CD28+ CD8+ Tem cells with a STAT1-dependent glucocorticoid receptor deficit contribute to steroid-refractory acute GVHD
Abstract
Abstract Steroid-refractory (SR) disease develops in a substantial fraction of patients with grade II to IV acute graft-versus-host disease (aGVHD) and is associated with poor long-term survival. Improved mechanistic insight is needed to identify reliable predictors of steroid resistance. We retrospectively profiled peripheral blood collected before glucocorticoid treatment from allogeneic hematopoietic cell transplantation recipients without aGVHD, with steroid-sensitive aGVHD, and with SR-aGVHD using an integrated multiomics approach, and validated our findings in an independent multicenter cohort. Mass cytometry revealed an expansion of activated CD28+ CD8+ effector-memory T (Tem) cells in SR-aGVHD. Absolute counts of these cells at neutrophil engraftment predicted subsequent steroid resistance in the multicenter cohort and performed comparably to established clinical classifiers. This phenotype was associated with a proinflammatory milieu enriched in interleukin-2 (IL-2), IL-27, and interferon gamma. Single-cell RNA sequencing and functional assays implicated a STAT1–glucocorticoid receptor (GR) regulatory axis, in which inflammatory cytokines induce STAT1 phosphorylation and suppress GR expression, consistent with intrinsic glucocorticoid resistance. JAK inhibition rescued cytokine-induced steroid resistance in vitro, whereas in patients with SR-aGVHD, clinical response to ruxolitinib was accompanied by reduced STAT1 activation, restoration of GR expression, and contraction of the expanded CD8+ Tem cell pool. These findings identify immune dysregulation in SR-aGVHD centered on CD8+ Tem cells with a STAT1-dependent GR deficit and support a mechanistic link to steroid refractoriness. CD28+ CD8+ Tem cell counts may serve as a biomarker of SR-aGVHD and inform the development of preemptive, pathway-targeted therapeutic strategies.
Article Details
Authors (22)
Zengkai Pan
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yujun Deng
Stanford Institute for Materials and Energy Sciences
Jingtao Huang
Haoxing Bian
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yiyin Chen
Aijie Huang
Chuanhe Jiang
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Luxiang Wang
State Key Laboratory of Chemistry and Utilization of Carbon Based Energy Resources College of Chemistry Xinjiang University Urumqi China
Zilu Zhang
State Key Laboratory of Elemento-Organic Chemistry, State Key Laboratory of Advanced Chemical Power Sources, College of Chemistry
Haiyang Lü
Su Li
State Key Laboratory of Coal Conversion, Institute of Coal Chemistry
Tong Yin
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Shanhe Yu
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jiang Zhu
Wei-Li Zhao
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jianmin Wang
Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), State Key Laboratory of Advanced Chemical Power Sources, College of Chemistry
Jie Ji
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry
Yang Xu
Hui Cheng
Jiahao Chen
Spin-X Institute, School of Chemistry and Chemical Engineering, School of Biomedical Sciences and Engineering, Guangdong-Hong Kong-Macao Joint Laboratory of Optoelectronic and Magnetic Functional Materials, State Key Laboratory of Luminescent Materials and Devices
Hongbo Hu
Xiaoxia Hu
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China