Biology subjects

Peeters, J.

Publications and source records attributed to Peeters, J..

3 recordsLinked to original sources

bioRxiv2024

Increased EZH2 function in regulatory T cells promotes their capacity to suppress autoimmunity by driving effector differentiation prior to activation

The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here we assessed whether increased EZH2 activity in Treg cells would improve Treg cell function. Using an Ezh2 gain-of-function mutation, Ezh2Y641F, we found that Treg cells expressing Ezh2Y641F displayed an increased effector Treg phenotype and were poised for improved homing to organ tissues. Expression of Ezh2Y641F in Treg cells led to more rapid remission from autoimmunity. H3K27me3 profiling and transcriptomic analysis revealed a redistribution of H3K27me3, which prompted a gene expression profile in naive Ezh2Y641F Treg cells that recapitulated aspects of CD28-activated Ezh2WT Treg cells. Altogether, increased EZH2 activity promotes the differentiation of effector Treg cells that can better suppress autoimmunity. HighlightsO_LIEZH2 function promotes effector differentiation of Treg cells. C_LIO_LIEZH2 function promotes Treg cell migration to organ tissues. C_LIO_LIEZH2 function in Treg cells improves remission from autoimmunity. C_LIO_LIEZH2 function poises naive Treg cells to adopt a CD28-activated phenotype. C_LI

immunology↗

bioRxiv2021

Epigenetic changes in autoimmune monocytes contribute to disease and can be targeted by JAKinhibition

How the local inflammatory environment regulates epigenetic changes in the context of autoimmune diseases remains unclear. Here we assessed the transcriptional and active enhancer profile of monocytes derived from the inflamed joints of Juvenile Idiopathic Arthritis (JIA) patients, a model well-suited for studying autoimmune diseases. RNA-sequencing analysis demonstrated that synovial-derived monocytes display an activated phenotype, characterized by increased expression of surface activation markers and multiple chemokines and cytokines. This increased expression is regulated on the epigenetic level, as ChIP-sequencing indicated increased H3K27 acetylation of genes upregulated in synovial monocytes. IFN signaling-associated genes are increased and epigenetically altered in synovial monocytes, suggesting a role for IFN in establishing the inflammatory phenotype. Treatment of human synovial monocytes with the Janus-associated kinase (JAK) inhibitor Ruxolitinib, which inhibits IFN signaling, transformed the activated enhancer landscape and reduced disease-associated gene expression, thereby inhibiting the inflammatory phenotype. Taken together, these data provide novel insight into epigenetic regulation of autoimmune disease-patient derived monocytes and suggest that altering the epigenetic profile can be a therapeutic approach for the treatment of autoimmune diseases.

immunology↗

bioRxiv2020

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

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.

immunology↗