The ascorbate-Tet axis is a checkpoint regulator of naive T-cell quiescence 2257733

An epigenetic polarity governing T cell tolerance for commensal microbiota 2250947

The study depicts an epigenetic polarity governing Treg-mediated immune tolerance, highlighting a fundamental asymmetry at the epigenetic level that differentially regulates Treg and conventional T cells.

H3.3 chaperone Hira primes the effector program and function of regulatory T cells

It is shown that the histone variant H3.3 is enriched in tissue Tregs compared to splenic Tregs and its chaperone Hira is a critical regulator of Treg effector program, revealing a previously unreported epigenetic mechanism critical for Treg effector differentiation and function.

Copper Shapes T Cell Metabolism and Epigenetics to Drive Pathogenic Th17 Cell Function in Autoimmunity 2259915

Pathogenic T helper 17 (pTh17) cells are a subset of CD4+ T cells driving autoimmune diseases including multiple sclerosis (MS). To identify transporters controlling pTh17 cells, we conducted an in vivo shRNA-based forward genetic screen using the experimental autoimmune encephalomyelitis (EAE) model of MS. Copper Transporter 1 (CTR1), essential for copper uptake, emerged as a key regulator of pTh17 cell differentiation and function. Copper supports different cellular processes including mitochondrial metabolism and reactive oxygen species (ROS) balance. Deletion of CTR1 in CD4 T cells decreased intracellular copper levels, disrupting mitochondrial respiration and rewiring metabolism. These changes disrupted the epigenetic landscape of pTh17 cells by inducing DNA hypermethylation and altered chromatin accessibility, impairing transcription factor binding. As a result, CTR1-deficient T cells showed defective differentiation into pTh17 cells, with decreased production of IL-17A and expression of Th17 signature genes, while differentiation of other CD4 subsets remained unaffected. Moreover, T cell-specific deletion of CTR1 protected mice from EAE by suppressing clonal expansion of autoreactive CD4+ T cells and CNS inflammation. These findings establish copper as a critical regulator of pTh17 differentiation and function, revealing a previously unknown molecular link between copper homeostasis, metabolism and epigenetic regulation governing Th17-mediated autoimmunity. Colton Autoimmunity Center Immune Response Regulation: Molecular Mechanisms (IRM)

TIF1γ regulates stability of regulatory T cells during inflammation

It is shown that TIF1γ-deficient Treg cells lose Foxp3 expression and acquire effector phenotypes in a cell-intrinsic manner upon inflammatory challenge, and TIF1γ is identified as a critical regulator of Treg cell stability that restrains β-catenin–TCF7 signaling.

Epigenetic mechanisms controlling longevity of T cell immunity 2259637

Long-lived T cell immunity can protect against endemic pathogens that result in iterative challenge to the host, but how such repeated activation of T cells impacts on the molecular mechanisms governing memory potential remains largely unclear. Here, we assessed the role of de novo epigenetic programs in shaping the repertoire and recall response of memory T cells in a setting of iterative acute viral infection. Using our previously established CRISPR system for deleting epigenetic regulators (Kang et al, 2024, Science), we optimized an iterative acute viral infection model with LCMV to serially activate Dnmt3a deficient memory T cells. CRISPR-edited Dnmt3a-deficient P14 CD8 T cells were adoptively transferred cells into B6 mice and subjected to acute infections. Based on our previously established acute viral infection, we evaluated the impact of repetitive antigen exposure on memory CD8 T cells differentiation, longevity, proliferation, cytotoxicity and anti-tumor activity. Dnmt3a KO retain potentially memory CD8 T cells stronger proliferative capacity during acutely prolonged stimulation, but non-target sgRNA group P14 ratio gradually decrease. Additionally, Dnmt3a knockout T cells displayed sustained memory precursor features, including higher CXCR3, Ly108, and TCF1, with lower PD-1 and Tim-3 expression. Functionally, they produced more IL-2, suggesting enhanced viral clearance and overall T cell survival. These results indicate that loss of Dnmt3a preserves stem-like properties and enhance the long-term persistence of memory CD8 T cells under repetitive antigen exposure, providing an epigenetic mechanism to improve immune durability. Our findings show that Dnmt3a KO T cells have increased T cell stemness and durability and indicate that Dnmt3a drives CD8 T cell memory capacity during iterative acute stimulation. These results clarify our research direction that de novo epigenetic programming continues to shape T cell repertoire and recall memory response. National Institutes of Health Immune Response Regulation: Molecular Mechanisms (IRM)

GRP75 sustains CD8+ T cell homeostasis and memory generation through ensuring mitochondrial fitness.