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Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases

Inflammation and Regeneration volume 41, Article number: 14 (2021) Cite this article

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.

Background

Autoimmune diseases are characterized by immune system dysregulation, which mounts immune responses against autoantigens, leading to severe inflammation in various tissues and organs [1]. Even though traditional therapies, such as immunosuppressants and corticosteroids, have improved the survival rate of patients with autoimmune diseases, some patients are non-responsive or resistant to these drugs. Therefore, the development of innovative therapeutics that can restore the immune system is urgently required.

T follicular helper (Tfh) cells are a heterogeneous subset of CD4+ T cells that participate in stimulating germinal center (GC) formation, supporting B cell survival, differentiation, and proliferation [2]. Tfh cells are characterized by the expression of receptor chemokine (C-X-C motif) receptor 5 (CXCR5), transcriptional repressor B cell lymphoma 6 (Bcl-6), programmed cell death protein-1 (PD-1), inducible T cell co-stimulator (ICOS), and interleukin (IL)-21 [3]. Dysregulation of Tfh cells is associated with the pathogenesis of a number of autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome, idiopathic inflammatory myopathies, Graves’ disease, Hashimoto’s disease, and type I diabetes [3].

Recently, a subpopulation of T regulatory (Treg) cells named T follicular regulatory (Tfr) cells that co-express markers of both Treg and Tfh cells has been identified [4,5,6,7]. Apart from expressing Tfh-related markers, Tfr cells also express regulatory markers, such as forkhead box p3 (Foxp3), CD25, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), IL-10, and transforming growth factor-beta (TGF-β) [4, 8, 9]. Tfr cells exhibit different phenotypic characteristics at different stages of maturation. For example, a study identified CD25− Tfr cells with inhibitive functions in the tonsils [10].

Tfr cells are involved in a specialized immune regulation of antibody maturation and germinal center formation via interactions with Tfh and/or B cells [4, 6, 9]. Recent studies have reported that Tfr cell dysregulation contributes to the accumulation of autoantibodies, leading to a wide range of autoimmune diseases [11]. Thus, targeting Tfr cells may be a useful strategy to treat autoimmune diseases. In this review, we discuss recent discoveries about Tfr cells, especially the mechanism of Tfr cell differentiation.

Roles of Tfr cells in inflammation and immunity

Several studies have demonstrated that Tfr cells restrict Tfh-cell activity and GC reaction, suppressing autoantibody expansion [12]. The regulatory mechanism of Tfr cells mainly depends on co-inhibitory receptors, inhibitory cytokines, and granzyme release. For example, CTLA-4 acts as a direct suppressor of Tfr cells. CTLA-4 can limit the expression of co-stimulatory ligands CD80 and CD86 on B cells and control the overreaction of GCs [13,14,15]. TGF-β, which is highly produced by Tfr cells, critically inhibits Tfh cell expansion, self-reactive B cell activation in the GC, and autoantibody production [16]. Additionally, exosomal TGF-β from hepatocytes infected with the hepatitis C virus promotes Tfr cell expansion and suppresses Tfh-cell functions [17].

However, a few recent studies have elucidated that Tfr cells can promote B cell growth in the GC. IL-10 from the precursor B cells in the marginal zone is required for the differentiation and positioning of Tfr cells in the secondary lymphoid tissues [18]. Previous studies have suggested that Tfr cells enhance the formation of IL-10–producing B cells or B regulatory cells [19, 20], thereby controlling aberrant GC responses. In contrast, IL-10 produced by Tfr cells can promote B cell differentiation and GC development not only in food allergy immune responses but also in acute infections with lymphocytic choriomeningitis virus [21, 22]. Notably, Tfr cells repress the development of granzyme-B–expressing cytotoxic Tfh cells and promote GC responses and production of high-affinity autoantibodies [23]. The above findings suggest that Tfr cells behave differently in different environments.

Modulators of Tfr cell differentiation

Tfr cells are located in the secondary lymphoid organs, including the spleen, lymph nodes, Peyer’s patches, and peripheral blood. Unlike Tfh-cell differentiation, which originates directly from naive CD4+ T cells or already differentiated effector T cells [8, 24], Tfr cell differentiation is thought to arise from thymus-derived Treg cells or naive Foxp3− precursors in a programmed death-1 ligand (PD-L1)-dependent manner [4, 6, 25]. During the initial stage, pre-Tfr cells are derived from CXCR5-Foxp3+ thymic natural Treg cells upon interaction with dendritic cells (DCs) [26] (Fig. 1). After priming with DCs, pre-Tfr cells can enter the peripheral blood or migrate to the B cell follicle [26]. The generation of circulating Tfr (cTfr) cells requires priming by DCs but does not require B cell interactions [27]. Furthermore, cTfr cells may move back to the follicles and GC post-reactivation [9]. In the B cell follicle, Tfr cells strengthen the transcriptional program following the upregulation of Bcl-6, ICOS, and PD-1 after interaction with follicle B cells [26]. At the final maturation process, Tfr cells move to the GC and terminally differentiate into mature Tfr cells, which can suppress Tfh and GC B cells [26]. Additionally, Tfr cells can be generated from the reprogramming of Tfh cells through IL-2 stimulation in vitro [28], indicating the conversion of Tfh cells into Tfr cells by IL-2 in the GC.

Fig. 1
figure 1

Model for T follicular regulatory (Tfr)-cell differentiation. Pre-Tfr cells are generated in the T cell zone where thymic natural Treg cells interact with dendritic cells. Pre-Tfr cells migrate into the B cell follicle, strengthening the Tfr cell transcriptional program. Alternatively, pre-Tfr cells can exit the secondary lymphoid tissues and enter the peripheral blood as circulating Tfr (cTfr) cells. In the germinal center (GC), Tfr cells terminally differentiate into mature Tfr cells, and this process fine-tunes Tfh and B cells. cTfr cells may migrate into follicles and the GC after reactivation. Furthermore, interleukin (IL)-2 might facilitate Tfh cell conversion into Tfr cells in the GC. Markers involved in Tfr cell differentiation are presented in black font

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Many positive and negative regulators are involved in Tfr cell differentiation. Understanding the signals regulating Tfr cell generation is vital for the development of targeted therapies. Therefore, we discuss co-stimulator molecules, cytokines, transcription factors, and noncoding-RNAs that can act as modulators of Tfr cell differentiation.

Co-stimulatory molecules

Tfr cell development requires T cell receptor and co-stimulatory signals through CD28 and ICOS [4, 28, 29]. In CD28- or ICOS-deficient mouse models, Tfr cells are attenuated in the lymph nodes [28, 29]. The specific mechanism of Tfr cell development reportedly involves the ICOS signaling, which transiently inactivates forkhead/winged-helix transcription factor 1, whereby Bcl-6 is upregulated, and Tfr cell differentiation is promoted [30]. Additionally, ICOS activation promotes Bcl-6–dependent Tfr cell differentiation by enhancing the interaction between intracellular osteopontin (OPN-i) and p85α, and this interaction plays a critical role in regulating phosphoinositide 3-kinases (PI3K) activity in mice [31] (Fig. 2). OX40L promotes Tfh-cell differentiation but blocks Treg-cell functions in both mice and humans [32, 33]. The suppressive ability of Tfr cells is impaired when they are exposed to soluble OX40L [34]. Moreover, glucocorticoid-induced TNF receptor family related protein skews the Tfh/Tfr ratio toward Tfh cells and upregulates IL-21, suppressing Tfr cell proliferation [35]. A case report has shown that cTfh and cTfr cells are severely compromised in a child with CD40 deficiency, indicating that CD40 is required for Tfh- and Tfr cell development [36]. However, CD40-CD40L interactions render resistance to Tfr-mediated suppression of Tfh-induced B cell proliferation [37].

Fig. 2
figure 2

Representative signaling modulation of Tfr cell differentiation. The ICOS signaling activates the p85α-OPN-i axis and promotes Bcl-6–dependent Tfr cell differentiation. IL-2–activated STAT3 and STAT5 selectively bind to FOXP3 and BCL6 genes, respectively, thereby converting memory Tfh cells to functional Tfr cells. IL-21 inhibits Tfr cell development by blocking the pAkt signaling, thereby reducing the expression of TGF-β and Foxp3. SOSTDC1 enhances Tfr cell differentiation and function by blocking the Wnt/β-catenin axis and subsequently upregulating Foxp3, CXCR5, and CTLA-4. miR-17-92 promotes Tfr cell differentiation by enhancing the PI3K-mTORC1 signaling.

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The impact of PD-1/PD-L1 signaling in the differentiation of Tfr cells is complex. Both Tfh and Tfr cells show high levels of PD-1 expression. PD-1 inhibits the differentiation and functioning of Tfr cells, and PD-1–deficient Tfr cells potently control antibody production in mouse models [29]. PD-L1 promotes the generation of Tfr cells from Foxp3-producing precursors cells after immunization [38]. Conversely, PD-L1 blockage supports Tfr cell accumulation in an allogeneic normal pregnant mouse model [39]. CTLA-4 is also highly expressed in Tfr cells [13]. Deletion of CTLA-4 increases the frequency and an absolute number of Tfr cells but leads to a defective suppression of antigen-specific antibody responses in the effector phase [13,14,15].

Cytokines

Tfh cells are repressed by IL-2 through the signal transducer and activator of transcription 5 (STAT5)-dependent suppression of Bcl-6 [40,41,42,43]. However, the role of IL-2 in Tfr cell differentiation is inconsistent. High concentrations of IL-2 at the peak of influenza infection facilitate Tfr cell development. However, as the infection resolves, IL-2 levels decrease, and IL-2Rαhi Treg cells differentiate into mature GC Tfr cells by downregulating IL-2Rα and upregulating Bcl-6 [44]. IL-2 dynamically regulates Tfr cell responses, and low IL-2 levels may be required to induce Tfr cells. In a human study, exogenous IL-2–activated STAT3 and STAT5 selectively bind to FOXP3 and BCL6 gene loci, respectively, thereby converting memory Tfh cells to functional Tfr cells [28] (Fig. 2). Moreover, IL-2 positively influences Tfr cell differentiation in the GC in vitro [45,46,47].

Tfr cells suppress Tfh-induced B cell proliferation by inhibiting IL-21 production [37]. IL-21 restrains Tfr cell development by reducing the phosphorylation of protein kinase B (Akt) and consequently suppresses Foxp3 and TGF-β production in mice [48] (Fig. 2). Additionally, IL-21 can stimulate the Tfr cell–suppressed B cell metabolism by enhancing glycolysis [49]. IL-21/IL-21R interaction inhibited Tfr cell development through Bcl-6 upregulation, constraining IL-2Rα (CD25) expression in mouse models [50]. Similarly, IL-6 may also affect Tfr cell development by preventing the binding of STAT5 to the IL2rb locus [41].

Transcription factors

Foxp3 and Bcl-6 are the master transcriptional factors for Tfr cell differentiation. Defects in the Bcl-6–nucleosome remodeling and deacetylase complex impair Tfr cell development [51]. Foxp3, along with the chromatin-modifying enzyme enhancer of zeste homolog 2, possesses the capacity to convert Tfh cells into functional suppressive Tfr-like cells [27]. B lymphocyte maturation protein 1 (Blimp-1) suppresses Tfh-cell differentiation by reducing Bcl-6 expression [52, 53]. Blimp-1 can lead to Tfr cell homing into the GC via CXCR5 and CCR7 expression regulation [54]. Additionally, Tfr cell-derived IL-10 is also controlled by Blimp-1 [21]. Notably, Blimp-1 loss doubles the Tfr population but reduces the suppressive ability of Tfr cells [55].

The nuclear factor of activated T cell, cytoplasmic 1 (NFATc1), is essential to enhance the expression of the chemokine CXCR5 on Tfr cells, whereas NFATc1-deficient Tfr cells cause augmented GC reactions [56]. Store-operated Ca2+ entry can control NFATc1-mediated Tfr cell differentiation via the expression of interferon regulatory factor 4, basic leucine zipper atf-like transcription factor, and Bcl-6 [57]. C-Musculoaponeurotic fibrosarcoma (c-Maf) promotes the expression of IL-21 and CXCR5 [58, 59], and deletion of c-Maf leads to a striking Tfr cell loss [60]. Additionally, inhibitors of DNA binding 2 (Id2) and Id3 directly upregulate Tfr-associated genes, such as IL-10 and CXCR5 [61]. Interestingly, the high expression of Id2 or Id3 strengthens the early Tfr cell checkpoint, whereas during the intermediate developmental phases, the low abundance of Id2 and Id3 ensures the development of fully mature Tfr cells [61].

Nuclear factor-kappa B (NF-κB) plays a vital role in regulating immune responses [62]. Patients with NF-κB2 mutations have reduced Tfh and Tfr cell counts [63]. The tumor necrosis factor receptor-associated factor 3 signaling maintains a high ICOS expression in Treg cells, and a high ICOS level is required for Tfr cell generation [64]. Moreover, in mice, sclerostin domain-containing protein 1, secreted by a Tfh cell subpopulation, facilitates Tfr cell differentiation by blocking the Wnt/β-catenin axis, upregulating Foxp3, CXCR5, and CTLA-4 expression [65] (Fig. 2).

Noncoding-RNAs

miR-17-92 overexpression leads to increased Tfh and Tfr cell frequencies in a viral infection mouse model [66]. Additionally, in mice, miR-17-92 promotes Tfr cell differentiation by suppressing the PI3K inhibitor phosphatase and tensin homolog (PTEN) expression and by enhancing the PI3K-Akt-mTOR signaling [67] (Fig. 2). Another study has shown that miR-17-92 deficiency in T cells increases the number of Tfr cells in a mouse model of chronic graft versus host disease. Thus, miR-17-92 might regulate Tfr cell development depending on the experimental models [68]. miR-155 maintains the competitive fitness of Foxp3+ regulatory T cells by targeting the suppressor of cytokine signaling (SOCS1), an inhibitory signaling pathway for the IL-2/STAT5 signaling pathway [69]. However, miR-155 overexpression leads to a lack of Tfr cells and enhances the B cell activation in the GC [70].

miR-146a deficiency in T cells promotes Tfr cell expansion by enhancing the ICOS signaling, suggesting that miR-146a inhibits Tfr cell differentiation [71]. Tfr cells express a higher level of miR-10a than Treg cells, and it has been proposed that miR-10a stimulates Treg cell conversion to Tfr cells via Bcl-6 expression regulation [72]. Moreover, blocking miR-124 expression enhances Tfr cell differentiation and increases IL-10 production [73].

Pathological significance of Tfr cells in autoimmune diseases

Tfr cells have been assessed in a wide range of autoimmune diseases. Since it is challenging to obtain Tfr cells from human lymphoid tissues, cTfr cells have been evaluated as an alternative population to assess GC reaction in most studies. Functional impairment and altered proportion of cTfr cells are associated with autoimmune diseases, such as RA, SLE, systemic sclerosis, ankylosing spondylitis, and IgG4-related disease [11]. Interestingly, coronavirus disease 2019 (COVID-19) convalescent patients with a severe disease showed a higher percentage of effector-memory-like cTfh cells but a lower percentage of cTfr cells compared with healthy donors [74].

As Tfh and Tfr cells play opposing regulatory roles in GC responses, an imbalance in their actions may eventually promote the development of autoimmune diseases. Indeed, a disrupted balance of Tfh and Tfr cells has been related to various autoimmune diseases, including RA, SLE, SSc, multiple sclerosis, ulcerative colitis, and autoimmune hepatitis [75,76,77,78,79,80,81]. The percentage of activated cTfr cells and activated Tfr/Tfh cell ratio are significantly decreased in SLE patients than in healthy donors, and active patients have a lower ratio of activated Tfr/Tfh cells than inactive patients [28]. Taken together, these results suggest that Tfr cells can be used as novel biomarkers and potential therapeutic targets for autoimmune diseases.

Targeting Tfr cells for the treatment of autoimmune diseases

Tfr cells play a prominent role in the pathogenesis of autoimmune diseases. Current therapeutic drugs work by altering Tfr cell differentiation or function. In RA patients, the percentages of cTfh and cTfr are significantly reduced after methotrexate treatment [82]. cTfr cell counts are decreased in type 1 diabetes, and this deficiency in cTfr cells can be rescued by rituximab, an anti-CD20 monoclonal antibody [83]. Abatacept, a CTLA-4-Ig fusion protein that binds to CD80 and CD86, decreases the proportions of cTfh and cTfr cells in patients with relapsing-remitting multiple sclerosis [84]. Furthermore, in patients with seasonal allergic rhinitis, cTfr cells are induced following grass-pollen subcutaneous immunotherapy or sublingual immunotherapy accompanied by an alteration in the epigenetic landscape [85]. Additionally, the number of cTfr cells is decreased in patients with allergic rhinitis, and the frequency and functions of cTfr cells are recovered after allergen immunotherapy [86].

Our recent study analyzed the influence of treatment status on Tfh and Tfr cell proportions in SLE patients [28]. No significant correlation was observed between the dose of corticosteroid and the numbers of activated peripheral Tfh and Tfr cells. Furthermore, immunosuppressants reduce the percentages of activated Tfh cells but not activated Tfr cells [28]. Similar to our results, in patients with antineutrophil cytoplasmic antibody-associated vasculitis, the remission achieved through immunosuppressive treatment decreases Tfh cell percentage, but no significant alterations have been observed in Tfr cells [87].

Proof-of-concept clinical trials have shown the efficacy of low-dose IL-2 treatment via selectively expanding Treg cells and inhibiting Th17 and Tfh cell proliferation in SLE patients [88, 89]. However, Tfr cells have not been explored yet. In an in vitro experiment, we discovered that a low-dose of IL-2 (10 ng/mL) restores Tfr cell functions by directly promoting activated Tfr cells and indirectly through Tfh cell reprogramming to Tfr cells via STAT3 and STAT5 activation. Fine-tuning the balance between Tfh and Tfr cells might provide therapeutic approaches in SLE (Fig. 3). Furthermore, the Treg-specific IL-2 therapy is under investigation; it will foreseeably help improve and establish low-dose IL-2 therapies [90,91,92].

Fig. 3
figure 3

Importance of IL-2 in Tfh/Tfr cell balance. The imbalance of Tfh/Tfr cells leads to defective IL-2 production. Exogenous IL-2 restores the balance between Tfh and Tfr cells, thus offering therapeutic approaches

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Conclusion

The discovery of Tfr cells shed new light on the regulation of GC formation and B cell maturation. Analyses of Tfr cells reveal that they may serve as a potential biomarker for disease severity, and targeted therapeutic approaches for the treatment of autoimmune diseases can be developed accordingly. Differentiation of Tfr cells requires various closely linked regulators, which play synergistic or antagonistic roles in Tfr cell differentiation. Further studies are required to clarify the manipulations of the molecular network regulating Tfr cell formation and physiology. Moreover, detailed studies on Tfr cells and clinical trials are needed to understand the immunotherapeutic efficacy of targeting Tfr cells.

Availability of data and materials

No additional data are available.

Abbreviations

Tfh:

T follicular helper

GC:

Germinal center

Tfr:

T follicular regulatory

CXCR5:

Chemokine receptor chemokine (C-X-C motif) receptor 5

CXCL13:

C-X-C motif chemokine ligand 13

PD-1:

Programmed death-1

ICOS:

Inducible T cell co-stimulator

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

TGF-β:

Transforming growth factor-beta

RA:

Rheumatoid arthritis

SLE:

Systemic lupus erythematosus

SSc:

Systemic sclerosis

OPN-i:

Intracellular osteopontin

Blimp-1:

B lymphocyte maturation protein 1

NFAT:

Nuclear factor of activated T cell

NF-κB:

Nuclear factor kappa B

Id:

Inhibitor of DNA binding

PI3K:

Phosphoinositide 3-kinases

IL:

Interleukin

Treg:

T regulatory

Bcl-6:

B cell lymphoma 6

Foxp3:

Forkhead box p3

DC:

Dendritic cell

cTfr:

Circulating Tfr

PD-L1:

Programmed death-1 ligand

STAT:

Signal transducer and activator of transcription

Akt:

Protein kinase B

c-Maf:

C-musculoaponeurotic fibrosarcoma

References

  1. Lang KS, Burow A, Kurrer M, Lang PA, Recher M. The role of the innate immune response in autoimmune disease. J Autoimmun. 2007;29(4):206–12. https://doi.org/10.1016/j.jaut.2007.07.018.

    Article  CAS  PubMed  Google Scholar 

  2. Nakayamada S, Kanno Y, Takahashi H, Jankovic D, Lu KT, Johnson TA, et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity. 2011;35(6):919–31. https://doi.org/10.1016/j.immuni.2011.11.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41(4):529–42. https://doi.org/10.1016/j.immuni.2014.10.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 2011;17(8):975–82. https://doi.org/10.1038/nm.2425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wollenberg I, Agua-Doce A, Hernández A, Almeida C, Oliveira VG, Faro J, et al. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J Immunol. 2011;187(9):4553–60. https://doi.org/10.4049/jimmunol.1101328.

    Article  CAS  PubMed  Google Scholar 

  6. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011;17(8):983–8. https://doi.org/10.1038/nm.2426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lim HW, Hillsamer P, Kim CH. Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. J Clin Invest. 2004;114(11):1640–9. https://doi.org/10.1172/JCI200422325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29(1):621–63. https://doi.org/10.1146/annurev-immunol-031210-101400.

    Article  CAS  PubMed  Google Scholar 

  9. Sage PT, Alvarez D, Godec J, von Andrian UH, Sharpe AH. Circulating T follicular regulatory and helper cells have memory-like properties. J Clin Invest. 2014;124(12):5191–204. https://doi.org/10.1172/JCI76861.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wing JB, Kitagawa Y, Locci M, Hume H, Tay C, Morita T, et al. A distinct subpopulation of CD25- T-follicular regulatory cells localizes in the germinal centers. Proc Natl Acad Sci U S A. 2017;114(31):E6400–9. https://doi.org/10.1073/pnas.1705551114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang Y, Chen Z, Wang H, Ba X, Shen P, Lin W, et al. Follicular regulatory T cells: a novel target for immunotherapy? Clin Transl Immunology. 2020;9:e1106.

    Article  Google Scholar 

  12. Clement RL, Daccache J, Mohammed MT, Diallo A, Blazar BR, Kuchroo VK, et al. Follicular regulatory T cells control humoral and allergic immunity by restraining early B cell responses. Nat Immunol. 2019;20(10):1360–71. https://doi.org/10.1038/s41590-019-0472-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sage PT, Paterson AM, Lovitch SB, Sharpe AH. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity. 2014;41(6):1026–39. https://doi.org/10.1016/j.immuni.2014.12.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wing JB, Ise W, Kurosaki T, Sakaguchi S. Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity. 2014;41(6):1013–25. https://doi.org/10.1016/j.immuni.2014.12.006.

    Article  CAS  PubMed  Google Scholar 

  15. Chao G, Li X, Ji Y, Zhu Y, Li N, Zhang N, et al. CTLA-4 regulates T follicular regulatory cell differentiation and participates in intestinal damage caused by spontaneous autoimmunity. Biochem Biophys Res Commun. 2018;505(3):865–71. https://doi.org/10.1016/j.bbrc.2018.09.182.

    Article  CAS  PubMed  Google Scholar 

  16. McCarron MJ, Marie JC. TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity. J Clin Invest. 2014;124(10):4375–86. https://doi.org/10.1172/JCI76179.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cobb DA, Kim OK, Golden-Mason L, Rosen HR, Hahn YS. Hepatocyte-derived exosomes promote T follicular regulatory cell expansion during hepatitis C virus infection. Hepatology. 2018;67(1):71–85. https://doi.org/10.1002/hep.29409.

    Article  CAS  PubMed  Google Scholar 

  18. Lal G, Kulkarni N, Nakayama Y, Singh AK, Sethi A, Burrell BE, et al. IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance. Immunol Lett. 2016;170:52–63. https://doi.org/10.1016/j.imlet.2016.01.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Song H, Liu A, Liu G, Wu F, Li Z. T follicular regulatory cells suppress Tfh-mediated B cell help and synergistically increase IL-10-producing B cells in breast carcinoma. Immunol Res. 2019;67(4-5):416–23. https://doi.org/10.1007/s12026-019-09090-y.

    Article  CAS  PubMed  Google Scholar 

  20. Li H, Zhou R, Wang C, Li Y, Zheng G, Jiang S, et al. T follicular regulatory cells infiltrate the human airways during the onset of acute respiratory distress syndrome and regulate the development of B regulatory cells. Immunol Res. 2018;66(4):548–54. https://doi.org/10.1007/s12026-018-9014-7.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Xie MM, Chen Q, Liu H, Yang K, Koh B, Wu H, et al. T follicular regulatory cells and IL-10 promote food antigen-specific IgE. J Clin Invest. 2020;130(7):3820–32. https://doi.org/10.1172/JCI132249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Laidlaw BJ, Lu Y, Amezquita RA, Weinstein JS, Vander Heiden JA, Gupta NT, et al. Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response. Sci Immunol. 2017;2:16.

    Article  Google Scholar 

  23. Xie MM, Fang S, Chen Q, Liu H, Wan J, Dent AL. Follicular regulatory T cells inhibit the development of granzyme B-expressing follicular helper T cells. JCI Insight. 2019;4:16.

    Google Scholar 

  24. Nakayamada S, Takahashi H, Kanno Y, O’Shea JJ. Helper T cell diversity and plasticity. Curr Opin Immunol. 2012;24(3):297–302. https://doi.org/10.1016/j.coi.2012.01.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Aloulou M, Carr EJ, Gador M, Bignon A, Liblau RS, Fazilleau N, et al. Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells. Nat Commun. 2016;7:1–10.

    Article  Google Scholar 

  26. Fonseca VR, Ribeiro F, Graca L. T follicular regulatory (Tfr) cells: dissecting the complexity of Tfr-cell compartments. Immunol Rev. 2019;288(1):112–27. https://doi.org/10.1111/imr.12739.

    Article  CAS  PubMed  Google Scholar 

  27. Hou S, Clement RL, Diallo A, Blazar BR, Rudensky AY, Sharpe AH, et al. FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program. J Exp Med. 2019;216(3):605–20. https://doi.org/10.1084/jem.20181134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hao H, Nakayamada S, Yamagata K, Ohkubo N, Iwata S, Inoue Y, et al. Conversion of T follicular helper cells to T follicular regulatory cells by interleukin-2 through transcriptional regulation in systemic lupus erythematosus. Arthritis Rheum. 2021;73(1):132–42. https://doi.org/10.1002/art.41457.

    Article  CAS  Google Scholar 

  29. Linterman MA, Rigby RJ, Wong R, Silva D, Withers D, Anderson G, et al. Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity. 2009;30(2):228–41. https://doi.org/10.1016/j.immuni.2008.12.015.

    Article  CAS  PubMed  Google Scholar 

  30. Sage PT, Francisco LM, Carman CV, Sharpe AH. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol. 2013;14(2):152–61. https://doi.org/10.1038/ni.2496.

    Article  CAS  PubMed  Google Scholar 

  31. Stone EL, Pepper M, Katayama CD, Kerdiles YM, Lai CY, Emslie E, et al. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity. 2015;42(2):239–51. https://doi.org/10.1016/j.immuni.2015.01.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Leavenworth JW, Verbinnen B, Yin J, Huang H, Cantor HA. p85α-osteopontin axis couples the receptor ICOS to sustained Bcl-6 expression by follicular helper and regulatory T cells. Nat Immunol. 2015;16(1):96–106. https://doi.org/10.1038/ni.3050.

    Article  CAS  PubMed  Google Scholar 

  33. Blanco P, Ueno H, Schmitt N. T follicular helper (Tfh) cells in lupus: activation and involvement in SLE pathogenesis. Eur J Immunol. 2016;46(2):281–90. https://doi.org/10.1002/eji.201545760.

    Article  CAS  PubMed  Google Scholar 

  34. Voo KS, Bover L, Harline ML, Vien LT, Facchinetti V, Arima K, et al. Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function. J Immunol. 2013;191(7):3641–50. https://doi.org/10.4049/jimmunol.1202752.

    Article  CAS  PubMed  Google Scholar 

  35. Jacquemin C, Augusto JF, Scherlinger M, Gensous N, Forcade E, Douchet I, et al. OX40L/OX40 axis impairs follicular and natural Treg function in human SLE. JCI Insight. 2018;3:24.

    Article  Google Scholar 

  36. Oja AE, Brasser G, Slot E, van Lier RA, Pascutti MF, Nolte MA. GITR shapes humoral immunity by controlling the balance between follicular T helper cells and regulatory T follicular cells. Immunol Lett. 2020;222:73–9. https://doi.org/10.1016/j.imlet.2020.03.008.

    Article  CAS  PubMed  Google Scholar 

  37. Cicalese MP, Gerosa J, Baronio M, Montin D, Licciardi F, Soresina A, et al. Circulating follicular helper and follicular regulatory T cells are severely compromised in human CD40 deficiency: a case report. Front Immunol. 2018;9:1761. https://doi.org/10.3389/fimmu.2018.01761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lopez-Ocasio M, Buszko M, Blain M, Wang K, Shevach EM. T follicular regulatory cell suppression of T follicular helper cell function is context-dependent in vitro. Front Immunol. 2020;11:637. https://doi.org/10.3389/fimmu.2020.00637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hams E, McCarron MJ, Amu S, Yagita H, Azuma M, Chen L, et al. Blockade of B7-H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells. J Immunol. 2011;186(10):5648–55. https://doi.org/10.4049/jimmunol.1003161.

    Article  CAS  PubMed  Google Scholar 

  40. Zeng W, Qin S, Wang R, Zhang Y, Ma X, Tian F, et al. 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;11:1–13.

    Article  Google Scholar 

  41. Leon B, Bradley JE, Lund FE, Randall TD, Ballesteros-Tato A. FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun. 2014;5:1–10.

    Article  Google Scholar 

  42. Papillion A, Powell MD, Chisolm DA, Bachus H, Fuller MJ, Weinmann AS, et al. Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-TFH cells. Sci Immunol. 2019;4:39.

    Article  Google Scholar 

  43. Basho K, Zoldan K, Schultheiss M, Bettinger D, Globig AM, Bengsch B, et al. IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis. J Hepatol. 2020;74(3):649–60. https://doi.org/10.1016/j.jhep.2020.10.012.

    Article  CAS  PubMed  Google Scholar 

  44. Botta D, Fuller MJ, Marquez-Lago TT, Bachus H, Bradley JE, Weinmann AS, et al. Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol. 2017;18(11):1249–60. https://doi.org/10.1038/ni.3837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Xie MM, Liu H, Corn C, Koh BH, Kaplan MH, Turner MJ, et al. Roles of T follicular helper cells and T follicular regulatory cells in autoantibody production in IL-2-deficient mice. Immunohorizons. 2019;3(7):306–16. https://doi.org/10.4049/immunohorizons.1900034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li L, Yang SH, Yao Y, Xie YQ, Yang YQ, Wang YH, et al. Block of both TGF-beta and IL-2 signaling impedes neurophilin-1(+) regulatory T cell and follicular regulatory T cell development. Cell Death Dis. 2016;7(10):e2439. https://doi.org/10.1038/cddis.2016.348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schulten V, Tripple V, Seumois G, Qian Y, Scheuermann RH, Fu Z, et al. Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells. J Allergy Clin Immunol. 2018;141(2):775–7. https://doi.org/10.1016/j.jaci.2017.04.032.

    Article  CAS  PubMed  Google Scholar 

  48. Ding Y, Li J, Yang P, Luo B, Wu Q, Zajac AJ, et al. Interleukin-21 promotes germinal center reaction by skewing the follicular regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice. Arthritis Rheum. 2014;66(9):2601–12. https://doi.org/10.1002/art.38735.

    Article  CAS  Google Scholar 

  49. Sage PT, Ron-Harel N, Juneja VR, Sen DR, Maleri S, Sungnak W, et al. Suppression by TFR cells leads to durable and selective inhibition of B cell effector function. Nat Immunol. 2016;17(12):1436–46. https://doi.org/10.1038/ni.3578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jandl C, Liu SM, Canete PF, Warren J, Hughes WE, Vogelzang A, et al. IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2. Nat Commun. 2017;8:1–4.

    Article  Google Scholar 

  51. Shen E, Wang Q, Rabe H, Liu W, Cantor H, Leavenworth JW. Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells. Proc Natl Acad Sci U S A. 2018;115(26):6780–5. https://doi.org/10.1073/pnas.1805239115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009;325(5943):1006–10. https://doi.org/10.1126/science.1175870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cimmino L, Martins GA, Liao J, Magnusdottir E, Grunig G, Perez RK, et al. Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression. J Immunol. 2008;181(4):2338–47. https://doi.org/10.4049/jimmunol.181.4.2338.

    Article  CAS  PubMed  Google Scholar 

  54. Shen E, Rabe H, Luo L, Wang L, Wang Q, Yin J, et al. Control of germinal center localization and lineage stability of follicular regulatory T cells by the Blimp1 transcription factor. Cell Rep. 2019;29(7):1848–61. https://doi.org/10.1016/j.celrep.2019.10.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yang G, Yang X, Zhang J, Li G, Zheng D, Peng A, et al. Transcriptional repressor Blimp1 regulates follicular regulatory T-cell homeostasis and function. Immunology. 2018;153(1):105–17. https://doi.org/10.1111/imm.12815.

    Article  CAS  PubMed  Google Scholar 

  56. Vaeth M, Muller G, Stauss D, Dietz L, Klein-Hessling S, Serfling E, et al. Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression. J Exp Med. 2014;211(3):545–61. https://doi.org/10.1084/jem.20130604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vaeth M, Eckstein M, Shaw PJ, Kozhaya L, Yang J, Berberich-Siebelt F, et al. Store-operated Ca2+ entry in follicular T cells controls humoral immune responses and autoimmunity. Immunity. 2016;44(6):1350–64. https://doi.org/10.1016/j.immuni.2016.04.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Kroenke MA, Eto D, Locci M, Cho M, Davidson T, Haddad EK, et al. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J Immunol. 2012;188(8):3734–44. https://doi.org/10.4049/jimmunol.1103246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wheaton JD, Yeh CH, Ciofani M. Cutting edge: c-Maf is required for regulatory T cells to adopt RORγt+ and follicular phenotypes. J Immunol. 2017;199(12):3931–6. https://doi.org/10.4049/jimmunol.1701134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Miyazaki M, Miyazaki K, Chen S, Itoi M, Miller M, Lu LF, et al. Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nat Immunol. 2014;15(8):767–76. https://doi.org/10.1038/ni.2928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hayden MS, Ghosh S. NF-kB in immunobiology. Cell Res. 2011;21(2):223–44. https://doi.org/10.1038/cr.2011.13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. De Leo P, Gazzurelli L, Baronio M, Montin D, Di Cesare S, Giancotta C, et al. NFKB2 regulates human Tfh and Tfr pool formation and germinal center potential. Clin Immunol. 2020;210:108309. https://doi.org/10.1016/j.clim.2019.108309.

    Article  CAS  PubMed  Google Scholar 

  64. Chang JH, Hu H, Jin J, Puebla-Osorio N, Xiao Y, Gilbert BE, et al. TRAF3 regulates the effector function of regulatory T cells and humoral immune responses. J Exp Med. 2014;211(1):137–51. https://doi.org/10.1084/jem.20131019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wu X, Wang Y, Huang R, Gai Q, Liu H, Shi M, et al. SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation. Science. 2020;369(6506):984–8. https://doi.org/10.1126/science.aba6652.

    Article  CAS  PubMed  Google Scholar 

  66. Baumjohann D, Kageyama R, Clingan JM, Morar MM, Patel S, de Kouchkovsky D, et al. The microRNA cluster miR-17 approximately 92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol. 2013;14(8):840–8. https://doi.org/10.1038/ni.2642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Essig K, Hu D, Guimaraes JC, Alterauge D, Edelmann S, Raj T, et al. Roquin suppresses the PI3K-mTOR signaling pathway to inhibit T helper cell differentiation and conversion of Treg to Tfr cells. Immunity. 2017;47(6):1067–82. https://doi.org/10.1016/j.immuni.2017.11.008.

    Article  CAS  PubMed  Google Scholar 

  68. Wu Y, Schutt S, Paz K, Zhang M, Flynn RP, Bastian D, et al. MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice. Blood. 2018;131(17):1974–86. https://doi.org/10.1182/blood-2017-06-789321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, et al. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity. 2009;30(1):80–91. https://doi.org/10.1016/j.immuni.2008.11.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chao G, Li X, Ji Y, Zhu Y, Li N, Zhang N, et al. MiR-155 controls follicular Treg cell-mediated humoral autoimmune intestinal injury by inhibiting CTLA-4 expression. Int Immunopharmacol. 2019;71:267–76. https://doi.org/10.1016/j.intimp.2019.03.009.

    Article  CAS  PubMed  Google Scholar 

  71. Pratama A, Srivastava M, Williams NJ, Papa I, Lee SK, Dinh XT, et al. MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nat Commun. 2015;6:1–14.

    Article  Google Scholar 

  72. Takahashi H, Kanno T, Nakayamada S, Hirahara K, Sciume G, Muljo SA, et al. TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat Immunol. 2012;13(6):587–95. https://doi.org/10.1038/ni.2286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang L, Cao D, Wang L, Zhao J, Nguyen LN, Dang X, et al. HCV-associated exosomes promote myeloid-derived suppressor cell expansion via inhibiting miR-124 to regulate T follicular cell differentiation and function. Cell Discov. 2018;4:1–15.

    Google Scholar 

  74. Gong F, Dai Y, Zheng T, Cheng L, Zhao D, Wang H, et al. Peripheral CD4+ T cell subsets and antibody response in COVID-19 convalescent individuals. J Clin Invest. 2020;130(12):6588–99. https://doi.org/10.1172/JCI141054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu C, Wang D, Lu S, Xu Q, Zhao L, Zhao J, et al. Increased circulating follicular Treg cells are associated with lower levels of autoantibodies in patients with rheumatoid arthritis in stable remission. Arthritis Rheum. 2018;70(5):711–21. https://doi.org/10.1002/art.40430.

    Article  CAS  Google Scholar 

  76. Xu B, Wang S, Zhou M, Huang Y, Fu R, Guo C, et al. The ratio of circulating follicular T helper cell to follicular T regulatory cell is correlated with disease activity in systemic lupus erythematosus. Clin Immunol. 2017;183:46–53. https://doi.org/10.1016/j.clim.2017.07.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Liu C, Wang D, Song Y, Lu S, Zhao J, Wang H. Increased circulating CD4+ CXCR5+ FoxP3+ follicular regulatory T cells correlated with severity of systemic lupus erythematosus patients. Int Immunopharmacol. 2018;56:261–8. https://doi.org/10.1016/j.intimp.2018.01.038.

    Article  CAS  PubMed  Google Scholar 

  78. Fonseca VR, Romao VC, Agua-Doce A, Santos M, Lopez-Presa D, Ferreira AC, et al. The ratio of blood T follicular regulatory cells to T follicular helper cells marks ectopic lymphoid structure formation while activated follicular helper T cells indicate disease activity in primary Sjogren’s syndrome. Arthritis Rheum. 2018;70(5):774–84. https://doi.org/10.1002/art.40424.

    Article  CAS  Google Scholar 

  79. Puthenparampil M, Zito A, Pantano G, Federle L, Stropparo E, Miante S, et al. Peripheral imbalanced TFH/TFR ratio correlates with intrathecal IgG synthesis in multiple sclerosis at clinical onset. Mult Scler. 2019;25(7):918–26. https://doi.org/10.1177/1352458518779951.

    Article  CAS  PubMed  Google Scholar 

  80. Liang M, Liwen Z, Juan D, Yun Z, Yanbo D, Jianping C. Dysregulated TFR and TFH cells correlate with B-cell differentiation and antibody production in autoimmune hepatitis. J Cell Mol Med. 2020;24(7):3948–57. https://doi.org/10.1111/jcmm.14997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Long Y, Xia C, Xu L, Liu C, Fan C, Bao H, et al. The imbalance of circulating follicular helper T cells and follicular regulatory T cells is associated with disease activity in patients with ulcerative colitis. Front Immunol. 2020;11:104. https://doi.org/10.3389/fimmu.2020.00104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang X, Yang C, Xu F, Qi L, Wang J, Yang P. Imbalance of circulating Tfr/Tfh ratio in patients with rheumatoid arthritis. Clin Exp Med. 2019;19(1):55–64. https://doi.org/10.1007/s10238-018-0530-5.

    Article  CAS  PubMed  Google Scholar 

  83. Xu X, Shen M, Zhao R, Cai Y, Jiang H, Shen Z, et al. Follicular regulatory T cells are associated with beta-cell autoimmunity and the development of type 1 diabetes. J Clin Endocrinol Metab. 2019;104(9):4199–213. https://doi.org/10.1210/jc.2019-00093.

    Article  Google Scholar 

  84. Glatigny S, Hollbacher B, Motley SJ, Tan C, Hundhausen C, Buckner JH, et al. Abatacept targets T follicular helper and regulatory T cells, disrupting molecular pathways that regulate their proliferation and maintenance. J Immunol. 2019;202(5):1373–82. https://doi.org/10.4049/jimmunol.1801425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sharif H, Acharya S, Dhondalay GKR, Varricchi G, Krasner-Macleod S, Laisuan W, et al. Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy. J Allergy Clin Immunol. 2020;147:663–76.

    Article  Google Scholar 

  86. Yao Y, Wang ZC, Wang N, Zhou PC, Chen CL, Song J, et al. Allergen immunotherapy improves defective follicular regulatory T cells in patients with allergic rhinitis. J Allergy Clin Immunol. 2019;144(1):118–28. https://doi.org/10.1016/j.jaci.2019.02.008.

    Article  CAS  PubMed  Google Scholar 

  87. Xu Y, Xu H, Zhen Y, Sang X, Wu H, Hu C, et al. Imbalance of circulatory T follicular helper and T follicular regulatory cells in patients with ANCA-associated vasculitis. Mediat Inflamm. 2019;2019:8421479.

    Google Scholar 

  88. He J, Zhang X, Wei Y, Sun X, Chen Y, Deng J, et al. Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016;22(9):991–3. https://doi.org/10.1038/nm.4148.

    Article  CAS  PubMed  Google Scholar 

  89. He J, Zhang R, Shao M, Zhao X, Miao M, Chen J, et al. Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2020;79(1):141–9. https://doi.org/10.1136/annrheumdis-2019-215396.

    Article  CAS  PubMed  Google Scholar 

  90. Karakus U, Sahin D, Mittl PR, Mooij P, Koopman G, Boyman O. Receptor-gated IL-2 delivery by an anti-human IL-2 antibody activates regulatory T cells in three different species. Sci Transl Med. 2020;12:574.

    Article  Google Scholar 

  91. Mizui M. Natural and modified IL-2 for the treatment of cancer and autoimmune diseases. Clin Immunol. 2019;206:63–70. https://doi.org/10.1016/j.clim.2018.11.002.

    Article  CAS  PubMed  Google Scholar 

  92. Buitrago-Molina LE, Pietrek J, Noyan F, Schlue J, Manns MP, Wedemeyer H, et al. Treg-specific IL-2 therapy can reestablish intrahepatic immune regulation in autoimmune hepatitis. J Autoimmun. 2020;117:102591.

    Article  Google Scholar 

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Acknowledgments

The authors thank all the medical staff members at the associated institutions for helpful advice and encouragement.

Funding

This work was supported in part by JSPS KAKENHI (JP20K08815).

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Authors and Affiliations

  1. First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu, 807-8555, Japan

    He Hao, Shingo Nakayamada & Yoshiya Tanaka

  2. Department of Immuno-oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China

    He Hao

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H.H., S.N., and Y.T. designed and wrote the manuscript. All authors have reviewed and approved the final manuscript.

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Dr. Nakayamada has received consulting fees, speaking fees, and/or honoraria from Bristol-Myers, GlaxoSmithKline, Chugai, Sanofi, Pfizer, Astellas, Asahi-kasei, and Boehringer Ingelheim and has received research grants from Mitsubishi-Tanabe, Novartis, and MSD. Dr. Tanaka has received speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, Pfizer, YL Biologics, Bristol-Myers, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, and Asahi-kasei, and has received research grants from Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, and Taisho-Toyama.

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Hao, H., Nakayamada, S. & Tanaka, Y. Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases. Inflamm Regener 41, 14 (2021). https://doi.org/10.1186/s41232-021-00164-9

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Keywords

  • T follicular regulatory cells
  • Differentiation
  • T follicular helper cells
  • Therapeutic targets
  • Autoimmune diseases

Inflammation and Regeneration

ISSN: 1880-8190

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