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Review
. 2022 Mar 2:13:861607.
doi: 10.3389/fimmu.2022.861607. eCollection 2022.

Epigenetic Control of Regulatory T Cell Stability and Function: Implications for Translation

Anthony M Joudi  1   2 , Carla P Reyes Flores  1   2 , Benjamin D Singer  1   2   3   4
Affiliations
Review

Epigenetic Control of Regulatory T Cell Stability and Function: Implications for Translation

Anthony M Joudi et al. Front Immunol. .

Abstract

FoxP3+ regulatory T (Treg) cells maintain immune homeostasis, promote self-tolerance, and have an emerging role in resolving acute inflammation, providing tissue protection, and repairing tissue damage. Some data suggest that FoxP3+ T cells are plastic, exhibiting susceptibility to losing their function in inflammatory cytokine-rich microenvironments and paradoxically contributing to inflammatory pathology. As a result, plasticity may represent a barrier to Treg cell immunotherapy. Here, we discuss controversies surrounding Treg cell plasticity and explore determinants of Treg cell stability in inflammatory microenvironments, focusing on epigenetic mechanisms that clinical protocols could leverage to enhance efficacy and limit toxicity of Treg cell-based therapeutics.

Keywords: DNA methylation; epigenetics; inflammation; plasticity; regulatory T cells; therapeutics.

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Conflict of interest statement

BS holds United States Patent No. US 10,905,706 B2, “Compositions and Methods to Accelerate Resolution of Acute Lung Inflammation,” and serves on the Scientific Advisory Board of Zoe Biosciences, in which he holds stock options. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Development and maintenance of Treg cell epigenetic landscapes. (A) Thymic Treg cell development involves establishment of a Treg cell-specific super-enhancer landscape at Foxp3 and other key loci. The chromatin organizer Satb1 establishes a super-enhancer landscape in Treg cells, characterized by active enhancer histone marks, and TET-mediated DNA hypomethylation. Loci encoding effector T cell signature genes are hypermethylated. (B) Maintenance of Treg cell epigenetic patterning requires the CoREST repressor complex (top) and the epigenetic regulator UHRF1 (bottom) to repress loci encoding inflammatory genes.
Figure 2
Figure 2
Cytokine-mediated epigenetic reprogramming of FoxP3+ T cell populations. (A) Specific cytokine microenvironments can repolarize FoxP3+ T cells with variable effects on FoxP3 expression and Th cell-like phenotypes. (B) TGF-β, NRP-1, and ATRA signal to maintain Treg cell-type epigenetic patterns. Inflammatory cytokines such as IL-6 can promote DNMT and HDAC activity to result in loss of Foxp3 gene expression and modulate PRC complexes to depress loci encoding inflammatory genes. TF, transcription factor.
Figure 3
Figure 3
Epigenetic strategies to promote Treg cell stability. Multiple orthogonal pathways could be leveraged during ex vivo generation of iTreg cells or expansion of nTreg cells to promote FoxP3 expression and Treg cell stability, enhancing the efficacy of therapeutic transfer.
See this image and copyright information in PMC

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