CD28+ CD8+ Tem cells with a STAT1-dependent glucocorticoid receptor deficit contribute to steroid-refractory acute GVHD

作者：Zengkai Pan, Yujun Deng, Jingtao Huang, Haoxing Bian, Y H Chen, Aijie Huang, Chuanhe Jiang, Luxiang Wang, Zilu Zhang, Haiyang Lu, Su Li, Tong Yin, Shanhe Yu, Jiang Zhu, Weili Zhao, Jianmin Wang, Jie Ji, Yang Xu, Hui Cheng, Jiahao Chen, Hongbo Hu, X X Hu · 发表于：Blood · 年份：2026 · DOI：10.1182/blood.2025032587 · 被引用次数：1 · 研究领域：Hematopoietic Stem Cell Transplantation、Adrenal Hormones and Disorders、T-cell and B-cell Immunology

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 contrac...