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Review
. 2022 Aug 12:13:911151.
doi: 10.3389/fimmu.2022.911151. eCollection 2022.

Nature vs. nurture: FOXP3, genetics, and tissue environment shape Treg function

Arielle Raugh  1   2 , Denise Allard  1 , Maria Bettini  1
Affiliations
Review

Nature vs. nurture: FOXP3, genetics, and tissue environment shape Treg function

Arielle Raugh et al. Front Immunol. .

Abstract

The importance of regulatory T cells (Tregs) in preventing autoimmunity has been well established; however, the precise alterations in Treg function in autoimmune individuals and how underlying genetic associations impact the development and function of Tregs is still not well understood. Polygenetic susceptibly is a key driving factor in the development of autoimmunity, and many of the pathways implicated in genetic association studies point to a potential alteration or defect in regulatory T cell function. In this review transcriptomic control of Treg development and function is highlighted with a focus on how these pathways are altered during autoimmunity. In combination, observations from autoimmune mouse models and human patients now provide insights into epigenetic control of Treg function and stability. How tissue microenvironment influences Treg function, lineage stability, and functional plasticity is also explored. In conclusion, the current efficacy and future direction of Treg-based therapies for Type 1 Diabetes and other autoimmune diseases is discussed. In total, this review examines Treg function with focuses on genetic, epigenetic, and environmental mechanisms and how Treg functions are altered within the context of autoimmunity.

Keywords: FOXP3; T cell; Treg - regulatory T cell; autoimmunity; genetic; type 1 diabetes.

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Conflict of interest statement

The 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
Tregs encounter increased stressors during autoimmunity. A) During homeostasis, Tregs are stimulated through TCR activation and proliferate using IL-2 from the surrounding environment (1, 5), allowing downstream transcription factor complexes to bind to a hypomethylated Foxp3 and enact critical Treg functions such as suppressive capabilities and repression of Teff programming (–18). B) In contrast, Tregs found during autoimmunity often have intrinsic defects in addition to environmental stressors (, –, –23). For example, non-coding RNAs can be dysregulated during autoimmunity (–26) leading to a dysregulated epigenetic signature with increased methylation of the Foxp3 Treg Specific Demethylated Region (TSDR) which can cause a loss of Foxp3 (27). In addition, a tissue environment rich in inflammatory cytokines can convert Tregs into Th17-like cells leading to the creation of ex-Tregs and decreased Treg stability (–34). Furthermore, these stressors encountered during autoimmunity can also lead to perturbations in FOXP3 isoform ratios (35, 36) and expression of inflammatory cytokines (32, 33) which in turn leads to decreased Treg stability.
Figure 2
Figure 2
Induced regulatory T cells. In the periphery, T lymphocytes can encounter stimuli that turn on downstream signaling leading to genetic reprogramming and a regulatory phenotype (90, 91). pTregs which have the capacity to be immunosuppressive and traffic to inflamed tissue sites are differentiated from CD4 naïve T cells under inflammatory conditions (–94). A rare and unique subpopulation of Tregs is the CD8+Foxp3+ Treg. In the periphery, when naïve CD8 Tconv cells encounter TGFβ, pSmad3 binds to CNS1 of Foxp3, and along with transcription factors Runx3 and Gata3 promote expression of Foxp3 (–97). CD8+Foxp3+ Tregs express similar markers as CD4 Tregs and have immunosuppressive functions.
Figure 3
Figure 3
Inflammatory and tissue specific signals shape Treg responses. Tissue Tregs are poised to respond to inflammatory tissue environments. In the presence of alarmin cytokines, tissue Tregs expressing the transcriptional regulators Batf and PPARγ (, –113) secrete the wound repair factor Amphiregulin (–116). Inflammatory cytokines that normally drive T-helper lineage specific factors like T-bet can similarly induce T-helper transcription factor expression in Tregs. IFNγ and TCR stimulation induce T-bet expression in Foxp3+ Tregs, which provides them with increased ability to suppress Th1 effector T cells (–119).
Figure 4
Figure 4
Tailoring Treg therapies for improved efficacy. Using human autologous Tregs is a promising approach for treatment of autoimmune and inflammatory disorders (196); however, the efficacy of such approaches depends on several factors. Loss of Treg suppressive capacity, stability, or stemness could be a side effect of in vitro expansion protocols (–207). The potential inherent defects in Tregs, lack of antigen specificity (–211), TSDR methylation status post expansion (206), and long-term functionality must also be considered. Potential solutions include engineering antigen specific TCRs (212), TRuCs (–215), and CARs (–219), utilizing Cas9/CRISPR technology for targeted demethylation of the TSDR (220), and using cytokine cocktails to optimize Treg expansion and functionality long-term (221, 222). Furthermore, clinical studies should be focused on accurately assessing the long-term in vivo Treg lineage stability, survival and disease-specific Treg suppressive mechanisms.
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