Regulatory T Cell-Specific Epigenomic Region Variants Are a Key Determinant of Susceptibility to Common Autoimmune Diseases

Ohkura, Naganari; Yasumizu, Yoshiaki; Kitagawa, Yohko; Tanaka, Atsushi; Nakamura, Yurika; Motooka, Daisuke; Nakamura, Shota; Okada, Yukinori; Sakaguchi, Shimon

doi:10.1016/j.immuni.2020.04.006

Cited by 88 publications

(86 citation statements)

References 52 publications

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“…P values resulting from Kolmogorov-Smirnov tests for cumulative distributions comparing all genes against either gene set are shown in G and H. jci.org spontaneously develop widespread inflammation reminiscent of the developmental phenotype observed in the constitutive conditional knockout animals, scurfy mice, and humans with the autoimmune IPEX syndrome. Indeed, missense variants of UHRF1BP (Uhrf1-binding protein) are associated with the development of systemic lupus erythematosus (58), and epigenomic region variants within Tregs are linked to autoimmunity (59). Thus, our results suggest caution when applying pharmacologic approaches to epigenetic modification in immune-dysregulated conditions, such as autoimmune and malignant disorders.…”

Section: Resultsmentioning

confidence: 86%

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Helmin¹,

Morales‐Nebreda²,

Acosta³

et al. 2020

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 86%

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Helmin¹,

Morales‐Nebreda²,

Acosta³

et al. 2020

Journal of Clinical Investigation

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“…The markers Helios 21 and neuropilin‐1 22,23 were suggested to distinguish pTregs from tTregs; however, controversies exist regarding specificity 24–27 . Hypomethylation of Treg signature genes is crucial for Treg transcriptional activity and stable functionality 28–33 . Few studies differentiate between tTregs and pTregs; however, several studies suggest that pTregs can acquire a Treg‐specific demethylation pattern similar to tTregs 28,29,34 .…”

Section: Regulatory T Cellsmentioning

confidence: 99%

Role of regulatory T cells in psoriasis pathogenesis and treatment

2020

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Psoriasis is a chronic inflammatory disease with a strong genetic component that can be triggered by environmental factors. Disease pathogenesis is mainly driven by type 1 and type 17 cytokine-producing cells which, in healthy individuals, are modulated by regulatory T cells (Tregs). Tregs play a fundamental role in immune homeostasis and contribute to the prevention of autoimmune disease by suppressing immune responses. In psoriasis, Tregs are impaired in their suppressive function leading to an altered T-helper 17/Treg balance. Although Treg dysfunction in patients with psoriasis is associated with disease exacerbation, it is unknown how they are functionally regulated. In this review, we discuss recent insights into Tregs in the setting of psoriasis with an emphasis on the effect of current treatments on Tregs and how already available therapeutics that modulate Treg frequency or functionality could be exploited for treatment of psoriasis.

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“…The overall modest phenotypic changes upon FOXP3 ablation prompted us to investigate its contribution to the maintenance of human Treg identity in lineage-committed cells. A wealth of studies have characterized the distinct molecular signatures of human Tregs at the DNA methylation (Schmidl et al, 2009;Zhang et al, 2013;Ohkura et al, 2020), transcript (Birzele et al, 2011;Ferraro et al, 2014;Pesenacker et al, 2016), and protein levels (Procaccini et al, 2016;Cuadrado et al, 2018). In mice, Foxp3 is necessary but not sufficient to confer Treg identity, especially with respect to DNA methylation (Ohkura et al, 2012;Samstein et al, 2012).…”

Section: Foxp3-independent Maintenance Of Human Treg Dna Methylationmentioning

confidence: 99%

Optimized CRISPR-mediated gene knock-in reveals FOXP3-independent control of human Treg identity

Lam

Lin

Gillies

et al. 2021

Preprint

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SummaryTreg cell therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knock-in in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we targeted the master transcription factor FOXP3 in naive and memory Tregs. Although FOXP3-knockout Tregs upregulated cytokine expression, effects on suppressive capacity manifested slowly and primarily in memory Tregs. Moreover, FOXP3-knockout Tregs retained their characteristic phenotype and had few changes in their DNA methylation landscape, with FOXP3 maintaining methylation at regions enriched for AP-1 binding sites. Thus, while FOXP3 is important for human Treg development, it has a limited role in maintaining mature Treg identity. Optimized gene knock-in with human Tregs will enable mechanistic studies and the development of tailored, next-generation Treg cell therapies.

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Regulatory T Cell-Specific Epigenomic Region Variants Are a Key Determinant of Susceptibility to Common Autoimmune Diseases

Abstract: Highlights d Autoimmune SNPs are enriched in naive Treg cell-specific CpG hypomethylated regions d Treg-specific CpG hypomethylation is associated with Treg cell super-enhancers d Naive Treg cell-specific epigenetics controls activated Treg cell function

Cited by 88 publications

References 52 publications

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Role of regulatory T cells in psoriasis pathogenesis and treatment

Optimized CRISPR-mediated gene knock-in reveals FOXP3-independent control of human Treg identity

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