<p>In graft-versus-host disease (GVHD), Ca²⁺ signals in alloreactive T cells are carefully controlled to determine whether cells survive or thrive, although how this is accomplished during GVHD remains poorly defined. We demonstrate that EZH2, a chromatin-modifying enzyme, promotes alloreactive T-cell survival in GVHD by acting as a Ca²⁺ signaling brake to limit excessive intracellular Ca²⁺ responses. <i>Ezh2</i> loss led to the upregulation of gene programs that promote effector differentiation in activated T cells, coincident with enhanced intracellular Ca²⁺ responses that ultimately caused massive cell death. Conditional deletion of <i>Stim1</i> (required for cytosolic Ca²⁺ entry) led to “synthetic rescue” of <i>Ezh2</i>-null T cells by protecting them from cell death without interfering with effector differentiation, resulting in severe GVHD. Interestingly, <i>Stim1</i> expression was unaffected by EZH2, whereas the expression of the endoplasmic reticulum Ca²⁺ release channel inositol 1,4,5-trisphosphate receptor 2 (<i>Itpr2</i>) was suppressed by EZH2. Notably, EZH2 and Ca²⁺ signals served mutually opposing roles in controlling the expression of genes in chimeric antigen receptor (CAR) T cells. Inhibiting Ca²⁺ signaling restored EZH2 function in CAR-T cells, significantly improving their antitumor activity. Our findings reveal the interdependent roles of EZH2 and Ca²⁺ signals in coordinating antigen-activated T-cell responses that mediate alloimmunity and tumor immunity.</p>