Ezh2 and intracellular Ca2+ signals interdependently coordinate GVHD and CAR T cell responses [RNA-seq_2]

How alloreac-tive T cells regulate a delicate regulate intracellular Ca2+ response to induce GVHD remains poorly defined. We demonstrate that Ezh2 acts as Ca2+ signaling brake to limit excessive intracellular Ca2+ responses in activated T cells, thereby promoting survival of alloreactive T cells that mediate GVHD.

Ezh2 loss resulted in enhanced intracellular Ca2+ responses and upregulation of gene programs that promote effector differen-tiation in activated T cells. Conditional deletion of Stim1 (which mediates cytosolic Ca2+ entry) synthetical-ly rescued antigen-activated non-viable Ezh2-null T cells and their capacity to induce GVHD. Ezh2 re-pressed the expression of endoplasmic reticulum Ca2+ release channel inositol 1,4,5-trisphosphate (InsP3) receptor 2 (Itpr2) to modulate intracellular Ca2+ responses.