SELL Marks an Effector-Deficient CD8+ T Cell Subset That Promotes Intracerebral Hemorrhage and Responds to Rutin Therapy

Background: Intracerebral hemorrhage (ICH) is a devastating stroke subtype with high mortality and limited therapeutic options. While neuroinflammation contributes to secondary brain injury, the role of peripheral CD8⁺ T cell dysfunction in ICH pathogenesis remains poorly characterized. This study is aimed at identifying disease-associated CD8⁺ T cell subpopulations and potential therapeutic targets through integrative multiomics analysis.

Methods: We performed bulk RNA Sequencing on peripheral blood from 130 patients (66 ICH and 64 hypertension controls) across two independent cohorts, combined with single-cell RNA Sequencing of 13 patients. The scPAS algorithm integrated bulk and single-cell data to identify phenotype-associated cells. Five machine learning algorithms (LASSO, random forest, XGBoost, SVM, and Boruta) were employed for biomarker discovery. The therapeutic efficacy of rutin was evaluated in murine hypertensive ICH models.

Results: We identified a distinct SELL-high CD8⁺ T cell subpopulation (scPAS⁺ cells) exhibiting comprehensive effector dysfunction, characterized by downregulation of cytotoxicity genes (GZMA, GZMB, GNLY, NKG7, and CCL5). Pseudotime trajectory analysis revealed progressive differentiation toward this dysfunctional phenotype. SELL emerged as a consensus diagnostic biomarker across all five algorithms, demonstrating excellent discriminative performance (AUC: 0.876-0.936). In vivo, rutin treatment reduced SELL expression, restored CD8⁺ T cell cytotoxicity, decreased hemorrhage incidence, and attenuated neuroinflammation and oxidative stress.

Conclusions: This study identifies SELL-marked effector-deficient CD8⁺ T cells as a hallmark of ICH and establishes SELL as a robust diagnostic biomarker. Rutin represents a promising therapeutic candidate targeting peripheral immune dysfunction in hypertensive ICH.