THE GATA-3 TRANSCRIPTION FACTOR IS CRUCIAL FOR THE IMMUNE RESPONSE

M. Di Gioacchino^* and L. Speranza

Department of Medicine and Ageing Sciences, University “G. D’Annunzio”, Chieti, Italy.

*Correspondence to:
Mario Di Gioacchino, MD,
Department of Medicine and Ageing Sciences,
“G’ d’Annunzio” University,
66100 Chieti, Italy.
e-mail: digioacchino@me.com

ABSTRACT
T cell differentiation into subtypes is mediated by GATAs, particularly GATA-binding protein 3 (GATA-3), along with T-bet, RORγt, FOXP3, and others. GATAs are transcription factors 1 to 6 that bind to GATA-DNA sequences, regulating differentiation, development, and cell identity. GATAs are important for the immune system, tumors, and the differentiation of CD4⁺ T cells. GATA-2 and GATA-3 are crucial for the development of neurons in the central nervous system (CNS). GATA-2 and GATA-3 play an important role in embryonic brain development and the formation of GABAergic neurons, and GATA-2 deficiency can lead to neuronal defects. GATA-3 mediates the development of the sympathetic nervous system, the maturation of some sensory neurons, and the differentiation of noradrenergic neurons. Anti-GATA agents such as SB010, a novel DNA enzyme capable of cleaving GATA-3 mRNA, may be useful in the treatment of diseases in which Th2 cells are inactive.

KEYWORDS: GATA-3, GATA-binding protein, T cell, transcription factor, cell differentiation

INTRODUCTION

Murine type 1 helper T lymphocytes (Th1) and type 2 helper T lymphocytes (Th2) (derived from Th cells), were discovered in 1986 by Robert Coffman and Timothy Mossman, on the basis of cytokine production (1). Subsequently, T cells underwent further division into Th9, Th17, Th22, Treg, and follicular helper T cells (2). The factor that drives the differentiation of these T cell subtypes is GATA-binding protein 3 (GATA-3), along with T-bet, RORγt, and FOXP3, amongst others (3).

GATAs are transcription factors ranging from GATA-1 to GATA-6 that bind to GATA DNA sequences, regulating differentiation, development, and cell identity (4). GATA-2 and GATA-3 are primary members of the GATA transcription factor family expressed in the central nervous system (CNS), where they regulate neuronal identity, survival, and differentiation (5). GATA-2 is important in the embryonic development of the CNS, where it is involved in neuronal specification, particularly in the spinal cord and autonomic nervous system, while GATA-3 is crucial for the peripheral CNS, especially for the development of sympathetic and sensory neurons (5).

GATA-3 is involved in embryonic development and the functioning of several tissues (6).  For example, it is implicated in the pathophysiology of immune cells, and cells of the breast and urinary tract (7). In breast cancer, GATA-3 is a marker and may have prognostic implications, while in the immune system, it is a transcription factor that is crucial for the development and function of specific cell subtypes, particularly Th2 (8).

GATA-3 promotes the differentiation of CD4⁺ T cells and regulates the expression of several cytokines, such as IL-4, IL-5, and IL-13 (9). These cytokines are produced mainly by Th2 lymphocytes and play a fundamental role in the allergic immune response and the response against extracellular parasites such as helminths (10).  IL-4 functions mainly in promoting the differentiation of naïve T lymphocytes into Th2 and stimulating B cells; it is fundamental in the production of immunoglobulins. IL-4 is involved in the expression of major histocompatibility complex II (MHC II) molecules and mediates allergic processes (11). The main function of IL-5 is to participate in the differentiation, activation and survival of eosinophils. It contributes to the defense against helminths and stimulates the production of mucus in allergic diseases (12). IL-13 has an action similar to IL-4, participating in the production of IgE, tissue remodeling, fibrosis, bronchial allergic hyperreactivity, and mucus production. GATA-3 inhibits the development of Th1 cells by suppressing T-bet (by reducing the TBX21 gene), which is the master regulator of Th1 cells responsible for the expression of interferon gamma (IFN-γ) (13). GATA-3 and T-bet can compete for common transcription factors or for DNA binding (14).  The balance between GATA-3 and T-bet determines the direction of the immune response. GATA-3 is also expressed in non-T cells, such as some types of epithelial cells, innate lymphoid cells type 2 (ILC2), and the thymus during maturation (15).

DISCUSSION

GATA-2 and GATA-3 are the most relevant transcription factors for the CNS and play an important role in embryonic brain development and the formation of GABAergic neurons (16). A deficiency in GATA-2 can lead to neuronal defects (17).  GATA-3 is important for the development of the sympathetic nervous system, the maturation of some other cells, and the differentiation of noradrenergic neurons (18). Mutated GATA-3 genes can lead to a transcriptional defect in Th2 cells and the development of sensory neurons, resulting in deafness (19).  GATA-3 is only expressed intracellularly and can be crucial for generating an effective immune response against microorganisms.

GATA-3 may be a therapeutic target for several diseases, including chronic infectious diseases (20).  In infectious processes, such as parasitic diseases, GATA-3-mediated Th2 responses are protective. GATA-3-activated cytokines, including IL-4, IL-5, and IL-13, help recruit eosinophils, stimulate IgE production, and increase mucus secretion and intestinal motility (21). GATA-3 is crucial for an effective response against pathogens. In viral and bacterial infections, a Th1 response occurs first, followed by a Th17 response (22,23). The Th17 immune response is adaptive and is mediated by a subpopulation of CD4^⁺ Th cells called Th17 (24).

Excessive production of GATA-3 can be harmful, as it suppresses Th1 responses, reducing the production of IFN-γ, which is essential for eliminating intracellular viruses and bacteria (25). GATA-3 is also expressed in ILC2s, which are important in viral respiratory infections where they promote tissue repair and mucus production (26). ILC2s can also promote allergic inflammation (27).

Treatment with anti-GATA (such as SB010, a novel DNA enzyme that can cleave GATA-3 mRNA) could be useful in the treatment of diseases where Th2 cells are inactive or involved in an ineffective response (28). GATA-3 is a therapeutic target represented by anti-GATA-3, which may be useful in allergic diseases such as asthma and atopic dermatitis (29).

GATA-3 is important in Th1 cellular immunity and Th2 humoral immunity (30). Th1 immunity involves the activation of macrophages against intracellular pathogens and the activation of IFN-g (31). GATA-3 mediates the Th2 response and therefore, humoral immunity. Th2 immunity involves the activation of antibodies, eosinophils, and mast cells against parasites (32). GATA-3 is involved in the differentiation of Th2 cells, such as naïve CD4^⁺ lymphocytes, and inhibits the Th1 fate (33). The most representative cytokines induced by GATA-3 are IL-4, IL-5, and IL-13 (34). These cytokines stimulate the production of antibodies, such as IgE and IgG4, in B lymphocytes and plasma cells, and activate mast cells in their involvement in parasitic and allergic diseases.

At the molecular level, GATA-3 begins with the activation of IL-4, which binds to T cells through its type II receptor, consisting of the IL-4Rα subunit and the IL-13Rα1 subunit (35). This activates the JAK–STAT pathway and STAT6 enters the nucleus and induces GATA-3 expression through a positive feedback loop; GATA-3 induces an increase in IL-4, which induces an increase in GATA-3.

GATA-3 also acts on DNA, where it binds to GATA sequences in the promoters/enhancers of IL-4, 5, and 13, recruiting transcriptional coactivators, such as p300/CBP (36). Another important effect of GATA-3 is to induce the acetylation of sarcomas, stabilizing the Th2 locus in an active state and making Th2 differentiation irreversible (25). GATA-3 inhibits cellular immunity by repressing T-bet, a crucial factor for Th1 lymphocytes. It also inhibits IFN-γ and the Th1 cellular response. It participates in the humoral response through cytokines IL-4 and IL-13, in the production of IgE released by B lymphocytes (Fig.1).

Fig. 1. When IL-4 binds its type II receptor, Th1 cells are activated to produce cytokines that activate cells involved in allergic disease. The binding of IL-4 to its type II receptor also activates the JAK-STAT pathway cascade that results in allergy.

CONCLUSIONS

GATAs are transcription factors that regulate cell differentiation, development, and identity. GATA-2 and GATA-3 are expressed in the CNS, where they regulate neuronal survival and differentiation. GATA-2 is important in embryonic CNS development, where it is involved in neuronal specification, while GATA-3 is crucial for the peripheral CNS and the development of sympathetic and sensory neurons. Recently, anti-GATA (such as SB010, a novel DNA enzyme capable of cleaving GATA-3 mRNA) has been shown to be effective in the treatment of GATA-3-mediated Th2 diseases.

GATA-3 also regulates the expression of cytokines, including IL-4, IL-5, and IL-13, produced mainly by Th2 lymphocytes. These cytokines play a crucial role in the allergic immune response, promoting the differentiation of naïve T lymphocytes into Th2 and stimulating B cells, producing immunoglobulins, expressing MHC II, and participating in differentiation.

Conflict of interest

The authors declare that they have no conflict of interest.

REFERENCES

1. Bluestone JA, Mackay CR, O’Shea JJ, Stockinger B. The functional plasticity of T cell subsets. Nature Reviews Immunology. 2009;9(11):811-816. doi:https://doi.org/10.1038/nri2654
2. Wang W, Sung N, Gilman-Sachs A, Kwak-Kim J. T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells. Frontiers in Immunology. 2020;11. doi:https://doi.org/10.3389/fimmu.2020.02025
3. Ozgur BA, Cinar SA, Coskunpinar E, et al. The role of cytokines and T-bet, GATA3, ROR-γt, and FOXP3 transcription factors of T cell subsets in the natural clinical progression of Type 1 Diabetes. Immunologic Research. 2023;71(3):451-462. doi:https://doi.org/10.1007/s12026-022-09355-z
4. Nakagawa R, Sakai Y, Takashima A, Terada T, Kobayashi A, Maeda M. GATA DNA-Binding Protein Expressed in Mouse I-10 Leydig Testicular Tumor Cells. Biochemical and Biophysical Research Communications. 2001;283(2):412-416. doi:https://doi.org/10.1006/bbrc.2001.4802
5. Bellomi F, Caturano C, Velardi V, et al. GATA Transcription Factors: A Cross‐Road for Erythropoiesis, Neurodevelopment, and Synucleinopathies. Developmental Neurobiology. 2025;85(3). doi:https://doi.org/10.1002/dneu.22975
6. Kouros-Mehr H, Kim J, Bechis SK, Werb Z. GATA-3 and the regulation of the mammary luminal cell fate. Current Opinion in Cell Biology. 2008;20(2):164-170. doi:https://doi.org/10.1016/j.ceb.2008.02.003
7. Usary J, Llaca V, Karaca G, et al. Mutation of GATA3 in human breast tumors. Oncogene. 2004;23(46):7669-7678. doi:https://doi.org/10.1038/sj.onc.1207966
8. Alberto, Cláudio Vinícius Brito, Levy D, et al. Diagnostic and prognostic implications of tumor expression of the GATA-3 gene in nodal peripheral T-cell lymphoma (nPTCL): Retrospective data from a Latin American cohort. Leukemia research. 2022;114:106794-106794. doi:https://doi.org/10.1016/j.leukres.2022.106794
9. Zhou M, Ouyang W, Gong Q, et al. Friend of GATA-1 Represses GATA-3–dependent Activity in CD4+ T Cells. The Journal of Experimental Medicine. 2001;194(10):1461-1471. doi:https://doi.org/10.1084/jem.194.10.1461
10. Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. Journal of Allergy and Clinical Immunology. 2015;135(3):626-635. doi:https://doi.org/10.1016/j.jaci.2014.11.001
11. Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB, Estes DM. Estrogen Receptor α (ERα) Deficiency in Macrophages Results in Increased Stimulation of CD4⁺T Cells while 17β-Estradiol Acts through ERα to Increase IL-4 and GATA-3 Expression in CD4⁺T Cells Independent of Antigen Presentation. The Journal of Immunology. 2005;175(9):5716-5723. doi:https://doi.org/10.4049/jimmunol.175.9.5716
12. Watanabe N, Tamauchi H, Ozawa H, Ito M, Ovary Z, Habu S. Th2 Immune Responses in GATA-3-Transgenic Mice Infected with Heligmosomoides polygyrus. International Archives of Allergy and Immunology. 2003;131(Suppl. 1):11-14. doi:https://doi.org/10.1159/000070475
13. Mehdi SJ, Moerman-Herzog A, Wong HK. Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma. BMC Cancer. 2021;21(1). doi:https://doi.org/10.1186/s12885-021-08142-7
14. Chen GY, Osada H, Santamaria-Babi LF, Reiji Kannagi. Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes. Proceedings of the National Academy of Sciences. 2006;103(45):16894-16899. doi:https://doi.org/10.1073/pnas.0607926103
15. Callender LA, Schroth J, Carroll EC, et al. GATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage. Nature Communications. 2021;12(1). doi:https://doi.org/10.1038/s41467-021-23715-7
16. Nardelli J, Thiesson D, Fujiwara Y, Tsai FY, Orkin SH. Expression and Genetic Interaction of Transcription Factors GATA-2 and GATA-3 during Development of the Mouse Central Nervous System. Developmental Biology. 1999;210(2):305-321. doi:https://doi.org/10.1006/dbio.1999.9278
17. Khalfallah O, Faucon-Biguet N, Nardelli J, Meloni R, Mallet J. Expression of the transcription factor Zfp191 during embryonic development in the mouse. Gene Expression Patterns. 2008;8(3):148-154. doi:https://doi.org/10.1016/j.gep.2007.11.002
18. Hoene V, Fischer M, Ivanova A, Wallach T, Berthold F, Dame C. GATA factors in human neuroblastoma: distinctive expression patterns in clinical subtypes. British Journal of Cancer. 2009;101(8):1481-1489. doi:https://doi.org/10.1038/sj.bjc.6605276
19. Koboldt DC, Fulton RS, McLellan MD, et al. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. doi:https://doi.org/10.1038/nature11412
20. Zou X, Wang K, Deng Y, et al. Hypoxia-inducible factor 2α promotes pathogenic polarization of stem-like Th2 cells via modulation of phospholipid metabolism. Immunity. 2024;57(12):2808-2826.e8. doi:https://doi.org/10.1016/j.immuni.2024.11.001
21. Zhu J. T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production. Cytokine. 2015;75(1):14-24. doi:https://doi.org/10.1016/j.cyto.2015.05.010
22. Kanhere A, Hertweck A, Bhatia U, et al. T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nature Communications. 2012;3(1). doi:https://doi.org/10.1038/ncomms2260
23. Chen XD, Xie J, Wei Y, et al. Immune modulation of Th1/Th2/Treg/Th17/Th9/Th21 cells in rabbits infected with Eimeria stiedai. Frontiers in Cellular and Infection Microbiology. 2023;13. doi:https://doi.org/10.3389/fcimb.2023.1230689
24. Levine AG, Mendoza A, Hemmers S, et al. Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature. 2017;546(7658):421-425. doi:https://doi.org/10.1038/nature22360
25. Hertweck A, Vila M, Barber PH, et al. The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes. Nucleic Acids Research. 2022;50(8):4557-4573. doi:https://doi.org/10.1093/nar/gkac258
26. Stockis J, Yip T, Moreno-Vicente J, et al. Cross-talk between ILC2 and Gata3 ^high T _regs locally constrains adaptive type 2 immunity. Science Immunology. 2024;9(97). doi:https://doi.org/10.1126/sciimmunol.adl1903
27. Liu J, Jiang X, Li L, et al. Iloprost inhibits acute allergic nasal inflammation by GATA3 -ILC2 pathway in mice. Respiratory Physiology & Neurobiology. 2020;276:103364. doi:https://doi.org/10.1016/j.resp.2019.103364
28. Krug N, Hohlfeld JM, Kirsten AM, et al. Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme. New England Journal of Medicine. 2015;372(21):1987-1995. doi:https://doi.org/10.1056/nejmoa1411776
29. Anna Maria Cesinaro, Lonardi S, Fabio Facchetti. Granuloma Faciale. ˜The œAmerican journal of surgical pathology. 2013;37(1):66-73. doi:https://doi.org/10.1097/pas.0b013e318271efd0
30. Zhou M, Ouyang W. The Function Role of GATA-3 in Th1 and Th2 Differentiation. Immunologic Research. 2003;28(1):25-38. doi:https://doi.org/10.1385/ir:28:1:25
31. Ferber I, Lee H, Zonin F, et al. GATA-3 Significantly Downregulates IFN-γ Production from Developing Th1 Cells in Addition to Inducing IL-4 and IL-5 Levels. Clin Immunol. 1999;91(2):134-144. doi:https://doi.org/10.1006/clim.1999.4718
32. Affinass N, Zhang H, Löhning M, Hartmann S, Rausch S. Manipulation of the balance between Th2 and Th2/1 hybrid cells affects parasite nematode fitness in mice. European Journal of Immunology. 2018;48(12):1958-1964. doi:https://doi.org/10.1002/eji.201847639
33. Liu D, He L, Ding N, et al. Bronchial epithelial cells of young and old mice directly regulate the differentiation of Th2 and Th17. Bioscience Reports. 2019;39(2). doi:https://doi.org/10.1042/bsr20181948
34. Tindemans I, Serafini N, Di Santo James P, Hendriks Rudi W. GATA-3 Function in Innate and Adaptive Immunity. Immunity. 2014;41(2):191-206. doi:https://doi.org/10.1016/j.immuni.2014.06.006
35. Cui W, Nagano Y, Morita S, et al. Diet-mediated constitutive induction of novel IL-4+ ILC2 cells maintains intestinal homeostasis in mice. Journal of Experimental Medicine. 2023;220(8). doi:https://doi.org/10.1084/jem.20221773
36. Qiang Z, Ibrahim Jubber, Lloyd K, Cumberbatch M, Griffin J. Gene of the month: GATA3. Journal of Clinical Pathology. 2023;76(12):793-797. doi:https://doi.org/10.1136/jcp-2023-209017