CD28⁺ CD8⁺ Tem Cells With a STAT1-Dependent Glucocorticoid Receptor Deficit Contribute to Steroid-Refractory Acute GVHD

Researchers from Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and collaborating hematology and immunology centers across China have identified a mechanistic immune signature underlying steroid-refractory acute graft-versus-host disease (SR-aGvHD). Published in Blood, the study shows that expansion of activated CD28⁺ CD8⁺ effector-memory T (Tem) cells, coupled to a STAT1-dependent deficit in glucocorticoid receptor (GR) signaling, contributes to impaired steroid responsiveness. The findings position these cells not only as drivers of treatment resistance but also as a clinically actionable biomarker for early risk stratification.

Acute GVHD remains a major complication after allogeneic hematopoietic cell transplantation, and corticosteroids are first-line therapy for grade II–IV disease. However, a substantial proportion of patients fail to respond, leading to poor long-term outcomes and an urgent need for predictors of steroid resistance before treatment failure becomes clinically evident. To address this gap, the authors retrospectively profiled peripheral blood collected before glucocorticoid exposure from transplant recipients without aGvHD, with steroid-sensitive aGvHD, and with SR-aGvHD. As such, they mapped immune-cell states associated with refractoriness and validated key findings in an independent multicenter cohort.

The study found that SR-aGvHD was marked by expansion of activated CD28⁺ CD8⁺ Tem cells, and that absolute counts of these cells at neutrophil engraftment predicted later steroid resistance with performance comparable to established clinical classifiers. This phenotype was linked to a proinflammatory cytokine environment enriched for IL-2, IL-27, and IFN-γ, which promoted STAT1 phosphorylation and suppressed GR expression, creating intrinsic glucocorticoid resistance. Importantly, JAK inhibition restored steroid sensitivity in vitro, and clinical response to ruxolitinib was associated with reduced STAT1 activation, recovered GR expression, and contraction of the CD8⁺ Tem population. Together, these data define a biologically grounded biomarker and support pre-emptive, pathway-targeted intervention for patients at high risk of SR-aGvHD.

Reference:

Pan Z, Deng Y, Huang J, et al. CD28⁺ CD8⁺ Tem cells with a STAT1-dependent glucocorticoid receptor deficit contribute to steroid-refractory acute GVHD. Blood. Published online April 14, 2026. http:/doi.org/10.1182/blood.2025032587