Regulatory T‐cell stability and functional plasticity in health and disease

Abstract

FOXP3-expressing regulatory T cells (T reg ) are indispensable for immune homeostasis and tolerance, and in addition tissue-resident T reg have been found to perform noncanonical, tissue-specific functions. For optimal tolerogenic function during inflammatory disease, T reg are equipped with mechanisms that assure lineage stability. T reg lineage stability is closely linked to the installation and maintenance of a lineage-specific epigenetic landscape, specifically a T regspecific DNA demethylation pattern. At the same time, for local and directed immune regulation T reg must possess a level of functional plasticity that requires them to partially acquire T helper cell (T H ) transcriptional programsthen referred to as T H -like T reg . Unleashing T H programs in T reg , however, is not without risk and may threaten the epigenetic stability of T reg with consequently pathogenic ex-T reg contributing to (auto-) inflammatory conditions. Here, we review how the T reg -stabilizing epigenetic landscape is installed and maintained, and further discuss the development, necessity and lineage instability risks of T H 1-, T H 2-, T H 17-like T reg and follicular T reg .

Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

“…Other examples for which, to our knowledge, no IRF4 heterodimer binding was demonstrated before are EP300, FLI1 and TCF7. In our dataset, we found an IRF4-EP300 steered regulation of Th17 and iTreg effector functions supporting data from previous studies, which reported a role of EP300 in Treg proliferation and suppressive function as well as FOXP3 stability 75,76 . In case of Th17 cells, EP300 is essential for the expression of pro-inflammatory cytokines and Th17 cell fate 77 .…”

The foreign body response: emerging cell types and considerations for targeted therapeutics

“…Studies have reported plasticity in Treg phenotypes, where their immunosuppressive activity is lost and they produce pro-inflammatory cytokines. 202 Similar phenomena appear in the FBR literature. In a volumetric muscle loss (VML) model, CD3 + T cells were isolated and sequenced from the inguinal lymph nodes that drain the injury site.…”

The High-Risk Human Papillomavirus Type Influences the Tissue Microenvironment in Cervical Intraepithelial Neoplasia Grade 2

“…Additionally, others have reported that Treg are increased in the stroma in high-grade disease [ 34 ]. CD4+FoxP3+ cells demonstrate functional plasticity [ 35 ]. We note that CD4+FoxP3+ cells were detected at a low frequency in the lesional tissue (around 10-fold less than the CD8 T cells), and it is unclear what functional impact this comparatively low number of cells may have.…”

“…Types included in the alpha genera are of particular interest because of their association with cancer. Thirteen HPV types within the α5 (type 51), α6 (type 56 and 66), α7 (type 18, 45, 39, and 59), and α9 (type 16,31,33,35,52, and 58) species are classified by the International Approval and Registration Centre (IARC) as Group 1 carcinogens (sufficient evidence for carcinogenicity in humans) [1].…”