From stability to dynamics: understanding molecular mechanisms of regulatory T cells through<i>Foxp3</i>transcriptional dynamics

Bending, David; Ono, M.

doi:10.1111/cei.13194

Cited by 23 publications

(22 citation statements)

References 101 publications

(145 reference statements)

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“…Foxp3 expression is primarily controlled by transcriptional and epigenetic regulation. A recent technological advancement to analyse temporal dynamics of Foxp3 transcription is providing new insights into Treg differentiation and function . Notably, highly sustained Foxp3 transcription over time induces the differentiation of eTreg, which is also known as Treg maturation .…”

Section: From Treg Classification To Foxp3 Expression Dynamicsmentioning

confidence: 99%

“…These new technologies will make breakthroughs in the understanding of the molecular mechanisms of Foxp3‐mediated immune suppression, which may well lead to the development of next‐generation immunotherapy for cancer and autoimmunity in the future. Learning from the history of Treg biology and immunotherapy, it is needed to obtain both mechanistic understanding of molecular and cellular mechanisms and systemic view on the entire T‐cell system and the immune system.…”

Section: Perspectivesmentioning

confidence: 99%

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Control of regulatory T‐cell differentiation and function by T‐cell receptor signalling and Foxp3 transcription factor complexes

Ono

2020

Immunology

130

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The transcription factor Foxp3 controls the differentiation and function of regulatory T-cells (Treg). Studies in the past decades identified numerous Foxp3-interacting protein partners. However, it is still not clear how Foxp3 produces the Treg-type transcriptomic landscape through cooperating with its partners. Here I show the current understanding of how Fox-p3 transcription factor complexes regulate the differentiation, maintenance and functional maturation of Treg. Importantly, T-cell receptor (TCR) signalling plays central roles in Treg differentiation and Foxp3-mediated gene regulation. Differentiating Treg will have recognized their cognate antigens and received TCR signals before initiating Foxp3 transcription, which is triggered by TCR-induced transcription factors including NFAT, AP-1 and NF-κB. Once expressed, Foxp3 seizes TCR signal-induced transcriptional and epigenetic mechanisms through interacting with AML1/Runx1 and NFAT. Thus, Foxp3 modifies gene expression dynamics of TCR-induced genes, which constitute cardinal mechanisms for Treg-mediated immune suppression. Next, I discuss the following key topics, proposing new mechanistic models for Foxp3-mediated gene regulation: (i) how Foxp3 transcription is induced and maintained by the Fox-p3-inducing enhanceosome and the Foxp3 autoregulatory transcription factor complex; (ii) molecular mechanisms for effector Treg differentiation (i.e. Treg maturation); (iii) how Foxp3 activates or represses its target genes through recruiting coactivators and corepressors; (iv) the 'decisionmaking' Foxp3-containing transcription factor complex for Th17 and Treg differentiation; and (v) the roles of post-translational modification in Fox-p3 regulation. Thus, this article provides cutting-edge understanding of molecular biology of Foxp3 and Treg, integrating findings by biochemical and genomic studies.

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Section: From Treg Classification To Foxp3 Expression Dynamicsmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

Control of regulatory T‐cell differentiation and function by T‐cell receptor signalling and Foxp3 transcription factor complexes

Ono

2020

Immunology

130

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“…CD25 high ). As well as a significant portion of previous research, however, we assume that the immune marking for FoxP3 + can generally express the great majority of Treg cells (Bending & Ono, ; Miyara et al, ).…”

Section: Discussionmentioning

confidence: 97%

Subset of CD8+ and FOXP3 + T cells in lichen planus associated with chronic hepatitis C infection

et al. 2019

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Objective: To verify whether there are differences between populations of CD8 + and FoxP3 + T cells in lesions of oral lichen planus associated with hepatitis C virus chronic infection (OLP-HCV) and lesions of idiopathic oral lichen planus (OLP-I). Materials and Methods:A case-control study was performed using a convenience sample of 11 paraffin-embedded tissue blocks of OLP-HCV and 19 of OLP-I.Histological sections stained with haematoxylin and eosin were used to classify the intensity of inflammatory infiltrate. Immunohistochemistry was used to identify CD8 + and FoxP3 + T cells. The count of positive cells was compared between the two groups and correlated to clinical and demographic data (p < 0.05).Results: There were no statistically significant differences in the distribution of CD8 + and FoxP3 + T cells regarding the inflammatory infiltrate in lesions of OLP-HCV and OLP-I. Atrophic/erosive lesions showed a higher relationship between counts of CD8/FoxP3 T cells per mm 2 (p = 0.018) and counts of CD8 + T cells per mm 2 (p = 0.034) in OLP-HCV group compared to OLP-I group.Conclusion: Overall, no difference was found between cell populations in the lesions of OLP-HCV and OLP-I. However, atrophic/erosive lesions of OLP-HCV had a higher amount of CD8 + T cells and lower FoxP3 expression. K E Y W O R D SCD8, extra-hepatic manifestations, FoxP3, hepatitis C, oral lichen planus | 1101 de CAMARGO et Al. de CAMARGO et Al. | CON CLUS IONAlthough the present study has evidenced greater amount of CD8 + T cells and higher ratio of CD8/FoxP3 + cells in erosive/ulcerated lesions in the OLP-HCV group compared to the OLP-I group, more studies should be carried out to confirm this trend and to assess whether this characteristic can actually influence the treatment of this type of LP. CO N FLI C T S O F I NTE R E S TNone to declare. AUTH O R CO NTR I B UTI O N SCamargo AR performed data collection and tabulation. Tenório JR and Martins F participated in the acquisition of histological sections and immunohistochemical staining. Grando LJ and Corrêa EBD performed the statistical analyzes. Trierveiler M participated as a reviewer and did the immunohistochemical analysis. Ortega KL designed the study and participated in all phases of article review.

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“…1 In addition, the transcription factor Foxp3 can be induced in activated T-cells, especially in humans, and plays a key role as an inducible negative regulator during inflammation. 2 COVID-19 is caused by the coronavirus SARS-CoV-2, which is closely related to the severe acute respiratory syndrome coronavirus (SARS-CoV). The major symptoms such as cough and diarrhoea in mild to moderate patients can be understood through the type of tissues that can be infected by SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

T-cell hyperactivation and paralysis in severe COVID-19 infection revealed by single-cell analysis

Kalfaoglu

Almeida‐Santos

Tye

et al. 2020

Preprint

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Severe COVID-19 patients can show respiratory failure, T-cell reduction, and cytokine release syndrome (CRS), which can be fatal in both young and aged patients and is a major concern of the pandemic. However, the pathogenetic mechanisms of CRS in COVID-19 are poorly understood. Here we show single cell-level mechanisms for T-cell dysregulation in severe SARS-CoV-2 infection, and thereby demonstrate the mechanisms underlying T-cell hyperactivation and paralysis in severe COVID-19 patients. By in silico sorting CD4+ T-cells from a single cell RNA-seq dataset, we found that CD4+ T-cells were highly activated and showed unique differentiation pathways in the lung of severe COVID-19 patients. Notably, those T-cells in severe COVID-19 patients highly expressed immunoregulatory receptors and CD25, whilst repressing the expression of the transcription factor FOXP3 and interestingly, both the differentiation of regulatory T-cells (Tregs) and Th17 was inhibited. Meanwhile, highly activated CD4 + T-cells express PD-1 alongside macrophages that express PD-1 ligands in severe patients, suggesting that PD-1-mediated immunoregulation was partially operating. Furthermore, we show that CD25 + hyperactivated T-cells differentiate into multiple helper T-cell lineages, showing multifaceted effector T-cells with Th1 and Th2 characteristics. Lastly, we show that CD4 + T-cells, particularly CD25-expressing hyperactivated T-cells, produce the protease Furin, which facilitates the viral entry of SARS-CoV-2. Collectively, CD4 + T-cells from severe COVID-19 patients are hyperactivated and FOXP3-mediated negative feedback mechanisms are impaired in the lung, while activated CD4 + T-cells continue to promote further viral infection through the production of Furin.Therefore, our study proposes a new model of T-cell hyperactivation and paralysis that drives pulmonary damage, systemic CRS and organ failure in severe COVID-19 patients.

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From stability to dynamics: understanding molecular mechanisms of regulatory T cells throughFoxp3transcriptional dynamics

Cited by 23 publications

References 101 publications

Control of regulatory T‐cell differentiation and function by T‐cell receptor signalling and Foxp3 transcription factor complexes

Control of regulatory T‐cell differentiation and function by T‐cell receptor signalling and Foxp3 transcription factor complexes

Subset of CD8+ and FOXP3 + T cells in lichen planus associated with chronic hepatitis C infection

T-cell hyperactivation and paralysis in severe COVID-19 infection revealed by single-cell analysis

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