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

Summary

This study identifies HDAC1 as a key epigenetic driver of CD8+ T-cell exhaustion in sepsis. Pharmacologic HDAC1 inhibition restored T-cell function, rebalanced AP-1/NFAT signaling, and improved survival in murine sepsis, highlighting a tractable immunomodulatory target.

Key Findings

• CD8+ T-cell depletion in septic patients correlated with worse outcomes; exhausted CD8+ T cells increased in murine lungs by scRNA-seq.
• HDAC1 expression was upregulated in septic patient CD8+ T cells; inhibition reduced PD-1 and preserved T-cell function.
• Pharmacologic HDAC1 inhibition improved survival and reversed exhaustion by restoring AP-1/NFAT balance.
• HDAC1 directly interacted with NFAT1, promoting its nuclear translocation and inhibitory molecule expression.

Clinical Implications

Suggests HDAC1 inhibitors as candidates for reversing T-cell exhaustion in septic patients, warranting translational studies to define dosing, timing, and safety.

Limitations

• Preclinical efficacy demonstrated in mice; no human interventional data
• Potential off-target effects and safety profile of HDAC1 inhibition in sepsis remain undefined

Future Directions

Translate to early-phase clinical trials testing HDAC1 inhibitors in sepsis, with biomarker-guided selection and pharmacodynamic endpoints for T-cell exhaustion.