ER stress sensor PERK promotes T cell pathogenicity in GVHD by regulating ER-associated degradation. J Clin Invest 2025 Dec 01;135(23)
Date
09/30/2025Pubmed ID
41026526Pubmed Central ID
PMC12646671DOI
10.1172/JCI190958Scopus ID
2-s2.0-105023549695 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
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 and regulates SEL1L expression, leading to augmented T cell allogeneic responses and GVHD development. In vivo, PERK deficiency in donor T cells alleviates GVHD through ER-associated degradation. Furthermore, pharmacological inhibition of PERK with AMG44 significantly suppresses the severity of GVHD induced by murine or human T cells. In summary, our findings validate PERK as a potential therapeutic target for the prevention of GVHD while preserving GVL responses, and uncover the mechanism by which PERK differentially regulates CD4+ versus CD8+ T cell allogeneic and antitumor responses.
Author List
Cheng Q, Choi HJ, Wu Y, Yuan X, Pugel A, Tian L, Hendrix M, Fu D, Alimohammadi R, Liu C, Yu XZAuthors
Reza Alimohammadi Postdoctoral Researcher 3 in the Obstetrics and Gynecology department at Medical College of WisconsinXue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCD8-Positive T-Lymphocytes
Endoplasmic Reticulum
Endoplasmic Reticulum Stress
Graft vs Host Disease
Graft vs Leukemia Effect
Humans
Mice
Mice, Knockout
Proteolysis
T-Lymphocytes, Regulatory
Th1 Cells
Th17 Cells
eIF-2 Kinase
