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

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.

Gearing up for battle: Harnessing adaptive T cell immunity against gram-negative pneumonia

“…Cftr -/mice developed chronic inflammation, which was mitigated by adoptive transfer of wild-type Cftr +/+ , but not by transfer of Cftr -/-Treg cells. While the mechanisms that underlie the impairment in Treg cell-mediated reparative function in this specific model remain unknown, these results support the emerging evidence that Treg cell-based immunotherapeutics can be leveraged to treat complex inflammatory conditionsincluding acute lung inflammation associated with pneumonia (Joudi et al, 2022).…”

DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+T cells of neonatal mice withE. colipneumonia

“…That CpGs in neonatal lung CD4 + T cells were more frequently hypomethylated than juveniles in response to DAC administration implies that juvenile CD4 + T cells have more robust epigenetic maintenance mechanisms in place to stabilize CpG methylation in response to a demethylating agent such as DAC. Methylation maintenance mechanisms are not fully understood, but previous evidence suggests that there is a mutual relationship between CpG methylation and the recruitment of DNA methyltransferase proteins such as DNMT3A/B (46)(47)(48)(49). Mammalian genomes become progressively hyper-methylated over the life course (50,51), suggesting that neonatal mice may lack effective methylation maintenance machinery, which results in phenotypic plasticity.…”

Advancing Lung Immunology Research: An Official American Thoracic Society Workshop Report

“…Foxp3 + (Forkhead Box P3) Treg cells are a subset of CD4 + T cells possessing immune-suppressive functions that maintain self-tolerance and dampen overexuberant immune system activation ( 216 , 217 ). Foxp3 gene mutations in mice result in the scurfy phenotype, characterized by severe multiorgan lymphoproliferative inflammation ( 218 , 219 ).…”