Transcriptional regulation of Treg homeostasis and functional specification

Wang, Ke; Fu, Wenxian

doi:10.1007/s00018-020-03534-7

Cited by 18 publications

(15 citation statements)

References 228 publications

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“…Other studies have also reported TCF1 and LEF1 levels to be reduced in Tregs [ 97 , 98 ]. Nevertheless, while certain steps of the interaction between Tregs and TCF1 have been illuminated, this potential link between Foxp3 and TCF1 requires further exploration [ 9 ]. Indeed, another study published in the same year reported no such signs of reduced Tcf7 gene expression [ 99 ].…”

Section: Role Of Tcf1 In Tregsmentioning

confidence: 99%

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The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

Jung

Baek

2021

Cancers

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T cell factor 1 (TCF1) is a transcription factor that has been highlighted to play a critical role in the promotion of T cell proliferation and maintenance of cell stemness in the embryonic and CD8+ T cell populations. The regulatory nature of TCF1 in CD8+ T cells is of great significance, especially within the context of T cell exhaustion, which is linked to the tumor and viral escape in pathological contexts. Indeed, inhibitory signals, such as programmed cell death 1 (PD-1) and cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), expressed on exhausted T lymphocytes (TEX), have become major therapeutic targets in immune checkpoint blockade (ICB) therapy. The significance of TCF1 in the sustenance of CTL-mediated immunity against pathogens and tumors, as well as its recently observed necessity for an effective anti-tumor immune response in ICB therapy, presents TCF1 as a potentially significant biomarker and/or therapeutic target for overcoming CD8+ T cell exhaustion and resistance to ICB therapy. In this review, we aim to outline the recent findings on the role of TCF1 in T cell development and discuss its implications in anti-tumor immunity.

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Section: Role Of Tcf1 In Tregsmentioning

confidence: 99%

“…In line with this, studies have found the subset of TCF1 + CD8 + T cells to be essential in mounting an effective immune response in viral infections and cancer [ 6 , 7 , 8 ]. In addition, TCF1 has been recently implicated in the regulation and determination of Foxp3 + regulatory T cells (Tregs) [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

Jung

Baek

2021

Cancers

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“…Rather, ST2 expression marked a distinct BM-Treg subset that co-expressed KLRG1, indicative VAT-like Treg signature ( Hu and Zhao, 2015 ). TCF-1 expression was significantly downregulated in BM-Treg; a hallmark of non-lymphoid tissue Treg, including those accumulated within VAT ( Wang and Fu, 2020 ). Previous work identified PPARγ as the major driving force behind the development of the VAT Treg phenotype ( Cipolletta et al, 2012 ; Wang and Fu, 2020 ) and we find that PPARγ is upregulated in BM-Treg.…”

Section: Discussionmentioning

confidence: 99%

“…TCF-1 expression was significantly downregulated in BM-Treg; a hallmark of non-lymphoid tissue Treg, including those accumulated within VAT ( Wang and Fu, 2020 ). Previous work identified PPARγ as the major driving force behind the development of the VAT Treg phenotype ( Cipolletta et al, 2012 ; Wang and Fu, 2020 ) and we find that PPARγ is upregulated in BM-Treg. As fatty acids from adipose tissue are naturally occurring ligands of PPARγ ( Wagenmakers et al, 2006 ; Tontonoz and Spiegelman, 2008 ), we propose the natural enrichment of adipose tissue within the BM niche may be a significant driving force in the development of this VAT-like BM-Treg subset.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow Regulatory T Cells Are a Unique Population, Supported by Niche-Specific Cytokines and Plasmacytoid Dendritic Cells, and Required for Chronic Graft-Versus-Host Disease Control

Nicholls

Cao

Texier

et al. 2021

Front. Cell Dev. Biol.

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Regulatory T cell (Treg) reconstitution is essential for reestablishing tolerance and maintaining homeostasis following stem-cell transplantation. We previously reported that bone marrow (BM) is highly enriched in autophagy-dependent Treg and autophagy disruption leads to a significant Treg loss, particularly BM-Treg. To correct the known Treg deficiency observed in chronic graft-versus-host disease (cGVHD) patients, low dose IL-2 infusion has been administered, substantially increasing peripheral Treg (pTreg) numbers. However, as clinical responses were only seen in ∼50% of patients, we postulated that pTreg augmentation was more robust than for BM-Treg. We show that BM-Treg and pTreg have distinct characteristics, indicated by differential transcriptome expression for chemokine receptors, transcription factors, cell cycle control of replication and genes linked to Treg function. Further, BM-Treg were more quiescent, expressed lower FoxP3, were highly enriched for co-inhibitory markers and more profoundly depleted than splenic Treg in cGVHD mice. In vivo our data are consistent with the BM and not splenic microenvironment is, at least in part, driving this BM-Treg signature, as adoptively transferred splenic Treg that entered the BM niche acquired a BM-Treg phenotype. Analyses identified upregulated expression of IL-9R, IL-33R, and IL-7R in BM-Treg. Administration of the T cell produced cytokine IL-2 was required by splenic Treg expansion but had no impact on BM-Treg, whereas the converse was true for IL-9 administration. Plasmacytoid dendritic cells (pDCs) within the BM also may contribute to BM-Treg maintenance. Using pDC-specific BDCA2-DTR mice in which diptheria toxin administration results in global pDC depletion, we demonstrate that pDC depletion hampers BM, but not splenic, Treg homeostasis. Together, these data provide evidence that BM-Treg and splenic Treg are phenotypically and functionally distinct and influenced by niche-specific mediators that selectively support their respective Treg populations. The unique properties of BM-Treg should be considered for new therapies to reconstitute Treg and reestablish tolerance following SCT.

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“…At a more advanced level of differentiation, aTreg cells can acquire the expression of tissue-or microenvironment-induced transcription factors historically linked to the polarization of Tconv cells into Thelper (TH) subsets. Indeed, T-Box Expressed in T cells (T-bet), GATA Binding Protein 3 (GATA3), Retinoic Acid Receptor (RAR)-related Orphan Receptor (ROR)γt, and B-Cell Lymphoma 6 protein (Bcl6), hallmarks of TH1, TH2, TH17, and T follicular helper cells, respectively, can also be expressed by aTreg cells and contribute to the diverse and highly adaptive functions of this population [31]. This precise molecular regulation of Treg cell identity has major implications for the regulation of cancer immunity that we will now emphasize.…”

Section: An Overview Of Treg Cell Subsets and Their Transcriptional Rmentioning

confidence: 99%

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Stéphan¹,

Lautraite²,

Voisin³

et al. 2020

Cancers

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Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

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Transcriptional regulation of Treg homeostasis and functional specification

Cited by 18 publications

References 228 publications

The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

Bone Marrow Regulatory T Cells Are a Unique Population, Supported by Niche-Specific Cytokines and Plasmacytoid Dendritic Cells, and Required for Chronic Graft-Versus-Host Disease Control

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

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