The transcription factor ZNF683 marks an exhaustion-like GZMB⁺ CD8⁺ T cell in sepsis

Abstract

Background: Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection and remains a major global cause of mortality. Persistent immunosuppression contributes to secondary infections and adverse outcomes, yet the mechanisms underlying late-phase T-cell dysfunction remain incompletely understood. Methods: We integrated publicly available human peripheral blood mononuclear cell single-cell RNA sequencing with a clinically relevant cecal ligation and puncture (CLP) mouse model to characterize CD8⁺ T-cell states during sepsis. Key computational findings were supported by flow cytometry and RNA fluorescence in situ hybridization (RNA FISH). The immunophenotypic effects of LAG3 blockade were evaluated in septic mice. Results: Single-cell analysis identified a GZMB⁺CD8⁺ T-cell population with an exhaustion-like transcriptional program in sepsis, characterized by increased expression of inhibitory receptors including LAG3 and elevated ZNF683. ZNF683 expression tracked with exhaustion-associated features within the CD8⁺GZMB⁺ compartment. In CLP mice, anti-LAG3 treatment partially improved frequency of GZMB⁺CD8⁺ T cells by flow cytometry. RNA FISH further showed reduced ZNF683 signals in the lungs and liver of septic mice following LAG3 blockade. Conclusion: ZNF683 is associated with an exhaustion-like GZMB⁺CD8⁺ T cell state in sepsis and may contribute to persistent T-cell dysfunction. Further mechanistic studies directly perturbing ZNF683 are needed to determine its causal role and therapeutic potential.