Molecular Insights Into Regulatory T-Cell Adaptation to Self, Environment, and Host Tissues: Plasticity or Loss of Function in Autoimmune Disease

Abstract

There has been much interest in the ability of regulatory T cells (Treg) to switch function in vivo, either as a result of genetic risk of disease or in response to environmental and metabolic cues. The relationship between levels of FOXP3 and functional fitness plays a significant part in this plasticity. There is an emerging role for Treg in tissue repair that may be less dependent on FOXP3, and the molecular mechanisms underpinning this are not fully understood. As a result of detailed, high-resolution functional genomics, the gene regulatory networks and key functional mediators of Treg phenotype downstream of FOXP3 have been mapped, enabling a mechanistic insight into Treg function. This transcription factor-driven programming of T-cell function to generate Treg requires the switching on and off of key genes that form part of the Treg gene regulatory network and raises the possibility that this is reversible. It is plausible that subtle shifts in expression levels of specific genes, including transcription factors and non-coding RNAs, change the regulation of the Treg gene network. The subtle skewing of gene expression initiates changes in function, with the potential to promote chronic disease and/or to license appropriate inflammatory responses. In the case of autoimmunity, there is an underlying genetic risk, and the interplay of genetic and environmental cues is complex and impacts gene regulation networks frequently involving promoters and enhancers, the regulatory elements that control gene expression levels and responsiveness. These promoter-enhancer interactions can operate over long distances and are highly cell type specific. In autoimmunity, the genetic risk can result in changes in these enhancer/promoter interactions, and this mainly impacts genes which are expressed in T cells and hence impacts Treg/conventional T-cell (Tconv) function. Genetic risk may cause the subtle alterations to the responsiveness of gene regulatory networks which are controlled by or control FOXP3 and its target genes, and the application of assays of the 3D organization of chromatin, enabling the connection of non-coding regulatory regions to the genes they control, is revealing the direct impact of environmental/metabolic/genetic risk on T-cell function and is providing mechanistic insight into susceptibility to inflammatory and autoimmune conditions.

Keywords: T-cell fate; T-cell plasticity; Treg FOXP3; gene regulation; genetic risk of disease.

Figure 1

Intersection of mouse and human FOXP3 target genes identified by chromatin immunoprecipitation.

Figure 2

Transcription factor-controlled function in both effector and Treg lineages gives rise to paired Treg to match effectors. These can be resolved by combinatorial chemokine receptor profiling and are predicted to be able to follow the same cues into specific tissues to manage a pathogen and the restoration of homeostasis once the pathogen is eliminated.

Figure 3

(A) In a negative feedback loop, FOXP3 binds directory to the target genes to repress transcription and also induces miRNA that targets the 3′ UTR of the same genes to degrade transcripts or blockade of translations. (B) In a positive feedforward loop, FOXP3 binds directory to the target genes to induce transcription and also represses miRNA that targets the 3′ UTR of the same genes to prevent degradation of transcripts or blockade of translations. In a stable Treg, FOXP3 represses miR-31 by direct binding to regulatory elements associated with the gene, and FOXP3 also targets the promoter of a suppressor function reinforcing the gene to turn it on. In effector T cells, miR-31 expression prevents the expression of FOXP3 by targeting FOXP3 mRNA for degradation.

Figure 4

Modeling the metabolic modifiers of T-cell function in Tconv and Treg, showing differential impacts of glycolysis and oxidative phosphorylation on each and the role of the mTOR pathway in mediating this.

Figure 5

(A) Functional roles of Treg and the impact of environment and genetic risk. (B) Modeling a functional link between FOXP3 levels and biological process.