Distinct Foxp3 enhancer elements coordinate development, maintenance, and function of regulatory T cells

Kawakami, Ryoji; Kitagawa, Yohko; Chen, Kelvin Y.; Arai, Mamoru; Ohara, Daiya; Nakamura, Yurika; Yasuda, Keiko; Osaki, Motonao; Mikami, Norihisa; Lareau, Caleb A.; Watanabe, Hidenobu; Kondoh, Gen; Hirota, Keiji; Ohkura, Naganari; Sakaguchi, Shimon

doi:10.1016/j.immuni.2021.04.005

Cited by 41 publications

(33 citation statements)

References 49 publications

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“…Foxp3 enhancers CNS0, CNS1, and CNS3 haven been shown to facilitate Foxp3 induction ( Figure 1A ) ( Dikiy et al, 2021 ; Feng et al, 2015 ; Kawakami et al, 2021 ; Zheng et al, 2010 ; Zong et al, 2021 ). CNS3 acts through histone acetylation, at least partially, to enable efficient Foxp3 induction.…”

Section: Resultsmentioning

confidence: 99%

Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation

et al. 2021

Cell Reports

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SUMMARY Regulatory T (T reg ) cells play crucial roles in suppressing deleterious immune response. Here, we investigate how T reg cells are mechanistically induced in vitro (iT reg ) and stabilized via transcriptional regulation of T reg lineage-specifying factor Foxp3. We find that acetylation of histone tails at the Foxp3 promoter is required for inducing Foxp3 transcription. Upon induction, histone acetylation signals via bromodomain-containing proteins, particularly targets of inhibitor JQ1, and sustains Foxp3 transcription via a global or trans effect. Subsequently, Tet-mediated DNA demethylation of Foxp3 cis -regulatory elements, mainly enhancer CNS2, increases chromatin accessibility and protein binding, stabilizing Foxp3 transcription and obviating the need for the histone acetylation signal. These processes transform stochastic iT reg induction into a stable cell fate, with the former sensitive and the latter resistant to genetic and environmental perturbations. Thus, sequential histone acetylation and DNA demethylation in Foxp3 induction and maintenance reflect stepwise mechanical switches governing iT reg cell lineage specification.

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Section: Resultsmentioning

confidence: 99%

Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation

et al. 2021

Cell Reports

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“…This Research Topic provides updates on the influences exerted by CD4 + and CD8 + Treg cells on the pathogenesis and modulation of SLE disease manifestations. Among the possibilities of Treg cell modulation, epigenetic manipulations that could improve Treg cell stability and function are actively investigated and expected to be tested in clinical trials (7,8). Several immunotherapeutic studies that focused on the numeric and functional modulation of CD4 + and CD8 + Treg cells, and have yielded promising laboratory results, are moving to the patient's bedside.…”

Section: Discussionmentioning

confidence: 99%

Editorial: Generating and Sustaining Stable Autoantigen-Specific CD4 and CD8 Regulatory T Cells in Lupus

et al. 2022

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Systemic lupus erythematosus (lupus) is a complex autoimmune disease that involves major components of the immune system. It has heterogeneous clinical manifestations and, at the earliest stages, it is characterized by a deficiency of IL-2 and TGF-b, (1, 2), and epigenetic abnormalities that include an abnormal development and stability of CD4 + CD25 + CD127 low T regulatory (Treg) cells (3). However, merely enumerating the levels of circulating Treg cells in lupus patients has yielded inconsistent results because some of those Treg cells are functionally inactive (4, 5), and Treg cells directed to major autoantigens of lupus are not detectable in patients with active disease (6) and Robinson et al. Therefore, generating stable Treg cells that preferentially suppress pathogenic activity of self-reactive immune cells represents a critical therapeutic goal for the modulation of lupus disease, as discussed in this Research Topic.Datta reviews the origins of the first experiments that showed that an endogenous self-antigen, namely nucleosomes from apoptotic cells, linked self-reactive lupus T helper (Th) and B cell with cognate interactions leading to the production of class-switched nephritogenic anti-dsDNA autoantibodies. Subsequently, minute doses of certain histone peptide epitopes from nucleosomes were found to induce autoantigen-specific CD4 + and CD8 + Treg cells. Surprisingly the epitopes were also found to render dendritic cells tolerogenic directly, which led to inhibition of multiple autoreactive cells participating in pathogenic autoimmune response in lupus.Wei et al. review cellular mechanisms that lead to production of high-affinity autoantibodies in SLE. The onset of autoantibodies in systemic autoimmunity requires a complex and highly regulated B-T cell functional crosstalk as well as mature germinal center (GC) formation in B cell follicles of secondary lymphoid tissues. A key regulator of such events is the T follicular regulatory cell (TFR), a specialized Treg cell population that protects from hyperactivity of self-reactive T and B cells. However, recent studies show that TFRs manifest functional plasticity as they can lose Foxp3 expression and convert into disease-promoting "ex-TFRs" that acquire potent effector/

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“…CNS2 contains highly conserved CpG motifs, known as Treg cell specific demethylated regions (TSDR) that represent the most definitive marker of commitment to the Treg cell lineage (58)(59)(60)(61). Importantly, it has been demonstrated that CNS2 deletion affects the stability of Foxp3 expression during proliferation (56,57,(62)(63)(64)(65).…”

Section: Genetic and Epigenetic Program Of The Foxp3 Locus Regulatory Elements Of The Foxp3 Locusmentioning

confidence: 99%

Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle

et al. 2021

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Regulatory T (Treg) cells, possess a strategic role in the maintenance of immune homeostasis, and their function has been closely linked to development of diverse pathologies including autoimmunity and cancer. Comprehensive studies in various disease contexts revealed an increased plasticity as a characteristic of Treg cells. Although Treg cell plasticity comes in various flavors, the major categories enclose the loss of Foxp3 expression, which is the master regulator of Treg cell lineage, giving rise to “ex-Treg” cells and the “fragile” Treg cells in which FOXP3 expression is retained but accompanied by the engagement of an inflammatory program and attenuation of the suppressive activity. Treg cell plasticity possess a tremendous therapeutic potential either by inducing Treg cell de-stabilization to promote anti-tumor immunity, or re-enforcing Treg cell stability to attenuate chronic inflammation. Herein, we review the literature on the Treg cell plasticity with lessons learned in autoimmunity and cancer and discuss challenges and open questions with potential therapeutic implications.

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Distinct Foxp3 enhancer elements coordinate development, maintenance, and function of regulatory T cells

Cited by 41 publications

References 49 publications

Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation

Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation

Editorial: Generating and Sustaining Stable Autoantigen-Specific CD4 and CD8 Regulatory T Cells in Lupus

Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle

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