BACH2: The Future of Induced T-Regulatory Cell Therapies

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2024 Jun 19

PMID 38891024

Authors

Daniel Zwick

Mai Tram Vo

Young Jun Shim

Helena Reijonen

Jeong-Su Do

Affiliations

Soon will be listed here.

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.

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References

Morita M, Gravel S, Hulea L, Larsson O, Pollak M, St-Pierre J . mTOR coordinates protein synthesis, mitochondrial activity and proliferation. Cell Cycle. 2015; 14(4):473-80. PMC: 4615141. DOI: 10.4161/15384101.2014.991572. View

Barbi J, Pardoll D, Pan F . Ubiquitin-dependent regulation of Foxp3 and Treg function. Immunol Rev. 2015; 266(1):27-45. PMC: 4930875. DOI: 10.1111/imr.12312. View

Son J, Ding H, Farb T, Efanov A, Sun J, Gore J . BACH2 inhibition reverses β cell failure in type 2 diabetes models. J Clin Invest. 2021; 131(24). PMC: 8670842. DOI: 10.1172/JCI153876. View

Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan A, Stroud J . FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 2006; 126(2):375-87. DOI: 10.1016/j.cell.2006.05.042. View

Hoshino H, Kobayashi A, Yoshida M, Kudo N, Oyake T, Motohashi H . Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. J Biol Chem. 2000; 275(20):15370-6. DOI: 10.1074/jbc.275.20.15370. View

Ferreira M, Matheson M, Duffy D, Marks G, Hui J, Le Souef P . Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet. 2011; 378(9795):1006-14. PMC: 3517659. DOI: 10.1016/S0140-6736(11)60874-X. View

Lourenco E, La Cava A . Natural regulatory T cells in autoimmunity. Autoimmunity. 2010; 44(1):33-42. PMC: 3057884. DOI: 10.3109/08916931003782155. View

Laffin M, Fedorak R, Wine E, Dicken B, Madsen K . A BACH2 Gene Variant Is Associated with Postoperative Recurrence of Crohn's Disease. J Am Coll Surg. 2018; 226(5):902-908. DOI: 10.1016/j.jamcollsurg.2018.01.052. View

Lesniewski M, Haviernik P, P Weitzel R, Kadereit S, Kozik M, Fanning L . Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells. Leukemia. 2008; 22(12):2201-7. DOI: 10.1038/leu.2008.234. View

10.

Miyagawa Y, Kiyokawa N, Ochiai N, Imadome K, Horiuchi Y, Onda K . Ex vivo expanded cord blood CD4 T lymphocytes exhibit a distinct expression profile of cytokine-related genes from those of peripheral blood origin. Immunology. 2010; 128(3):405-19. PMC: 2770688. DOI: 10.1111/j.1365-2567.2009.03122.x. View

11.

Zhang H, Hu Q, Zhang M, Yang F, Peng C, Zhang Z . Bach2 Deficiency Leads to Spontaneous Expansion of IL-4-Producing T Follicular Helper Cells and Autoimmunity. Front Immunol. 2019; 10:2050. PMC: 6737000. DOI: 10.3389/fimmu.2019.02050. View

12.

Kruger C, Schallreuter K . A review of the worldwide prevalence of vitiligo in children/adolescents and adults. Int J Dermatol. 2012; 51(10):1206-12. DOI: 10.1111/j.1365-4632.2011.05377.x. View

13.

Tan C, Kuchroo J, Sage P, Liang D, Francisco L, Buck J . PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance. J Exp Med. 2020; 218(1). PMC: 7543091. DOI: 10.1084/jem.20182232. View

14.

Chapman N, Chi H . mTOR signaling, Tregs and immune modulation. Immunotherapy. 2014; 6(12):1295-311. PMC: 4291176. DOI: 10.2217/imt.14.84. View

15.

Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell L . PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015; 6:6692. PMC: 4389235. DOI: 10.1038/ncomms7692. View

16.

Cushing K, Du X, Chen Y, Stetson L, Kuppa A, Chen V . Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer. Inflamm Bowel Dis. 2022; 28(11):1667-1676. PMC: 9924040. DOI: 10.1093/ibd/izab336. View

17.

Weitzel R, Lesniewski M, Haviernik P, Kadereit S, Leahy P, Greco N . microRNA 184 regulates expression of NFAT1 in umbilical cord blood CD4+ T cells. Blood. 2009; 113(26):6648-57. PMC: 2710921. DOI: 10.1182/blood-2008-09-181156. View

18.

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. Mediators Inflamm. 2020; 2019:2609737. PMC: 7012215. DOI: 10.1155/2019/2609737. View

19.

Sidwell T, Liao Y, Garnham A, Vasanthakumar A, Gloury R, Blume J . Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis. Nat Commun. 2020; 11(1):252. PMC: 6959360. DOI: 10.1038/s41467-019-14112-2. View

20.

Araki K, Turner A, Shaffer V, Gangappa S, Keller S, Bachmann M . mTOR regulates memory CD8 T-cell differentiation. Nature. 2009; 460(7251):108-12. PMC: 2710807. DOI: 10.1038/nature08155. View