HDAC1 modulates sepsis-induced immunosuppression by driving the exhaustion of CD8+ T cells.

Summary

Multi-system evidence implicates HDAC1 as a driver of CD8+ T-cell exhaustion in sepsis. Pharmacologic HDAC1 inhibition restored T-cell function, rebalanced AP-1/NFAT signaling, and reduced mortality in preclinical models, positioning HDAC1 as a therapeutic target for sepsis-induced immunosuppression.

Key Findings

• Reduced peripheral lymphocytes, especially CD8+ T-cell depletion, correlated with worse outcomes in sepsis patients.
• scRNA-seq in murine sepsis showed fewer CD8+ T cells and more exhausted CD8+ T cells; adoptive CD8+ T-cell transfer reduced mortality.
• HDAC1 was upregulated in patient CD8+ T cells; HDAC1 inhibition preserved function, lowered PD-1, restored AP-1/NFAT balance, and improved survival.
• HDAC1 directly interacted with NFAT1, promoting nuclear translocation and inhibitory molecule expression.

Clinical Implications

Supports exploration of selective HDAC1 inhibitors and biomarker-guided immunomodulation to reverse T-cell exhaustion in sepsis; highlights prognostic value of lymphocyte and CD8+ T-cell monitoring.

Limitations

• Preclinical findings require confirmation in human interventional trials
• Patient cohort size and heterogeneity are not detailed in the abstract, limiting external validity assessment

Future Directions

Early-phase clinical trials of selective HDAC1 inhibitors in biomarker-defined septic patients; longitudinal monitoring of T-cell exhaustion markers to guide therapy.