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TCR Signaling Induced Kdm6b Antagonizes Ezh2 to Sustain Tissue Regulatory T Cells [ATAC-seq]

ABSTRACT: Regulatory T cells (Tregs) expressing Forkhead Box P3 (Foxp3) play crucial roles in maintaining immune tolerance and tissue integrity. Ezh2, a Histone H3 lysine 27 (H3K27) methyltransferase, is known as a crucial regulator of Treg cell identity and suppressive function upon activation, raising a question about whether overactivation of this pathway would further boost Treg cell function. Here, we demonstrate that lysine demethylase Kdm6b catalyzing the reverse reaction to Ezh2 is also required for Treg cell identity and function after activation. Treg-specific deletion of Kdm6b impairs tissue Treg cell fate and function, such as in the lung after injury or adipose tissue during animal aging. Mechanistically, T cell receptor (TCR) signaling upregulates Kdm6b expression and recruits it to Foxp3-bound chromatin to restrict H3K27me3. This antagonism helps suppress the expression of inflammatory cytokines and promote the expression of Treg functional genes, thus supporting tissue Treg cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE316006 | GEO | 2026/04/08

REPOSITORIES: GEO

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Project description:Regulatory T cells (Treg) contribute to the crucial immunological processes of self-tolerance and immune homeostasis. However, the mechanisms underlying Treg function and cell fate decisions to differentiate between Treg and conventional T cells (Tconv) remain to be fully elucidated, especially at the histone modification level. Covalent modifications of histones establish and maintain chromatin structure, and regulate gene transcription events by facilitating access to cis-elements by trans-acting factors during mammalian development and cellular differentiation. We aimed to investigate the role of the methylation form of histone modification as related to Treg function and phenotype. High-resolution maps of the genome-wide distribution of monomethylated histone H3 lysine 4, H3K4me1, and the trimethylated form H3K4me3 were generated for human activated conventional CD4+CD25+FOXP3- T cells (aTconv) and CD4+CD25+FOXP3+ regulatory T cells (Treg) by sequencing using the Solexa 1G Genetic Analyzer. We found 2115 H3K4me3 regions corresponding to proximal promoter regions; the genes associated with these regions in Treg cells included the crucial transcription factor forkhead box P3 (FOXP3) and the chemokine receptor CCR7. We also identified 41024 Treg cell type-specific H3K4me1 regions. The majority of the H3K4me1 regions differing between the Treg and aTconv cells were located at promoter-distal sites, some of which were selected and consolidated to further examine enhancer activity in in vitro reporter gene assays. The findings from our study provide a comprehensive genome-wide dataset of lineage-specific H3K4me1 and H3K4me3 patterns in Treg and aTconv cells, which may control the differentiation decision, lineage commitment and cell type-specific gene regulation. This basic principle is likely not confined to the two closely-related T cell populations, but may apply generally to somatic cell lineages in adult organisms. Genome-wide distribution of monomethylated histone H3 lysine 4, H3K4me1, and the trimethylated form H3K4me3 in human activated conventional CD4+CD25+FOXP3- T cells (aTconv) and CD4+CD25+FOXP3+ regulatory T cells (Treg) (5 samples in total)

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TCR Signaling Induced Kdm6b Antagonizes Ezh2 to Sustain Tissue Regulatory T Cells [ATAC-seq]

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