Conserved human effector Treg signature is reflected in transcriptomic and epigenetic landscape

Abstract

Treg are critical regulators of immune homeostasis, and increasing evidence demonstrates that environment-driven Treg differentiation into effector (e)Treg is crucial for optimal functioning. However, human Treg programming under inflammatory conditions remains poorly understood. Here, we combine transcriptional and epigenetic profiling to identify the human eTreg core signature. Functional autoimmune inflammation-derived Treg display a unique transcriptional profile characterized by upregulation of both a core Treg (FOXP3, CTLA-4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identified a specific human eTreg signature that includes the vitamin D receptor (VDR) as predicted key-regulator in eTreg differentiation. H3K27ac/H3K4me1 occupancy revealed pronounced changes in the (super-)enhancer landscape, including enrichment of the binding motif for VDR and BATF. The observed Treg profile showed striking overlap with tumor-infiltrating Treg. Our data demonstrate that human inflammation-derived Treg acquire a specific eTreg profile guided by epigenetic changes. The core eTreg profile is conserved, and fine-tuned by environment-specific adaptations.

RegEnrich: An R package for gene regulator enrichment analysis reveals key role of ETS transcription factor family in interferon signaling

“…More recently, we studied the mechanism of human T regulatory (Treg) cells programming under inflammatory conditions. Using RegEnrich, we predicted a network of key regulators important for effector Treg differentiation, including the vitamin D receptor (VDR), which is further validated by H3K27ac and H3K4me1 ChIP-seq experiments 53 . These two independent experimental studies support that RegEnrich is able to accurately rank the key gene regulators that are mechanistically involved in immune cell development and functions.…”

Tissue–Resident Memory T Cells in Chronic Inflammation—Local Cells with Systemic Effects?

“…In this instance, they may be comparable to TIL-like cells in cancer settings, functionally overlapping with T EM . Interestingly overlap in phenotype and transcriptome has been demonstrated for inflamed joint- and tumor-derived Treg [ 69 ]. The transient expression of CD69 upon activation may be a gradient along which we can discern T RM from T EM , though TCR sequencing and single cell transcriptomics may provide a robust additional layer of characterization.…”

“…Tregs are a crucial part of suppressive immunity and have been shown to differ phenotypically and functionally in non-diseased and diseased states [ 60 , 68 , 69 , 70 ]. It has been shown that Tregs are part of the T RM compartment i.e., CD69-expressing Treg in synovial, uterus, and gut tissue [ 60 , 71 ].…”

“…Tissue migration capacities by upregulation of integrins is induced in the lymph nodes, and can be driven by inflammatory stimuli (such as infections) but also less harmful antigens derived from food or commensals (as seen in early life seeding of naïve peripheral tissues such as the gut). Once in the tissue, cells may differentiate/adapt through tissue-specific, antigen, and inflammatory cues both for Treg and non-Treg cells [ 60 , 69 , 70 , 71 , 73 ]. It is currently unknown how selective maintenance in different tissues is regulated.…”

Optimized CRISPR-mediated gene knock-in reveals FOXP3-independent control of human Treg identity

“…Analogously, we found that FOXP3-induced Treg dysfunction was associated with DNA demethylation in specific regions which were enriched for AP-1 binding sites. AP-1 family members are thought to prepare sites for Foxp3 binding in Treg precursors (Samstein et al, 2012) and control the effector and tissuespecific Treg programs (DiSpirito et al, 2018;Mijnheer et al, 2020). On the other hand, Foxp3 opposes AP-1 activity by competing for binding with NFAT (Wu et al, 2006;Lee, Gao and Fang, 2008).…”