The transcription factor ZNF683 marks an exhaustion-like GZMBCD8T 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 CD8T-cell states during sepsis. Key computational findings were supported by flow cytometry and RNA fluorescencehybridization (RNA FISH). The immunophenotypic effects of LAG3 blockade were evaluated in septic mice. RESULTS: Single-cell analysis identified a GZMBCD8T-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 CD8GZMBcompartment. In CLP mice, anti-LAG3 treatment partially improved frequency of GZMBCD8T 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 GZMBCD8T 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.