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.
Highlights
Establishing and Maintaining Immune HomeostasisTo maintain health, the immune system continuously and dynamically balances robust reactivity against pathogens with tolerance or unresponsiveness to self-antigens, commensal bacteria, food, and external harmless antigens [1]
This specificity is generated during CD4/CD8 commitment, differentiation, and selection in the thymus, in a process that includes deletion of self-reactive TCRbearing T cells as a mechanism to prevent autoreactive TCRbearing clones being released into the periphery
We hypothesize that as the disease linked to a failure of selftolerance, Treg cells would in some way be impacted by this genetic risk, so we intersected the genetic risk loci with our FOXP3 chromatin immunoprecipitation (ChIP) data [57]
Summary
The immune system continuously and dynamically balances robust reactivity against pathogens with tolerance or unresponsiveness to self-antigens, commensal bacteria, food, and external harmless antigens [1]. This is in part mediated by the effector arm of the adaptive immune system, and two of the major T-cell mediators of this are CD8 and CD4 cells. Antigen specificity is determined by the affinity and avidity of T-cell receptors (TCRs) This specificity is generated during CD4/CD8 commitment, differentiation, and selection in the thymus, in a process that includes deletion of (strongly) self-reactive TCRbearing T cells as a mechanism to prevent autoreactive TCRbearing clones being released into the periphery. The key difference between these subsets is that pTreg provide immune surveillance of specific organs and biological processes in the periphery for which there is no inherited specificity, such as tolerization of the conceptus in pregnancy or the bacteria and food antigens in the gut by pTreg [3]
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