeted BACH2 expression to promote plasma-cell differentiation [61]. Another study identified that miR 150-5p regulates BACH2 to modulate T-cell activation in a mouse model of severe aplastic anemia [62].
miR regulation of BACH2 has been implicated in regulating the proportion of Tregs in diffuse large B-cell lymphoma [63].

4.2. Metabolic Regulation of BACH2

An emerging research area is the regulation of BACH2 by metabolic status. BACH2 is regulated by oxidative stress [64,65]. Several studies indicate the mammalian target of rapamycin (mTOR) signaling regulates BACH2 function [37,66] (see Figure 2 and Figure 4). mTOR signaling plays a key role in T-cell development, CD4 T-cell differentiation, and regulatory T-cell generation in vivo [67,68,69]. Among its effects on cellular functions, mTOR signaling plays a critical role in modulating mitochondrial function [70]. Interestingly, one study showed that mitochondrial function regulates BACH2, and in turn controls B cell fate outcomes [71]. Subsequent work revealed that protein kinase C (PKC) beta regulates B cell fate through mTOR signaling, metabolic programming involving mitochondrial remodeling, heme metabolism, and BACH2 inhibition [72].
In support of the importance of metabolic regulation of BACH2 in stabilizing iTreg phenotypes, mesenchymal stromal cell (MSC) co-culture during iTreg expansion stabilizes BACH2 expression and is associated with a reduced expression of markers of exhaustion and senescence [73]. The phenotype of iTregs cultured on MSCs was consistent with the core phenotype of natural Tregs (nTregs), showing positive staining for FOXP3, CD25, and cytotoxic T lymphocyte antigen-4 (CTLA4).
More generally, accumulating studies have shown that FOXP3 expression and Treg function are regulated by metabolic inputs. Fatty acid oxidation regulates Treg differentiation and function [74,75]. Further, oleic acid treatment is observed to overcome defects in suppressive function in Tregs from multiple sclerosis (MS) patients [76].
In addition to metabolism regulating Treg stability, signaling modulates metabolism in T cells, which may have consequences for BACH2 function. PD1 inhibits T-cell activation in part via inhibiting metabolic programming through the inhibition of glycolysis and fatty acid oxidation [77]. Tan et al. recently identified that PD1 restraint of Treg activation plays a role in immune tolerance, in part via PD1 inhibition of phosphoinositide 3 kinase (PI3k)–Akt signaling [78]. Thus, it is of interest to investigate whether these and other metabolic inputs may potentially affect BACH2 expression and/or function as well.
FOXP3 can also modulate metabolism, increasing oxidative phosphorylation and nicotinamide adenine dinucleotide (NAD) oxidation, which serves to adapt Tregs to low-glucose conditions [79]. In addition, mitochondrial stress during continual T-cell stimulation under hypoxic conditions, as in the tumor microenvironment, was found to drive T-cell exhaustion, and modulating T cell reactive oxygen species (ROS) could ameliorate exhaustion. Because mitochondrial function regulates BACH2 function and control of Treg suppression, mitochondrial stress in Tregs may influence BACH2 function and thereby contribute to T-cell exhaustion and the loss of suppressive function during ex vivo expansion of induced Tregs (iTregs).

4.3. Regulation of BACH2 by SUMOylation and Role in iTreg Stability

Several studies have shed light on new mechanisms of BACH2 regulation and the links between metabolism, BACH2, FOXP3, and iTreg stability [73]. Previous studies identified that the small ubiquitin modifier (SUMO) sentrin-specific protease SENP3 serves as a sensor of metabolic status, particularly intracellular ROS, which regulates the nuclear translocation of SUMOylated BACH2 [80,81], the association of SUMOylated BACH2 with promyelocytic leukemia nuclear bodies, and the repression of associated transcriptional targets [65] (Figure 2 and Figure 4). During T-cell activation, increased levels of intracellular ROS induce the accumulation of SENP3 in the nucleus. In turn, SENP3 induces the deSUMOylation of BACH2, which inhibits the nuclear export of BACH2. Accumulated nuclear BACH2 in turn modulates the expression of genes that regulate FOXP3 iTreg stability [82].
Additional studies support the importance of ubiquitylation in regulating FOXP3 and iTreg stability more generally (reviewed in detail in [83]). The ubiquitin ligase Itch and deubiquitinase ubiquitin specific protease 44 (USP44) regulate FOXP3 stability [84,85]. A recent study utilizing a CRISPR screening identified additional ubiquitin-related regulators of FOXP3 and Treg stability, including USP22 and the E3 ligase Rnf20 [86]. Further, SWI and BAF proteins were identified as regulators of the maintenance of FOXP3 expression and Treg stability in mouse nTregs by CRISPR/Cas-9 screening [87].

5. BACH2-Associated Diseases

5.1. BACH2 in Murine T Cell Inflammatory Disease Models and Autoimmunity

The variety of diseases resulting from aberrant BACH2 expression and/or function highlights its important role in immune cells (Table 1). BACH2-deficient mice exhibit defects in B cell class switch recombination and Treg differentiation. Further, BACH2 deficiency or mutation results in severe autoimmunity [5,21]. BACH2 was also recently implicated in the repression of innate lymphoid cell memory in a mouse model of asthma [88]. In addition, it has been identified that BACH2 serves to suppress T follicular helper cell expansion and aberrant germinal center formation via suppressing the transcription of CXCR5 and c-Maf genes in mice [89]. In addition to global BACH2 deficiency, the impact of Treg-specific deletion of BACH2 has been examined. Further supporting a key role for BACH2 in the restraint of autoimmunity, BACH2 deficiency in Tregs leads to dysregulated type 2 allergic inflammatory responses in mice [90].

5.2. BACH2 in Human Autoimmune Conditions

BACH2 has been linked to susceptibility to a variety of autoimmune conditions. A new syndrome termed ‘BACH2-related immunodeficiency and autoimmunity’ (BRIDA) appears to be a monogenic primary immunodeficiency resulting from novel deleterious heterozygous point mutations in BACH2. These mutations result in reduced BACH2 expression and transcriptional repression of BLIMP in patient lymphoblastoid cells, reduced memory B cells, and systemic lupus erythematosus (SLE) symptoms [21,22]. BACH2-promoter methylation is associated with irritable bowel syndrome (IBS) [16]. A variant of BACH2 is associated with Crohn’s disease [17]. A recent genome-wide association study (GWAS) identified BACH2 as a risk locus for Addison’s disease [34]. BACH2 is also associated with protection from chronic pancreatitis [19]. Another report identified associations between BACH2 mutations that cause BACH2 haploinsufficiency and disease conditions [21]. Additionally, a report linked a BACH2 polymorphism with polyglandular autoimmunity [91].
Type 1 diabetes mellitus (T1DM) impacts approximately 10–15% of individuals diagnosed with diabetes mellitus (DM). It arises from the autoimmune destruction of pancreatic beta cells, necessitating lifelong dependence on insulin for affected patients [92]. BACH2 has been recognized for its role in regulating the survival of pancreatic beta cells through intricate crosstalk with several proteins involved in critical cellular pathways. This regulatory function involves molecular interactions that modulate key processes essential for the viability and functionality of pancreatic beta cells in T1D [27].
Vitiligo is a persistent autoimmune skin condition marked by the depletion of melanocytes, the cells responsible for melanin production [93]. While its exact cause remains elusive, experts suspect a blend of genetic, environmental, and immunological factors. Ongoing research explores the interplay between vitiligo and BACH2, a gene identified in GWAS as potentially linked to the condition. Though no direct causal relationship has been definitively established, there is a growing curiosity surrounding BACH2’s role in vitiligo’s pathogenesis, particularly regarding immune system dysregulation and autoimmune mechanisms.
MS is a chronic autoimmune disorder characterized by inflammation and damage to the central nervous system (CNS), including the brain and spinal cord [94]. Immune-mediated mechanisms, such as the activation of autoreactive T cells and the production of pro-inflammatory cytokines, are believed to play a significant role in the development and progression of MS [95]. Studies have suggested that dysregulation of BACH2 may contribute to immune dysfunction and the development of autoimmune diseases, including MS. GWASs have identified genetic variants in the BACH2 gene that may be associated with an increased risk of developing MS [96]. While the exact role of BACH2 in MS is not fully elucidated, there is growing interest in understanding its potential involvement in the pathogenesis of the disease, particularly in the context of immune dysregulation and inflammation.
Thus, BACH2 plays a central role in restraining autoimmunity (See Table 1). Overall, mutation in the BACH2 gene can disrupt immune regulation, Treg function, B-cell differentiation, and antioxidant responses, increasing susceptibility to autoimmune diseases. Understanding the mechanisms by which BACH2 mutations contribute to autoimmunity is essential for developing targeted therapies for these conditions.

5.3. BACH2 in Murine Tumor Models and Human Cancers

BACH2’s significance extends beyond murine tumor models, as it also plays a pivotal role in human cancers. Studies have highlighted its crucial involvement in tumor immunosuppression, where BACH2-deficient mice implanted with tumors exhibit markedly reduced tumor growth compared with their wild-type counterparts [97]. This underscores BACH2’s impact on tumor progression and the modulation of immune responses within the tumor microenvironment. In the context of cancer, BACH2 exerts its regulatory influence on TCR-induced transcriptional changes, particularly those crucial for maintaining Treg quiescence and homeostasis [41], mechanisms involved in cancer immunosuppression [55]. BACH2 has also been associated with leukemia [23]. In addition, inhibition of the BACH2 immunosuppressive function has been implicated in KRAS-associated lung cancer resistance to chemotherapy [98]. Another study revealed that BACH2 inhibits NK maturation and cell function in mice and humans, limiting the cytotoxic response to cancer [99]. BACH2 exerts multifaceted effects in tumor immunosuppression and cancer pathogenesis, influencing diverse aspects of immune cell function and tumor biology. Its complicated regulatory functions in both innate and adaptive immune responses underscore its potential as a therapeutic target for enhancing antitumor immunity and improving treatment outcomes in various cancers.

6. Prospects for Stabilizing iTreg Phenotype and Function via Targeting BACH2

6.1. Approaches to Modulating iTreg Stability

Strategies to stabilize FOXP3 expression have shown promise in enhancing the stability of the iTreg phenotype and its function. A gene editing approach that utilized homology-directed repair for targeted insertion of an enhancer was able to overcome epigenetic silencing and enforce FOXP3 expression in primary human CD4 T cells [100]. Several approaches are being pursued to enhance and preserve Treg identity and function in chronic inflammatory conditions [101]. Strategies to enhance FOXP3 expression by modulating surface molecule function through pharmacologic means have shown promise. In a graft-versus-host disease (GVHD) model, TGF-β-induced FOXP3 expression could be stabilized, and iTreg suppressor function was enhanced by co-treatment with rapamycin and IL-2/anti-IL-2 antibody complexes [102,103]. Yet, rapamycin impairs the overall efficiency of Treg expansion [104] and can promote the formation of potentially pathogenic memory T cells [105]. Notably, numerous approaches aimed at stabilizing iTreg function target epigenetic mechanisms, including binding to the FOXP3 enhancer at conserved non-coding sequence (CNS)-1, inducing the demethylation of the CNS2 of FOXP3 and the Treg-specific demethylated region (TSDR) of CD25 and inhibiting histone deacetylase (HDAC) [106]. The broad range of targets regulated by HDAC raises concerns of off-target effects of HDAC inhibitors. In light of this concern, new approaches to stabilizing iTreg function are needed.

6.2. Identifying Targets for Pharmacological Modulation of BACH2 Function

The multiple inputs regulating BACH2 function offer hints at avenues for therapeutic stabilization of iTreg function (see Figure 2). Potentially, small molecules modulating BACH2 function or specific related genes could be useful in this context, although more targeted approaches are needed. While there are no known direct activators or inhibitors of BACH2, the HDAC3 inhibitor RGFP966 inhibits the repressor function of BACH2 in T cells and at the Prdm1 locus in B cells [107]. In another study, BACH2 was found to be involved in the response to cytotoxic drug-induced ROS and apoptosis of B lymphoma cells. Further, PI3K inhibition attenuated the nuclear translocation of BACH2 and increased sensitization to cytotoxic drugs [80]. BACH2 has been found to regulate cell survival in the context of germinal-center B-cell development via direct repression of the pro-apoptotic mediator Bim [108]. The notion of BACH2 involvement in cell survival and stress responses has also been reported in relation to BACH2 expression in stressed islet cells in T2D. In this context, one report identified that islet-specific BACH2 knockout restores nondiabetic phenotype in human T2D islets, and BACH2 inhibition can reverse T2D in mice [109].
The identification of downstream signaling molecules involved in pathways of metabolic regulation of BACH2 function in cell stress and survival may lead to more directed therapeutics. CRISPR technology has revolutionized the discovery of novel target genes in a variety of disease contexts. A recent report confirmed HDAC1 as a key regulator of BACH2 function in plasma cell differentiation via CRISPR screening [110]. Transcriptional changes mediated by BACH2 in conventional T cells (Tconv) were examined using a luciferase reporter assay under a tetracycline-inducible BACH2 expression system [111]. While this study utilized Tconvs, it suggested the general applicability of this approach in studies of BACH2 regulation of various target genes in iTreg cells. Another study utilized high-throughput allele-specific reporter assays to prioritize a BACH2 SNP with effects on gene expression and tested it in a human T cell line while deleting the orthologous sequence in mice. This approach revealed a BACH2 SNP rs72928038 with effects on BACH2 expression and CD8 T-cell function [112]. These studies may contribute to defining the underlying mechanisms of BACH2 regulation and function, enabling the screening of compounds that may regulate BACH2.
Identifying the upstream and downstream targets of BACH2 in different disease conditions may advance the development of targeted therapies. Ongoing studies also seek to further decipher the mechanisms by which BACH2 contributes to enhanced FOXP3 stability and iTreg suppressor function.

7. Conclusions and Future Perspectives

BACH2 stands out as a critical regulator in immune cell differentiation and function and the maintenance of immune balance. Its intricate regulation by various factors such as microRNAs, metabolic pathways, and interactions with other transcription factors underscores its significance in the cellular processes underlying autoimmune diseases and cancer immunosuppression. Indeed, several cancers and autoimmune disease conditions have been associated with altered BACH2 expression and specific BACH2 variants. Therapeutic strategies targeting BACH2, including modulation of its function and downstream signaling pathways, offer promising avenues for stabilizing regulatory T cell phenotypes in the context of autoimmunity and cancer. Future research should focus on further unraveling the mechanisms underlying BACH2’s regulatory roles across different immune cell types and disease contexts. Interdisciplinary efforts combining basic research, translational studies, and clinical trials are crucial for unlocking the therapeutic potential of targeting BACH2, potentially leading to more effective immune-modulating therapies and improved patient outcomes.

Author Contributions

Conceptualization, D.Z. and J.-s.D.; writing—original draft preparation, M.T.V., Y.J.S., H.R., D.Z. and J.-s.D.; writing—review and editing, M.T.V., Y.J.S., H.R., D.Z. and J.-s.D.; visualization, M.T.V., Y.J.S., H.R., D.Z. and J.-s.D. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by Margie & Robert Petersen Foundation (H.R, J-s. D).

Data Availability Statement

No data were used to support the findings of this study.

Acknowledgments

We thank the Cleveland Cord Blood Center for support. We gratefully acknowledge authors whose work could not be included in this review due to space limitations.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Muto, A.; Tashiro, S.; Nakajima, O.; Hoshino, H.; Takahashi, S.; Sakoda, E.; Ikebe, D.; Yamamoto, M.; Igarashi, K. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 2004, 429, 566–571. [Google Scholar] [CrossRef] [PubMed]
  2. Kometani, K.; Nakagawa, R.; Shinnakasu, R.; Kaji, T.; Rybouchkin, A.; Moriyama, S.; Furukawa, K.; Koseki, H.; Takemori, T.; Kurosaki, T. Repression of the transcription factor Bach2 contributes to predisposition of IgG1 memory B cells toward plasma cell differentiation. Immunity 2013, 39, 136–147. [Google Scholar] [CrossRef] [PubMed]
  3. Roychoudhuri, R.; Clever, D.; Li, P.; Wakabayashi, Y.; Quinn, K.M.; Klebanoff, C.A.; Ji, Y.; Sukumar, M.; Eil, R.L.; Yu, Z.; et al. BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers. Nat. Immunol. 2016, 17, 851–860. [Google Scholar] [CrossRef] [PubMed]
  4. Richer, M.J.; Lang, M.L.; Butler, N.S. T Cell Fates Zipped Up: How the Bach2 Basic Leucine Zipper Transcriptional Repressor Directs T Cell Differentiation and Function. J. Immunol. 2016, 197, 1009–1015. [Google Scholar] [CrossRef]
  5. Roychoudhuri, R.; Hirahara, K.; Mousavi, K.; Clever, D.; Klebanoff, C.A.; Bonelli, M.; Sciume, G.; Zare, H.; Vahedi, G.; Dema, B.; et al. BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature 2013, 498, 506–510. [Google Scholar] [CrossRef] [PubMed]
  6. Tsukumo, S.; Unno, M.; Muto, A.; Takeuchi, A.; Kometani, K.; Kurosaki, T.; Igarashi, K.; Saito, T. Bach2 maintains T cells in a naive state by suppressing effector memory-related genes. Proc. Natl. Acad. Sci. USA 2013, 110, 10735–10740. [Google Scholar] [CrossRef] [PubMed]
  7. Mills, K.H. Regulatory T cells: Friend or foe in immunity to infection? Nat. Rev. Immunol. 2004, 4, 841–855. [Google Scholar] [CrossRef]
  8. Lourenco, E.V.; La Cava, A. Natural regulatory T cells in autoimmunity. Autoimmunity 2011, 44, 33–42. [Google Scholar] [CrossRef]
  9. Chen, W.; Jin, W.; Hardegen, N.; Lei, K.J.; Li, L.; Marinos, N.; McGrady, G.; Wahl, S.M. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 2003, 198, 1875–1886. [Google Scholar] [CrossRef]
  10. Davidson, T.S.; DiPaolo, R.J.; Andersson, J.; Shevach, E.M. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J. Immunol. 2007, 178, 4022–4026. [Google Scholar] [CrossRef]
  11. Schmitt, E.G.; Williams, C.B. Generation and function of induced regulatory T cells. Front. Immunol. 2013, 4, 152. [Google Scholar] [CrossRef] [PubMed]
  12. Romano, M.; Fanelli, G.; Albany, C.J.; Giganti, G.; Lombardi, G. Past, Present, and Future of Regulatory T Cell Therapy in Transplantation and Autoimmunity. Front. Immunol. 2019, 10, 43. [Google Scholar] [CrossRef] [PubMed]
  13. Yang, L.; Chen, S.; Zhao, Q.; Sun, Y.; Nie, H. The Critical Role of Bach2 in Shaping the Balance between CD4+ T Cell Subsets in Immune-Mediated Diseases. Mediat. Inflamm. 2019, 2019, 2609737. [Google Scholar] [CrossRef] [PubMed]
  14. Trujillo-Ochoa, J.L.; Kazemian, M.; Afzali, B. The role of transcription factors in shaping regulatory T cell identity. Nat. Rev. Immunol. 2023, 23, 842–856. [Google Scholar] [CrossRef] [PubMed]
  15. Zhou, Y.; Wu, H.; Zhao, M.; Chang, C.; Lu, Q. The Bach Family of Transcription Factors: A Comprehensive Review. Clin. Rev. Allergy Immunol. 2016, 50, 345–356. [Google Scholar] [CrossRef] [PubMed]
  16. Klasic, M.; Markulin, D.; Vojta, A.; Samarzija, I.; Birus, I.; Dobrinic, P.; Ventham, N.T.; Trbojevic-Akmacic, I.; Simurina, M.; Stambuk, J.; et al. Promoter methylation of the MGAT3 and BACH2 genes correlates with the composition of the immunoglobulin G glycome in inflammatory bowel disease. Clin. Epigenetics 2018, 10, 75. [Google Scholar] [CrossRef] [PubMed]
  17. Laffin, M.R.; Fedorak, R.N.; Wine, E.; Dicken, B.; Madsen, K.L. A BACH2 Gene Variant Is Associated with Postoperative Recurrence of Crohn's Disease. J. Am. Coll. Surg. 2018, 226, 902–908. [Google Scholar] [CrossRef]
  18. Cushing, K.C.; Du, X.; Chen, Y.; Stetson, L.C.; Kuppa, A.; Chen, V.L.; Kahlenberg, J.M.; Gudjonsson, J.E.; Vanderwerff, B.; Higgins, P.D.R.; et al. Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer. Inflamm. Bowel Dis. 2022, 28, 1667–1676. [Google Scholar] [CrossRef]
  19. Sasikala, M.; Ravikanth, V.V.; Murali Manohar, K.; Deshpande, N.; Singh, S.; Pavan Kumar, P.; Talukdar, R.; Ghosh, S.; Aslam, M.; Rao, G.V.; et al. Bach2 repression mediates Th17 cell induced inflammation and associates with clinical features of advanced disease in chronic pancreatitis. United Eur. Gastroenterol. J. 2018, 6, 272–282. [Google Scholar] [CrossRef]
  20. Morris, D.L.; Sheng, Y.; Zhang, Y.; Wang, Y.F.; Zhu, Z.; Tombleson, P.; Chen, L.; Cunninghame Graham, D.S.; Bentham, J.; Roberts, A.L.; et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat. Genet. 2016, 48, 940–946. [Google Scholar] [CrossRef]
  21. Afzali, B.; Gronholm, J.; Vandrovcova, J.; O'Brien, C.; Sun, H.W.; Vanderleyden, I.; Davis, F.P.; Khoder, A.; Zhang, Y.; Hegazy, A.N.; et al. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat. Immunol. 2017, 18, 813–823. [Google Scholar] [CrossRef] [PubMed]
  22. Zhou, L.; Sun, G.; Chen, R.; Chen, J.; Fang, S.; Xu, Q.; Tang, W.; Dai, R.; Zhang, Z.; An, Y.; et al. An early-onset SLE patient with a novel paternal inherited BACH2 mutation. J. Clin. Immunol. 2023, 43, 1367–1378. [Google Scholar] [CrossRef] [PubMed]
  23. Ge, Z.; Zhou, X.; Gu, Y.; Han, Q.; Li, J.; Chen, B.; Ge, Q.; Dovat, E.; Payne, J.L.; Sun, T.; et al. Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia. Oncotarget 2017, 8, 8022–8034. [Google Scholar] [CrossRef] [PubMed]
  24. Ciardullo, C.; Szoltysek, K.; Zhou, P.; Pietrowska, M.; Marczak, L.; Willmore, E.; Enshaei, A.; Walaszczyk, A.; Ho, J.Y.; Rand, V.; et al. Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia. Cancers 2021, 14, 23. [Google Scholar] [CrossRef]
  25. Ferreira, M.A.; Matheson, M.C.; Duffy, D.L.; Marks, G.B.; Hui, J.; Le Souëf, P.; Danoy, P.; Baltic, S.; Nyholt, D.R.; Jenkins, M.; et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 2011, 378, 1006–1014. [Google Scholar] [CrossRef] [PubMed]
  26. Cooper, J.D.; Smyth, D.J.; Smiles, A.M.; Plagnol, V.; Walker, N.M.; Allen, J.E.; Downes, K.; Barrett, J.C.; Healy, B.C.; Mychaleckyj, J.C.; et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat. Genet. 2008, 40, 1399–1401. [Google Scholar] [CrossRef] [PubMed]
  27. Marroqui, L.; Santin, I.; Dos Santos, R.S.; Marselli, L.; Marchetti, P.; Eizirik, D.L. BACH2, a candidate risk gene for type 1 diabetes, regulates apoptosis in pancreatic beta-cells via JNK1 modulation and crosstalk with the candidate gene PTPN2. Diabetes 2014, 63, 2516–2527. [Google Scholar] [CrossRef]
  28. Franke, A.; McGovern, D.P.; Barrett, J.C.; Wang, K.; Radford-Smith, G.L.; Ahmad, T.; Lees, C.W.; Balschun, T.; Lee, J.; Roberts, R.; et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 2010, 42, 1118–1125. [Google Scholar] [CrossRef] [PubMed]
  29. Dubois, P.C.; Trynka, G.; Franke, L.; Hunt, K.A.; Romanos, J.; Curtotti, A.; Zhernakova, A.; Heap, G.A.; Adany, R.; Aromaa, A.; et al. Multiple common variants for celiac disease influencing immune gene expression. Nat. Genet. 2010, 42, 295–302. [Google Scholar] [CrossRef]
  30. Jin, Y.; Birlea, S.A.; Fain, P.R.; Ferrara, T.M.; Ben, S.; Riccardi, S.L.; Cole, J.B.; Gowan, K.; Holland, P.J.; Bennett, D.C.; et al. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat. Genet. 2012, 44, 676–680. [Google Scholar] [CrossRef]
  31. Sawcer, S.; Hellenthal, G.; Pirinen, M.; Spencer, C.C.A.; Patsopoulos, N.A.; Moutsianas, L.; Dilthey, A.; Su, Z.; Freeman, C.; Hunt, S.E.; et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011, 476, 214–219. [Google Scholar] [CrossRef] [PubMed]
  32. Igarashi, K.; Ochiai, K.; Itoh-Nakadai, A.; Muto, A. Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network. Immunol. Rev. 2014, 261, 116–125. [Google Scholar] [CrossRef] [PubMed]
  33. McAllister, K.; Yarwood, A.; Bowes, J.; Orozco, G.; Viatte, S.; Diogo, D.; Hocking, L.J.; Steer, S.; Wordsworth, P.; Wilson, A.G.; et al. Identification of BACH2 and RAD51B as rheumatoid arthritis susceptibility loci in a meta-analysis of genome-wide data. Arthritis Rheumatol. 2013, 65, 3058–3062. [Google Scholar] [CrossRef] [PubMed]
  34. Eriksson, D.; Røyrvik, E.C. GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility. Nat. Commun. 2021, 12, 959. [Google Scholar] [CrossRef] [PubMed]
  35. Pazderska, A.; Oftedal, B.E.; Napier, C.M.; Ainsworth, H.F.; Husebye, E.S.; Cordell, H.J.; Pearce, S.H.; Mitchell, A.L. A Variant in the BACH2 Gene Is Associated with Susceptibility to Autoimmune Addison’s Disease in Humans. J. Clin. Endocrinol. Metab. 2016, 101, 3865–3869. [Google Scholar] [CrossRef] [PubMed]
  36. Igarashi, K.; Ochiai, K.; Muto, A. Architecture and dynamics of the transcription factor network that regulates B-to-plasma cell differentiation. J. Biochem. 2007, 141, 783–789. [Google Scholar] [CrossRef] [PubMed]
  37. Ando, R.; Shima, H.; Tamahara, T.; Sato, Y.; Watanabe-Matsui, M.; Kato, H.; Sax, N.; Motohashi, H.; Taguchi, K.; Yamamoto, M.; et al. The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization. J. Biol. Chem. 2016, 291, 1826–1840. [Google Scholar] [CrossRef] [PubMed]
  38. Schroeder, A.R.; Xia, X.; Nguyen, K.; Zhu, F.; Geng, J.; Sialer, D.O.; Hu, H. Bach2 Integrates Cytokine Signals to Arbitrate Differentiation Decisions between T Follicular Helper and Th17 Lineages. J. Immunol. 2023, 211, 1756–1761. [Google Scholar] [CrossRef] [PubMed]
  39. Yao, C.; Lou, G.; Sun, H.-W.; Zhu, Z.; Sun, Y.; Chen, Z.; Chauss, D.; Moseman, E.A.; Cheng, J.; D’Antonio, M.A.; et al. BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+ T cells. Nat. Immunol. 2021, 22, 370–380. [Google Scholar] [CrossRef]
  40. Russ, B.E.; Barugahare, A.; Dakle, P.; Tsyganov, K.; Quon, S.; Yu, B.; Li, J.; Lee, J.K.C.; Olshansky, M.; He, Z.; et al. Active maintenance of CD8+ T cell naivety through regulation of global genome architecture. Cell Rep. 2023, 42, 113301. [Google Scholar] [CrossRef]
  41. Sidwell, T.; Liao, Y.; Garnham, A.L.; Vasanthakumar, A.; Gloury, R.; Blume, J.; Teh, P.P.; Chisanga, D.; Thelemann, C.; de Labastida Rivera, F.; et al. Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis. Nat. Commun. 2020, 11, 252. [Google Scholar] [CrossRef] [PubMed]
  42. Kim, E.H.; Gasper, D.J.; Lee, S.H.; Plisch, E.H.; Svaren, J.; Suresh, M. Bach2 regulates homeostasis of Foxp3+ regulatory T cells and protects against fatal lung disease in mice. J. Immunol. 2014, 192, 985–995. [Google Scholar] [CrossRef] [PubMed]
  43. Miyagawa, Y.; Kiyokawa, N.; Ochiai, N.; Imadome, K.; Horiuchi, Y.; Onda, K.; Yajima, M.; Nakamura, H.; Katagiri, Y.U.; Okita, H.; et al. Ex vivo expanded cord blood CD4 T lymphocytes exhibit a distinct expression profile of cytokine-related genes from those of peripheral blood origin. Immunology 2009, 128, 405–419. [Google Scholar] [CrossRef]
  44. Lesniewski, M.L.; Haviernik, P.; Weitzel, R.P.; Kadereit, S.; Kozik, M.M.; Fanning, L.R.; Yang, Y.C.; Hegerfeldt, Y.; Finney, M.R.; Ratajczak, M.Z.; et al. Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells. Leukemia 2008, 22, 2201–2207. [Google Scholar] [CrossRef] [PubMed]
  45. Zhang, H.; Dai, D.; Hu, Q.; Yang, F.; Xue, Y.; Li, F.; Shen, N.; Zhang, M.; Huang, C. Bach2 attenuates IL-2R signaling to control Treg homeostasis and Tfr development. Cell Rep. 2021, 35, 109096. [Google Scholar] [CrossRef]
  46. Zheng, Y.; Lu, Y.; Huang, X.; Han, L.; Chen, Z.; Zhou, B.; Ma, Y.; Xie, G.; Yang, J.; Bian, B.; et al. BACH2 regulates the function of human CD4+ CD45RA(-) Foxp3(l) degrees cytokine-secreting T cells and promotes B-cell response in systemic lupus erythematosus. Eur. J. Immunol. 2020, 50, 426–438. [Google Scholar] [CrossRef] [PubMed]
  47. Do, J.S.; Zhong, F.; Huang, A.Y.; Van’t Hof, W.J.; Finney, M.; Laughlin, M.J. Foxp3 expression in induced T regulatory cells derived from human umbilical cord blood vs. adult peripheral blood. Bone Marrow Transplant. 2018, 53, 1568–1577. [Google Scholar] [CrossRef]
  48. Hogan, P.G. Calcium-NFAT transcriptional signalling in T cell activation and T cell exhaustion. Cell Calcium 2017, 63, 66–69. [Google Scholar] [CrossRef] [PubMed]
  49. Wu, Y.; Borde, M.; Heissmeyer, V.; Feuerer, M.; Lapan, A.D.; Stroud, J.C.; Bates, D.L.; Guo, L.; Han, A.; Ziegler, S.F.; et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006, 126, 375–387. [Google Scholar] [CrossRef]
  50. Shaulian, E.; Karin, M. AP-1 as a regulator of cell life and death. Nat. Cell Biol. 2002, 4, E131–E136. [Google Scholar] [CrossRef]
  51. Atsaves, V.; Leventaki, V.; Rassidakis, G.Z.; Claret, F.X. AP-1 Transcription Factors as Regulators of Immune Responses in Cancer. Cancers 2019, 11, 1037. [Google Scholar] [CrossRef] [PubMed]
  52. Jang, E.; Lee, H.R.; Lee, G.H.; Oh, A.R.; Cha, J.Y.; Igarashi, K.; Youn, J. Bach2 represses the AP-1-driven induction of interleukin-2 gene transcription in CD4 T cells. BMB Rep. 2017, 50, 472–477. [Google Scholar] [CrossRef] [PubMed]
  53. Zhang, Y.; Zeng, X.; Zha, X.; Lai, J.; Tan, G.; Chen, S.; Yu, X.; Li, Y.; Xu, L. Correlation of the transcription factors IRF4 and BACH2 with the abnormal NFATC1 expression in T cells from chronic myeloid leukemia patients. Hematology 2022, 27, 523–529. [Google Scholar] [CrossRef] [PubMed]
  54. Utzschneider, D.T.; Gabriel, S.S.; Chisanga, D.; Gloury, R.; Gubser, P.M.; Vasanthakumar, A.; Shi, W.; Kallies, A. Early precursor T cells establish and propagate T cell exhaustion in chronic infection. Nat. Immunol. 2020, 21, 1256–1266. [Google Scholar] [CrossRef] [PubMed]
  55. Grant, F.M.; Yang, J.; Nasrallah, R.; Clarke, J.; Sadiyah, F.; Whiteside, S.K.; Imianowski, C.J.; Kuo, P.; Vardaka, P.; Todorov, T.; et al. BACH2 drives quiescence and maintenance of resting Treg cells to promote homeostasis and cancer immunosuppression. J. Exp. Med. 2020, 217, e20190711. [Google Scholar] [CrossRef] [PubMed]
  56. O'Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front. Endocrinol. 2018, 9, 402. [Google Scholar] [CrossRef] [PubMed]
  57. Weitzel, R.P.; Lesniewski, M.L.; Greco, N.J.; Laughlin, M.J. Reduced methyl-CpG protein binding contributing to miR-184 expression in umbilical cord blood CD4+ T-cells. Leukemia 2011, 25, 169–172. [Google Scholar] [CrossRef] [PubMed]
  58. Weitzel, R.P.; Lesniewski, M.L.; Haviernik, P.; Kadereit, S.; Leahy, P.; Greco, N.J.; Laughlin, M.J. microRNA 184 regulates expression of NFAT1 in umbilical cord blood CD4+ T cells. Blood 2009, 113, 6648–6657. [Google Scholar] [CrossRef] [PubMed]
  59. Li, S.; Song, Z.; Dong, J.; Shu, R. microRNA-142 is upregulated by tumor necrosis factor-alpha and triggers apoptosis in human gingival epithelial cells by repressing BACH2 expression. Am. J. Transl. Res. 2017, 9, 175–183. [Google Scholar]
  60. Liu, X.; Su, K.; Kuang, S.; Fu, M.; Zhang, Z. miR-16-5p and miR-145-5p trigger apoptosis in human gingival epithelial cells by down-regulating BACH2. Int. J. Clin. Exp. Pathol. 2020, 13, 901–911. [Google Scholar]
  61. Porstner, M.; Winkelmann, R.; Daum, P.; Schmid, J.; Pracht, K.; Corte-Real, J.; Schreiber, S.; Haftmann, C.; Brandl, A.; Mashreghi, M.F.; et al. miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2. Eur. J. Immunol. 2015, 45, 1206–1215. [Google Scholar] [CrossRef] [PubMed]
  62. Li, Y.; Yu, J.; Wang, F.; Guo, R.; Xing, H.; Chen, Y.; Chen, D.; Xie, X.; Wan, D.; Jiang, Z. MiR-150-5p regulate T cell activation in severe aplastic anemia by targeting Bach2. Cell Tissue Res. 2021, 384, 423–434. [Google Scholar] [CrossRef] [PubMed]
  63. Zhou, J.; Xu, M.; Chen, Z.; Huang, L.; Wu, Z.; Huang, Z.; Liu, L. circ_SPEF2 Regulates the Balance of Treg Cells by Regulating miR-16-5p/BACH2 in Lymphoma and Participates in the Immune Response. Tissue Eng. Regen. Med. 2023, 20, 1145–1159. [Google Scholar] [CrossRef] [PubMed]
  64. Hoshino, H.; Kobayashi, A.; Yoshida, M.; Kudo, N.; Oyake, T.; Motohashi, H.; Hayashi, N.; Yamamoto, M.; Igarashi, K. Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. J. Biol. Chem. 2000, 275, 15370–15376. [Google Scholar] [CrossRef] [PubMed]
  65. Muto, A.; Tashiro, S.; Tsuchiya, H.; Kume, A.; Kanno, M.; Ito, E.; Yamamoto, M.; Igarashi, K. Activation of Maf/AP-1 repressor Bach2 by oxidative stress promotes apoptosis and its interaction with promyelocytic leukemia nuclear bodies. J. Biol. Chem. 2002, 277, 20724–20733. [Google Scholar] [CrossRef] [PubMed]
  66. Tamahara, T.; Ochiai, K.; Muto, A.; Kato, Y.; Sax, N.; Matsumoto, M.; Koseki, T.; Igarashi, K. The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation. Mol. Cell. Biol. 2017, 37, e00418-17. [Google Scholar] [CrossRef] [PubMed]
  67. Zeng, H.; Yang, K.; Cloer, C.; Neale, G.; Vogel, P.; Chi, H. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 2013, 499, 485–490. [Google Scholar] [CrossRef] [PubMed]
  68. Chapman, N.M.; Chi, H. mTOR signaling, Tregs and immune modulation. Immunotherapy 2014, 6, 1295–1311. [Google Scholar] [CrossRef] [PubMed]
  69. Chapman, N.M.; Zeng, H.; Nguyen, T.M.; Wang, Y.; Vogel, P.; Dhungana, Y.; Liu, X.; Neale, G.; Locasale, J.W.; Chi, H. mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis. Nat. Commun. 2018, 9, 2095. [Google Scholar] [CrossRef]
  70. Morita, M.; Gravel, S.P.; Hulea, L.; Larsson, O.; Pollak, M.; St-Pierre, J.; Topisirovic, I. mTOR coordinates protein synthesis, mitochondrial activity and proliferation. Cell Cycle 2015, 14, 473–480. [Google Scholar] [CrossRef]
  71. Jang, K.J.; Mano, H.; Aoki, K.; Hayashi, T.; Muto, A.; Nambu, Y.; Takahashi, K.; Itoh, K.; Taketani, S.; Nutt, S.L.; et al. Mitochondrial function provides instructive signals for activation-induced B-cell fates. Nat. Commun. 2015, 6, 6750. [Google Scholar] [CrossRef] [PubMed]
  72. Tsui, C.; Martinez-Martin, N.; Gaya, M.; Maldonado, P.; Llorian, M.; Legrave, N.M.; Rossi, M.; MacRae, J.I.; Cameron, A.J.; Parker, P.J.; et al. Protein Kinase C-beta Dictates B Cell Fate by Regulating Mitochondrial Remodeling, Metabolic Reprogramming, and Heme Biosynthesis. Immunity 2018, 48, 1144–1159.e1145. [Google Scholar] [CrossRef] [PubMed]
  73. Do, J.S.; Zwick, D.; Kenyon, J.D.; Zhong, F.; Askew, D.; Huang, A.Y.; Van't Hof, W.; Finney, M.; Laughlin, M.J. Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability. Sci. Rep. 2021, 11, 10676. [Google Scholar] [CrossRef] [PubMed]
  74. Michalek, R.D.; Gerriets, V.A.; Jacobs, S.R.; Macintyre, A.N.; MacIver, N.J.; Mason, E.F.; Sullivan, S.A.; Nichols, A.G.; Rathmell, J.C. Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 2011, 186, 3299–3303. [Google Scholar] [CrossRef] [PubMed]
  75. Gerriets, V.A.; Kishton, R.J.; Johnson, M.O.; Cohen, S.; Siska, P.J.; Nichols, A.G.; Warmoes, M.O.; de Cubas, A.A.; MacIver, N.J.; Locasale, J.W.; et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 2016, 17, 1459–1466. [Google Scholar] [CrossRef] [PubMed]
  76. Pompura, S.L.; Wagner, A.; Kitz, A.; LaPerche, J.; Yosef, N.; Dominguez-Villar, M.; Hafler, D.A. Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis. J. Clin. Investig. 2021, 131, e138519. [Google Scholar] [CrossRef] [PubMed]
  77. Patsoukis, N.; Bardhan, K.; Chatterjee, P.; Sari, D.; Liu, B.; Bell, L.N.; Karoly, E.D.; Freeman, G.J.; Petkova, V.; Seth, P.; et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 2015, 6, 6692. [Google Scholar] [CrossRef] [PubMed]
  78. Tan, C.L.; Kuchroo, J.R.; Sage, P.T.; Liang, D.; Francisco, L.M.; Buck, J.; Thaker, Y.R.; Zhang, Q.; McArdel, S.L.; Juneja, V.R.; et al. PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance. J. Exp. Med. 2021, 218, e20182232. [Google Scholar] [CrossRef] [PubMed]
  79. Angelin, A.; Gil-de-Gómez, L.; Dahiya, S.; Jiao, J.; Guo, L.; Levine, M.H.; Wang, Z.; Quinn, W.J.; Kopinski, P.K.; Wang, L.; et al. Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metab. 2017, 25, 1282–1293.e1287. [Google Scholar] [CrossRef]
  80. Chen, Z.; Pittman, E.F.; Romaguera, J.; Fayad, L.; Wang, M.; Neelapu, S.S.; McLaughlin, P.; Kwak, L.; McCarty, N. Nuclear translocation of B-cell-specific transcription factor, BACH2, modulates ROS mediated cytotoxic responses in mantle cell lymphoma. PLoS ONE 2013, 8, e69126. [Google Scholar] [CrossRef]
  81. Tashiro, S.; Muto, A.; Tanimoto, K.; Tsuchiya, H.; Suzuki, H.; Hoshino, H.; Yoshida, M.; Walter, J.; Igarashi, K. Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2. Mol. Cell. Biol. 2004, 24, 3473–3484. [Google Scholar] [CrossRef] [PubMed]
  82. Yu, X.; Lao, Y.; Teng, X.L.; Li, S.; Zhou, Y.; Wang, F.; Guo, X.; Deng, S.; Chang, Y.; Wu, X.; et al. SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation. Nat. Commun. 2018, 9, 3157. [Google Scholar] [CrossRef] [PubMed]
  83. Barbi, J.; Pardoll, D.M.; Pan, F. Ubiquitin-dependent regulation of Foxp3 and Treg function. Immunol. Rev. 2015, 266, 27–45. [Google Scholar] [CrossRef]
  84. Venuprasad, K.; Huang, H.; Harada, Y.; Elly, C.; Subramaniam, M.; Spelsberg, T.; Su, J.; Liu, Y.C. The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat. Immunol. 2008, 9, 245–253. [Google Scholar] [CrossRef] [PubMed]
  85. Yang, J.; Wei, P.; Barbi, J.; Huang, Q.; Yang, E.; Bai, Y.; Nie, J.; Gao, Y.; Tao, J.; Lu, Y.; et al. The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation. EMBO Rep. 2020, 21, e50308. [Google Scholar] [CrossRef]
  86. Cortez, J.T.; Montauti, E.; Shifrut, E.; Gatchalian, J.; Zhang, Y.; Shaked, O.; Xu, Y.; Roth, T.L.; Simeonov, D.R.; Zhang, Y.; et al. CRISPR screen in regulatory T cells reveals modulators of Foxp3. Nature 2020, 582, 416–420. [Google Scholar] [CrossRef] [PubMed]
  87. Loo, C.-S.; Gatchalian, J.; Liang, Y.; Leblanc, M.; Xie, M.; Ho, J.; Venkatraghavan, B.; Hargreaves, D.C.; Zheng, Y. A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function. Immunity 2020, 53, 143–157.e148. [Google Scholar] [CrossRef] [PubMed]
  88. Verma, M.; Michalec, L. The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma. J. Exp. Med. 2021, 218, e20201354. [Google Scholar] [CrossRef] [PubMed]
  89. Zhang, H.; Hu, Q.; Zhang, M.; Yang, F.; Peng, C.; Zhang, Z.; Huang, C. Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity. Front. Immunol. 2019, 10, 2050. [Google Scholar] [CrossRef]
  90. Contreras, A.; Wiesner, D.L.; Kingstad-Bakke, B.; Lee, W.; Svaren, J.P.; Klein, B.S.; Suresh, M. BACH2 in TRegs Limits the Number of Adipose Tissue Regulatory T Cells and Restrains Type 2 Immunity to Fungal Allergens. J. Immunol. Res. 2022, 2022, 6789055. [Google Scholar] [CrossRef]
  91. Fichna, M.; Żurawek, M.; Słomiński, B.; Sumińska, M.; Czarnywojtek, A.; Rozwadowska, N.; Fichna, P.; Myśliwiec, M.; Ruchała, M. Polymorphism in BACH2 gene is a marker of polyglandular autoimmunity. Endocrine 2021. [Google Scholar] [CrossRef] [PubMed]
  92. American Diabetes, A. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes. Diabetes Care 2018, 41, S13–S27. [Google Scholar] [CrossRef]
  93. Kruger, C.; Schallreuter, K.U. A review of the worldwide prevalence of vitiligo in children/adolescents and adults. Int. J. Dermatol. 2012, 51, 1206–1212. [Google Scholar] [CrossRef] [PubMed]
  94. Compston, A.; Coles, A. Multiple sclerosis. Lancet 2008, 372, 1502–1517. [Google Scholar] [CrossRef] [PubMed]
  95. Haase, S.; Linker, R.A. Inflammation in multiple sclerosis. Ther. Adv. Neurol. Disord. 2021, 14, 17562864211007687. [Google Scholar] [CrossRef] [PubMed]
  96. Perga, S.; Montarolo, F.; Martire, S.; Berchialla, P.; Malucchi, S.; Bertolotto, A. Anti-inflammatory genes associated with multiple sclerosis: A gene expression study. J. Neuroimmunol. 2015, 279, 75–78. [Google Scholar] [CrossRef] [PubMed]
  97. Roychoudhuri, R.; Eil, R.L.; Clever, D.; Klebanoff, C.A.; Sukumar, M.; Grant, F.M.; Yu, Z.; Mehta, G.; Liu, H.; Jin, P.; et al. The transcription factor BACH2 promotes tumor immunosuppression. J. Clin. Investig. 2016, 126, 599–604. [Google Scholar] [CrossRef] [PubMed]
  98. Petanidis, S.; Domvri, K.; Porpodis, K.; Anestakis, D.; Freitag, L.; Hohenforst-Schmidt, W.; Tsavlis, D.; Zarogoulidis, K. Inhibition of kras-derived exosomes downregulates immunosuppressive BACH2/GATA-3 expression via RIP-3 dependent necroptosis and miR-146/miR-210 modulation. Biomed. Pharmacother. 2020, 122, 109461. [Google Scholar] [CrossRef] [PubMed]
  99. Li, S.; Bern, M.D.; Miao, B.; Fan, C.; Xing, X.; Inoue, T.; Piersma, S.J.; Wang, T.; Colonna, M.; Kurosaki, T.; et al. The transcription factor Bach2 negatively regulates murine natural killer cell maturation and function. Elife 2022, 11, e77294. [Google Scholar] [CrossRef]
  100. Honaker, Y.; Hubbard, N.; Xiang, Y.; Fisher, L.; Hagin, D.; Sommer, K.; Song, Y.; Yang, S.J.; Lopez, C.; Tappen, T.; et al. Gene editing to induce FOXP3 expression in human CD4+ T cells leads to a stable regulatory phenotype and function. Sci. Transl. Med. 2020, 12, eaay6422. [Google Scholar] [CrossRef]
  101. Lan, Q.; Fan, H.; Quesniaux, V.; Ryffel, B.; Liu, Z.; Zheng, S.G. Induced Foxp3+ regulatory T cells: A potential new weapon to treat autoimmune and inflammatory diseases? J. Mol. Cell Biol. 2012, 4, 22–28. [Google Scholar] [CrossRef] [PubMed]
  102. Hippen, K.L.; Merkel, S.C.; Schirm, D.K.; Nelson, C.; Tennis, N.C.; Riley, J.L.; June, C.H.; Miller, J.S.; Wagner, J.E.; Blazar, B.R. Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease. Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg. 2011, 11, 1148–1157. [Google Scholar] [CrossRef] [PubMed]
  103. Zhang, P.; Tey, S.K.; Koyama, M.; Kuns, R.D.; Olver, S.D.; Lineburg, K.E.; Lor, M.; Teal, B.E.; Raffelt, N.C.; Raju, J.; et al. Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo. J. Immunol. 2013, 191, 5291–5303. [Google Scholar] [CrossRef] [PubMed]
  104. Battaglia, M.; Stabilini, A.; Roncarolo, M.G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005, 105, 4743–4748. [Google Scholar] [CrossRef]
  105. Araki, K.; Turner, A.P.; Shaffer, V.O.; Gangappa, S.; Keller, S.A.; Bachmann, M.F.; Larsen, C.P.; Ahmed, R. mTOR regulates memory CD8 T-cell differentiation. Nature 2009, 460, 108–112. [Google Scholar] [CrossRef] [PubMed]
  106. Kanamori, M.; Nakatsukasa, H.; Okada, M.; Lu, Q.; Yoshimura, A. Induced Regulatory T Cells: Their Development, Stability, and Applications. Trends Immunol. 2016, 37, 803–811. [Google Scholar] [CrossRef] [PubMed]
  107. Tanaka, H.; Muto, A.; Shima, H.; Katoh, Y.; Sax, N.; Tajima, S.; Brydun, A.; Ikura, T.; Yoshizawa, N.; Masai, H.; et al. Epigenetic Regulation of the Blimp-1 Gene (Prdm1) in B Cells Involves Bach2 and Histone Deacetylase 3. J. Biol. Chem. 2016, 291, 6316–6330. [Google Scholar] [CrossRef]
  108. Hu, Q.; Xu, T.; Zhang, W.; Huang, C. Bach2 regulates B cell survival to maintain germinal centers and promote B cell memory. Biochem. Biophys. Res. Commun. 2022, 618, 86–92. [Google Scholar] [CrossRef]
  109. Son, J.; Ding, H.; Farb, T.B.; Efanov, A.M.; Sun, J.; Gore, J.L.; Syed, S.K.; Lei, Z.; Wang, Q.; Accili, D.; et al. BACH2 inhibition reverses beta cell failure in type 2 diabetes models. J. Clin. Investig. 2021, 131, e153876. [Google Scholar] [CrossRef]
  110. Xiong, E.; Popp, O.; Salomon, C.; Mertins, P.; Kocks, C.; Rajewsky, K.; Chu, V.T. A CRISPR/Cas9-mediated screen identifies determinants of early plasma cell differentiation. Front. Immunol. 2022, 13, 1083119. [Google Scholar] [CrossRef]
  111. Vardaka, P.; Lozano, T.; Bot, C.; Ellery, J.; Whiteside, S.K.; Imianowski, C.J.; Farrow, S.; Walker, S.; Okkenhaug, H.; Yang, J.; et al. A cell-based bioluminescence assay reveals dose-dependent and contextual repression of AP-1-driven gene expression by BACH2. Sci. Rep. 2020, 10, 18902. [Google Scholar] [CrossRef]
  112. Mouri, K.; Guo, M.H.; de Boer, C.G.; Lissner, M.M.; Harten, I.A.; Newby, G.A.; DeBerg, H.A.; Platt, W.F.; Gentili, M.; Liu, D.R.; et al. Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells. Nat. Genet. 2022, 54, 603–612. [Google Scholar] [CrossRef]
Cells 13 00891 g001
Figure 1. BACH2 structure and mutations. The domain structure of BACH2 is shown, along with the location and effects of known disease-associated mutations and experimental mutations.
Figure 1. BACH2 structure and mutations. The domain structure of BACH2 is shown, along with the location and effects of known disease-associated mutations and experimental mutations.
Cells 13 00891 g001
Cells 13 00891 g002
Figure 2. BACH2 regulates T-cell activation. T-cell receptor (TCR) engagement leads to phosphorylation of signaling molecules and the nuclear translocation of BACH2 and other transcription factors that regulate gene expression and T-cell activation. Metabolic status and other inputs regulate BACH2 localization and function. Inhibitors of the different steps of signal transduction pursued to stabilize iTreg phenotype and function are shown. The off-target effects of inhibiting HDACs and other pleiotropic factors raise the need for new, more targeted approaches. BACH2 is central to iTreg stability, regulating transcriptional responses to multiple signaling inputs. The further elucidation of the iTreg-specific roles of BACH2 should enable the identification of more targeted approaches to iTreg stabilization.
Figure 2. BACH2 regulates T-cell activation. T-cell receptor (TCR) engagement leads to phosphorylation of signaling molecules and the nuclear translocation of BACH2 and other transcription factors that regulate gene expression and T-cell activation. Metabolic status and other inputs regulate BACH2 localization and function. Inhibitors of the different steps of signal transduction pursued to stabilize iTreg phenotype and function are shown. The off-target effects of inhibiting HDACs and other pleiotropic factors raise the need for new, more targeted approaches. BACH2 is central to iTreg stability, regulating transcriptional responses to multiple signaling inputs. The further elucidation of the iTreg-specific roles of BACH2 should enable the identification of more targeted approaches to iTreg stabilization.
Cells 13 00891 g002
Cells 13 00891 g003
Figure 3. BACH2, AP-1 and NFAT consensus recognition sites in FOXP3 promoter. The overlap of BACH2 consensus binding sites with those of AP-1 (indicated by underline) and NFAT1 (indicated in gray) is shown. Competition between BACH2 and these transcription factors for binding sites in the FOXP3 promoter may regulate FOXP3 transcriptional stabilization.
Figure 3. BACH2, AP-1 and NFAT consensus recognition sites in FOXP3 promoter. The overlap of BACH2 consensus binding sites with those of AP-1 (indicated by underline) and NFAT1 (indicated in gray) is shown. Competition between BACH2 and these transcription factors for binding sites in the FOXP3 promoter may regulate FOXP3 transcriptional stabilization.
Cells 13 00891 g003
Cells 13 00891 g004
Figure 4. Mechanisms regulating BACH2 function. BACH2 integrates diverse metabolic and signaling inputs and mediates transcriptional responses controlling Treg stability and cell fate.
Figure 4. Mechanisms regulating BACH2 function. BACH2 integrates diverse metabolic and signaling inputs and mediates transcriptional responses controlling Treg stability and cell fate.
Cells 13 00891 g004
Table 1. Conditions associated with BACH2 variants and altered functions.
Table 1. Conditions associated with BACH2 variants and altered functions.
DiseaseBACH2 MutationRole of BACH2 in DiseaseReference
Inflammatory Bowel SyndromeBACH2 promoter methylationAffects IgG glycosylation associated with IBS[16]
Crohn’s Disease, IBS and Non-melanoma skin cancerBACH2 variant, SNP intron variant and genic upstream transcript variantAssociated with post-operative recurrence of Crohn’s Disease[17,18]
Chronic pancreatitisBACH2 associated with protectionBACH2 repression associated with features of advanced disease[19]
Systemic lupus erythematosusSNP rs597325Associated with SLE[20]
BRIDAT71C, G2362A G1727TBACH2 related immunodeficiency[21,22]
LeukemiaBACH2 associated with incidence, genome wide association studies, and SNPsLow expression associated with poor overall survival[23,24]
AsthmaSNP associated with disease risk[25]
Type 1 Diabetes (T1D)[26,27]
Crohn’s and Celiac’s disease[28,29]
Vitiligo[30]
MS[31,32]
Rhumatoid Arthritis[33]
Addison’s Disease[34,35]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Zwick, D.; Vo, M.T.; Shim, Y.J.; Reijonen, H.; Do, J.-s. BACH2: The Future of Induced T-Regulatory Cell Therapies. Cells 2024, 13, 891. https://doi.org/10.3390/cells13110891

AMA Style

Zwick D, Vo MT, Shim YJ, Reijonen H, Do J-s. BACH2: The Future of Induced T-Regulatory Cell Therapies. Cells. 2024; 13(11):891. https://doi.org/10.3390/cells13110891

Chicago/Turabian Style

Zwick, Daniel, Mai Tram Vo, Young Jun Shim, Helena Reijonen, and Jeong-su Do. 2024. "BACH2: The Future of Induced T-Regulatory Cell Therapies" Cells 13, no. 11: 891. https://doi.org/10.3390/cells13110891

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop