Lactate inhibits T-cell activation in sepsis through CD40LG downregulation and SOCS3-mediated JAK1/STAT3 pathway suppression.

OBJECTIVES

Lactate, an indicator of sepsis severity, affects kinase activity and is often associated with immunosuppression. This study investigates the impact of lactate on kinases and immune cells and identifies pivotal genes governing their interactions.

METHODS

Differentially expressed genes (DEGs) between sepsis and control groups were screened using the limma package. The correlation between lactate-related DEGs (lrDEGs) and kinase-related DEGs (krDEGs) was then assessed. Hub genes were identified using the algorithms in CytoHubba and weighted gene co-expression network analysis (WGCNA). The aberrant immune status of sepsis patients was evaluated using xCell. The findings were ultimately validated through cellular experiments.

RESULTS

In sepsis, a stronger correlation between lrDEGs and krDEGs was observed among the 998 identified DEGs compared to controls. Eight hub genes were identified through CytoHubba and WGCNA. The correlation between lrDEGs (or krDEGs) and T lymphoid cell score was particularly strong among the hub genes. CD40LG and SOCS3 were identified as key regulators of T cell function. These genes were closely associated with lrDEGs. Cellular experiments demonstrated that lactate inhibits T cell activation through downregulation of CD40LG and suppression of the SOCS3-mediated JAK1/STAT3 pathway.

CONCLUSION

Lactate-induced inhibition of T lymphocyte activation in sepsis is associated with altered expression of kinase-related genes. Elevated lactate levels downregulate CD40LG and SOCS3 expression, leading to T cell suppression by inhibiting the JAK-STAT signaling pathway.