Differentiation, Functions, and Roles of T Follicular Regulatory Cells in Autoimmune Diseases

Overview

Journal Inflamm Regen

Publisher Biomed Central

Date 2021 May 3

PMID 33934711

Citations 13

Authors

He Hao

Shingo Nakayamada

Yoshiya Tanaka

Affiliations

Soon will be listed here.

Abstract

T follicular helper cells participate in stimulating germinal center (GC) formation and supporting B cell differentiation and autoantibody production. However, T follicular regulatory (Tfr) cells suppress B cell activation. Since changes in the number and functions of Tfr cells lead to dysregulated GC reaction and autoantibody response, targeting Tfr cells may benefit the treatment of autoimmune diseases. Differentiation of Tfr cells is a multistage and multifactorial process with various positive and negative regulators. Therefore, understanding the signals regulating Tfr cell generation is crucial for the development of targeted therapies. In this review, we discuss recent studies that have elucidated the roles of Tfr cells in autoimmune diseases and investigated the modulators of Tfr cell differentiation. Additionally, potential immunotherapies targeting Tfr cells are highlighted.

Citing Articles

Analysis of effector/memory regulatory T cells from arrhythmogenic cardiomyopathy patients identified IL-32 as a novel player in ACM pathogenesis.

Soussi S, Maione A, Lefevre L, Pizzinat N, Iacovoni J, Gonzalez-Fuentes I Cell Death Dis. 2025; 16(1):87.

PMID: 39934117 PMC: 11814135. DOI: 10.1038/s41419-025-07364-y.

T follicular helper cell is essential for M2 macrophage polarization and pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension.

Li C, Liu P, Zhu H, Yang H, Zha J, Yao H Respir Res. 2024; 25(1):428.

PMID: 39633343 PMC: 11619207. DOI: 10.1186/s12931-024-03058-9.

Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function.

Gootjes C, Zwaginga J, Roep B, Nikolic T Cells. 2024; 13(11.

PMID: 38891073 PMC: 11172350. DOI: 10.3390/cells13110941.

Diphtheria toxin-derived, anti-PD-1 immunotoxin, a potent and practical tool to selectively deplete PD-1 cells.

Zhang T, Dong S, Zhai Y, Naatz L, Zhou Z, Chen M Protein Sci. 2023; 32(9):e4741.

PMID: 37515422 PMC: 10443333. DOI: 10.1002/pro.4741.

Immune Phenotype as a Biomarker for Systemic Lupus Erythematosus.

Nakayamada S, Tanaka Y Biomolecules. 2023; 13(6).

PMID: 37371540 PMC: 10295858. DOI: 10.3390/biom13060960.

References

Cobb D, Kim O, Golden-Mason L, Rosen H, Hahn Y . Hepatocyte-derived exosomes promote T follicular regulatory cell expansion during hepatitis C virus infection. Hepatology. 2017; 67(1):71-85. PMC: 5739980. DOI: 10.1002/hep.29409. View

Xu Y, Xu H, Zhen Y, Sang X, Wu H, Hu C . Imbalance of Circulatory T Follicular Helper and T Follicular Regulatory Cells in Patients with ANCA-Associated Vasculitis. Mediators Inflamm. 2019; 2019:8421479. PMC: 6914973. DOI: 10.1155/2019/8421479. View

Hiramatsu Y, Suto A, Kashiwakuma D, Kanari H, Kagami S, Ikeda K . c-Maf activates the promoter and enhancer of the IL-21 gene, and TGF-beta inhibits c-Maf-induced IL-21 production in CD4+ T cells. J Leukoc Biol. 2010; 87(4):703-12. DOI: 10.1189/jlb.0909639. View

Vaeth M, Eckstein M, Shaw P, Kozhaya L, Yang J, Berberich-Siebelt F . Store-Operated Ca(2+) Entry in Follicular T Cells Controls Humoral Immune Responses and Autoimmunity. Immunity. 2016; 44(6):1350-64. PMC: 4917422. DOI: 10.1016/j.immuni.2016.04.013. View

Botta D, Fuller M, Marquez-Lago T, Bachus H, Bradley J, Weinmann A . Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol. 2017; 18(11):1249-1260. PMC: 5679073. DOI: 10.1038/ni.3837. View

Essig K, Hu D, Guimaraes J, Alterauge D, Edelmann S, Raj T . Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. Immunity. 2017; 47(6):1067-1082.e12. DOI: 10.1016/j.immuni.2017.11.008. View

Nakayamada S, Takahashi H, Kanno Y, OShea J . Helper T cell diversity and plasticity. Curr Opin Immunol. 2012; 24(3):297-302. PMC: 3383341. DOI: 10.1016/j.coi.2012.01.014. View

Wang L, Cao D, Wang L, Zhao J, Nguyen L, Dang X . HCV-associated exosomes promote myeloid-derived suppressor cell expansion via inhibiting miR-124 to regulate T follicular cell differentiation and function. Cell Discov. 2018; 4:51. PMC: 6131392. DOI: 10.1038/s41421-018-0052-z. View

Baumjohann D, Kageyama R, Clingan J, Morar M, Patel S, de Kouchkovsky D . The microRNA cluster miR-17∼92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol. 2013; 14(8):840-8. PMC: 3720769. DOI: 10.1038/ni.2642. View

10.

Xie M, Chen Q, Liu H, Yang K, Koh B, Wu H . T follicular regulatory cells and IL-10 promote food antigen-specific IgE. J Clin Invest. 2020; 130(7):3820-3832. PMC: 7324176. DOI: 10.1172/JCI132249. View

11.

Hayden M, Ghosh S . NF-κB in immunobiology. Cell Res. 2011; 21(2):223-44. PMC: 3193440. DOI: 10.1038/cr.2011.13. View

12.

Huang Y, Chen Z, Wang H, Ba X, Shen P, Lin W . Follicular regulatory T cells: a novel target for immunotherapy?. Clin Transl Immunology. 2020; 9(2):e1106. PMC: 7019198. DOI: 10.1002/cti2.1106. View

13.

Lang K, Burow A, Kurrer M, Lang P, Recher M . The role of the innate immune response in autoimmune disease. J Autoimmun. 2007; 29(4):206-12. DOI: 10.1016/j.jaut.2007.07.018. View

14.

Zeng W, Qin S, Wang R, Zhang Y, Ma X, Tian F . PDL1 blockage increases fetal resorption and Tfr cells but does not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy. Cell Death Dis. 2020; 11(2):119. PMC: 7016117. DOI: 10.1038/s41419-020-2313-7. View

15.

Fonseca V, Ribeiro F, Graca L . T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr-cell compartments. Immunol Rev. 2019; 288(1):112-127. DOI: 10.1111/imr.12739. View

16.

Lopez-Ocasio M, Buszko M, Blain M, Wang K, Shevach E . T Follicular Regulatory Cell Suppression of T Follicular Helper Cell Function Is Context-Dependent . Front Immunol. 2020; 11:637. PMC: 7181357. DOI: 10.3389/fimmu.2020.00637. View

17.

Chang J, Hu H, Jin J, Puebla-Osorio N, Xiao Y, Gilbert B . TRAF3 regulates the effector function of regulatory T cells and humoral immune responses. J Exp Med. 2014; 211(1):137-51. PMC: 3892978. DOI: 10.1084/jem.20131019. View

18.

Shen E, Rabe H, Luo L, Wang L, Wang Q, Yin J . Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor. Cell Rep. 2019; 29(7):1848-1861.e6. PMC: 6897316. DOI: 10.1016/j.celrep.2019.10.012. View

19.

Buitrago-Molina L, Pietrek J, Noyan F, Schlue J, Manns M, Wedemeyer H . Treg-specific IL-2 therapy can reestablish intrahepatic immune regulation in autoimmune hepatitis. J Autoimmun. 2021; 117:102591. DOI: 10.1016/j.jaut.2020.102591. View

20.

Leon B, Bradley J, Lund F, Randall T, Ballesteros-Tato A . FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun. 2014; 5:3495. PMC: 4013682. DOI: 10.1038/ncomms4495. View