ER stress sensor PERK promotes T cell pathogenicity in GVHD by regulating ER-associated degradation.

ABSTRACT: Endoplasmic reticulum (ER) stress through IRE1/XBP1 is implicated in the onset and progression of graft-versus-host disease (GVHD), but the role of the ER stress sensor PERK in T cell allogeneic responses and GVHD remains unexplored. Here, we report that PERK is a key regulator in T cell allogeneic response and GVHD induction. PERK augments GVHD through increasing Th1 and Th17 population, while reducing Treg differentiation by activating the Nrf2 pathway. Genetic deletion or selective inhibition of PERK pharmacologically reduces GVHD while preserving graft-versus-leukemia (GVL) activity. At the cellular level, PERK positively regulates CD4+ T cell pathogenicity while negatively regulating CD8+ T cell pathogenicity in the induction of GVHD. At the molecular level, PERK interacts with SEL1L

SUBMITTER: Cheng Q 

PROVIDER: S-EPMC12646671 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature