Transcription factor Foxp1 regulates Foxp3 chromatin binding and coordinates regulatory T cell function

Konopacki, Catherine; Pritykin, Yuri; Rubtsov, Yuri P.; Leslie, Christina; Rudensky, Alexander Y.

doi:10.1038/s41590-018-0291-z

Cited by 66 publications

(49 citation statements)

References 56 publications

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“…Interestingly, when making a complex with NFATc2, the forkhead domain bound the DNA sequence that are occupied by Fos and Jun when they bind NFAT, suggesting that Foxp3 competitively inhibit the NFATc2:Fos:Jun complex by binding NFATc2 and replacing Fos and Jun . However, this view is challenged, as another Foxp member, Foxp1, is constitutively expressed by CD4 + T‐cells, which means that Foxp1 may constitutively make a complex with NFAT in the absence of Foxp3.…”

Section: Foxp3 Interacts With Tcr Signalling Downstream Transcriptionmentioning

confidence: 99%

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

Ono

2020

Immunology

108

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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: Foxp3 Interacts With Tcr Signalling Downstream Transcriptionmentioning

confidence: 99%

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

Ono

2020

Immunology

108

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“…CUT&RUN and control reads were counted in 150bp windows around ATAC-seq peak summits. To estimate library sizes, control regions were obtained by shifting ATAC-seq peak summit regions by 2Kb in either direction, extending the shifted segments by 500bp preserving their center, and excluding those that overlapped with ATAC-seq peak summit regions, and then calculating control and CUT&RUN read counts in these control regions and using DESeq2 v1.22.2, as described previously (79). Differential CUT&RUN count analysis was then run using DESeq2, identifying 3325 TCF1 binding sites in the progenitor dysfunctional cells defined as ATAC-seq peak summit regions with significantly higher TCF1 CUT&RUN read counts than IgG control (adjusted p-value < 0.1).…”

Section: Identification Of Transcription Factor Binding Sitesmentioning

confidence: 99%

A unified atlas of CD8 T cell dysfunctional states in cancer and infection

Pritykin

Veeken

Pine

et al. 2020

Preprint

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CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across different experimental and clinical settings. By carrying out a unified analysis of over 300 ATAC-seq and RNA-seq experiments from twelve independent studies of CD8 T cell dysfunction in cancer and infection we defined a shared differentiation trajectory towards terminal dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell activation states across models. Experimental dissection of acute and chronic viral infection using scATAC-seq and allele-specific scRNA-seq identified state-specific transcription factors and captured the early emergence of highly similar TCF1+ progenitor-like populations at an early branch point, at which epigenetic features of functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.

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“…198 Besides, demethylation of Foxp1 could help Foxp3 DNA binding and increase CD8 + Treg suppressive function as reported for CD4 + Tregs. 199 Otherwise, targeting genes such as HIF-1alpha KO would switch Treg metabolism from glycolytic-driven migration to an oxidative phosphorylation-driven immunosuppression. 200 On the other hand, overexpression of Hdr1 could help Tregs to face to ER stress response to an inflammatory environment.…”

Section: Tcr/car and Othersmentioning

confidence: 99%

Future prospects for CD8⁺ regulatory T cells in immune tolerance

Flippe

Bézie

Anegón

et al. 2019

Immunological Reviews

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CD8+ Tregs have been long described and significant progresses have been made about their phenotype, their functional mechanisms, and their suppressive ability compared to conventional CD4+ Tregs. They are now at the dawn of their clinical use. In this review, we will summarize their phenotypic characteristics, their mechanisms of action, the similarities, differences and synergies between CD8+ and CD4+ Tregs, and we will discuss the biology, development and induction of CD8+ Tregs, their manufacturing for clinical use, considering open questions/uncertainties and future technically accessible improvements notably through genetic modifications.

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Transcription factor Foxp1 regulates Foxp3 chromatin binding and coordinates regulatory T cell function

Cited by 66 publications

References 56 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

A unified atlas of CD8 T cell dysfunctional states in cancer and infection

Future prospects for CD8⁺ regulatory T cells in immune tolerance

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Transcription factor Foxp1 regulates Foxp3 chromatin binding and coordinates regulatory T cell function

Cited by 66 publications

References 56 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

A unified atlas of CD8 T cell dysfunctional states in cancer and infection

Future prospects for CD8+ regulatory T cells in immune tolerance

Contact Info

Product

Resources

About

Future prospects for CD8⁺ regulatory T cells in immune tolerance