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ResearchIn-Press PreviewImmunologyInflammation Open Access | 10.1172/JCI190958

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

Qiao Cheng,1 Hee-Jin Choi,1 Yongxia Wu,1 Xiaohong Yuan,1 Allison Pugel,1 Linlu Tian,1 Michael Hendrix,1 Denggang Fu,1 Reza Alimohammadi,1 Chen Liu,2 and Xue-Zhong Yu1

1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

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1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

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1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

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1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

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1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

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1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

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1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

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1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

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1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

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1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

Find articles by Liu, C. in: PubMed | Google Scholar

1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, United States of America

2Department of Pathology, Yale University, New Haven, United States of America

Find articles by Yu, X. in: PubMed | Google Scholar |

Published September 30, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI190958.
Copyright © 2025, Cheng et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 30, 2025 - Version history
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Abstract

Endoplasmic reticulum (ER) stress through IRE1/XBP-1 is implicated in the onset and progression of graft-versus-host disease (GVHD), but the role of 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 Nrf2 pathway. Genetical deletion or selective inhibition of PERK pharmacologically reduces GVHD while preserving graft-versus-leukemia (GVL) activity. At cellular level, PERK positively regulates CD4+ T-cell pathogenicity, while negatively regulating CD8+ T-cell pathogenicity in the induction of GVHD. At 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 alleviate GVHD through ER-associated degradation (ERAD). 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 anti-tumor responses.

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