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EZH2 and Intracellular Ca2+ Signals Interdependently Coordinate Alloreactive and CAR T Cell Responses

Researchers from the Hackensack University Medical Center have demonstrated that EZH2, a chromatin-modifying epigenetic enzyme, promotes alloreactive T cell survival during graft-versus-host disease (GVHD). Published in Cellular & Molecular Immunology, the authors suggest EZH2 functions as a brake on intracellular calcium (Ca²⁺) signaling. Specifically, EZH2 and Ca²⁺ signaling serve mutually opposing roles in coordinating antigen-driven T cell responses, with direct translational implications for GVHD prevention and CAR T cell engineering.

GVHD remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Calcineurin inhibitors (CNIs), the standard prophylactic regimen, target the Ca²⁺/NFAT pathway but only partially prevent GVHD and promote memory T cell persistence. To date, the epigenetic mechanisms coordinating Ca²⁺ signal homeostasis in activated T cells has not been defined. Using murine GVHD models and CAR T cell system models, the authors sought to determine the interaction between EZH2 and Ca²⁺ signaling pathways in both alloreactive and antigen-specific T cell contexts.

Loss of Ezh2 in donor T cells (EKO) completely abrogated GVHD induction in lethally irradiated BALB/c recipients, while Stim1 knockout (SKO) T cells caused intermediate disease (62.5% survival vs. 0% in WT). Transcriptomic analysis identified 737 overlapping differentially expressed genes between EKO and SKO T cells (p < 2.0×10⁻¹⁶), with opposing regulation of cell cycle and Th1 effector programs. Mechanistically, EZH2 was shown to directly repress Itpr2, which encodes the ER Ca²⁺ release channel InsP3R2, via H3K27me3 deposition at its promoter and enhancer regions. Conditional double knockout of Ezh2 and Stim1 (ESKO) produced synthetic rescue of EKO T cells, restoring their capacity to induce lethal GVHD (100% mortality vs. 0% in EKO alone). Selective deletion of Itpr2 but not Itpr1 or Itpr3 in EKO T cells similarly restored GVHD capacity (70% mortality, p<0.05) and rescued antitumor activity in an AML model. Critically, ex vivo priming of CAR-T cells with the CNI tacrolimus enhanced EZH2 function, increased H3K27me3 levels, reduced terminal exhaustion, and significantly improved in vivo leukemia control. This study establishes the EZH2-InsP3R2-Ca²⁺ axis as a conserved epigenetic checkpoint in T cell immunity, opening new avenues for rational GVHD prophylaxis and next-generation CAR T cell manufacturing strategies.

Reference:

Wang Y, Huang Q, Zhou Y, et al. EZH2 and intracellular Ca²⁺ signals interdependently coordinate alloreactive and CAR-T-cell responses. Cell Mol Immunol. Published online April 22, 2026. http:doi.org/10.1038/s41423-026-01413-y