An epigenetic polarity governing T cell tolerance for commensal microbiota 2250947

Targeting genome organizer Satb1 in regulatory T cells safely and potently enhances cancer immunity 2309560

Deletion of Satb1 specifically in Tregs impaired the function of Satb1+ pro-tumorigenic Tregs, leading to enhanced CD8+ T cell antitumor immune responses, and complete tumor eradication without any systemic autoimmune conditions.

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

Foxp3+ regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune tolerance and tissue homeostasis. While several transcription factors such as Batf and JunB have been reported to be essential for eTreg differentiation and function, the underlying epigenetic mechanism remains unclear. Here, we show 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. Treg specific-deletion of Hira resulted in reduced eTreg population, impaired suppressive function and multi-organ inflammation in mice. Mechanistically, Hira-dependent H3.3 deposition establishes a permissive epigenetic environment by enhancing chromatin accessibility, facilitating H3K36me3 and preventing H3K27me3 modifications on loci of genes enriched for AP-1 family binding motifs and associated with Treg effector function. Furthermore, overexpression of Batf in Hira-deficient Treg cells largely ameliorates their regulatory defects. Together, our findings reveal a previously unreported epigenetic mechanism critical for Treg effector differentiation and function.

Canonical WNT pathway utilizes LEF1 to coordinate innate immune memory 2335059

Wnt signaling is a fundamental and evolutionarily conserved pathway that governs cell fate, proliferation, and tissue homeostasis. While canonical Wnt/β-catenin signaling has been extensively characterized in stem and stromal cells, its function in lymphocytes remains context dependent and poorly understood. Natural killer (NK) cells provide a powerful system to interrogate this pathway, as they bridge innate and adaptive immunity and undergo antigen-specific clonal expansion and memory formation during antiviral responses such as cytomegalovirus (CMV) infection. Given the capacity of canonical Wnt/β-Catenin signaling to orchestrate core cellular processes, defining how NK cells access and interpret this conserved pathway to shape the transcriptional architecture of antiviral immunity is of particular interest. We used a well-established model of mouse CMV (MCMV) infection, in which Ly49H+ NK cells recognize the viral glycoprotein m157 on infected targets. Molecular, genomic, and epigenomic approaches were applied to dissect how NK cells utilize Wnt signaling during viral infection. We identify a cytokine-independent mechanism of NK cell expansion mediated by canonical Wnt signaling. We found that NK cells uniquely express the Wnt ligand receptor Frizzled-5 (Fzd5), which is essential for regulating β-catenin-dependent canonical Wnt signaling. During MCMV, we demonstrate that the Wnt-Fzd5 signaling pathway requires β-catenin as a co-factor and LEF1 as a downstream transcription factor to activate key regulators of cell cycle entry and proliferation. These findings establish Fzd5-mediated canonical Wnt signaling and LEF1 activity as critical drivers of the adaptive NK cell response during viral infection, offering new insights into the regulation of innate immunity. T32 AI134632-05; F31AI178958 Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)

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

T-cell peripheral tolerance is crucial for maintaining immune homeostasis and preventing autoimmunity, which is characterized by limited response of conventional T cells to antigen stimulation. The mechanisms controlling this process remain to be fully elucidated. To investigate the role of nutritional factors and related epigenetic mechanisms, we conducted in vivo CRISPR screening and identified ascorbate transporter Slc23a2. Ablation of Slc23a2 in T cells decreases intracellular ascorbate levels, leading to DNA hypermethylation in specific regions. This results in increased differentiation of naive T (Tn) cells into effector and memory T cells, accompanied by low-grade autoimmune inflammation, which is comparable to ascorbate deprivation, Tet dioxygenase deletion, and aged T cells. Mechanistically, Slc23a2 through ascorbate activates Tet methylcytosine dioxygenases to restrict Tn cell activation and differentiation into effector or memory T cells by attenuating TCR signaling, reducing helper T-cell determinants, and enhancing Tcf1 expression and chromatin binding. Tcf1 ablation partially mimics Slc23a2 deficiency, while Tcf1 overexpression suppresses its effect. Therefore, the ascorbate-Tet axis functions as a checkpoint regulator for Tn quiescence, ensuring peripheral tolerance, particularly during aging. N/A Immune Response Regulation: Cellular Mechanisms (IRC)

Th1-Adapted Regulatory T Cells in Tumor Immunity and Inflammatory Diseases.

Site-Selective Proximity-Synthetic Editors Rewrite p53 Acetylation to Dynamically Control Treg Lineage Differentiation 2307367

Regulatory T cells arise when CD4+ T cells commit to a regulatory fate, a process essential for immune tolerance and graft acceptance but whose failure drives autoimmunity; conversely, reinforcing this program in tumors enables immune evasion. Despite this bidirectional role, no pharmacological strategy can directly control Treg lineage commitment. p53, the guardian of the genome, integrates metabolic and chromatin signals via post-translational modifications, yet its role in CD4+ T-cell fate remains poorly understood. We combined in silico modeling with biochemical acetylation assays and functional immunology approaches. Lysine-selective p53 acetylation was examined using genetic and pharmacological tools. We engineered first-in-class Proximity-Synthetic Editors (PSEs), bifunctional small molecules linking a cell-penetrant p53-binding peptide to selective TIP60 or p300 activators. Treg differentiation and function were assessed in vitro and in vivo in cardiac allograft and experimental autoimmune encephalomyelitis models. We identify a binary p53 acetylation logic governing Treg lineage fate. TIP60-mediated acetylation of p53 at K120 is required for efficient Treg induction, whereas p300-driven C-terminal acetylation at K373—382 suppresses Treg differentiation. TIP60-directed PSEs enforce K120 acetylation, promoting Foxp3 expression and Treg differentiation, resulting in prolonged allograft survival and ameliorated EAE. Conversely, p300-directed PSEs inhibit Treg differentiation, accelerate graft rejection, and exacerbate EAE scores. These findings define p53 acetylation as a decisive molecular code governing Treg lineage commitment and demonstrate that proximity-induced pharmacology enables direct, reversible, and site-selective control of intracellular fate decisions. By enabling bidirectional manipulation of immune tolerance with small molecules, this platform establishes a new paradigm for precision immunomodulation across autoimmunity and organ transplantation. n/a Therapeutic Approaches to Autoimmunity (THER)