TCF7 and LEF-1 downregulation in sepsis promotes immune suppression by inhibiting CD4⁺ T cell proliferation

Previous studies have shown that sepsis is implicated in a reduction in the number and function of CD4⁺ T cells. TCF7 and LEF-1 facilitate early T cell development and lineage selection of CD4⁺ T cells. However, the function and mechanism of TCF7 and LEF-1 in sepsis are uncharacterized. This study intended to delineate effect of TCF7 and LEF-1 on sepsis and the impact on proliferation of CD4⁺ T cells in sepsis.

A mouse sepsis model was constructed by cecal ligation and puncture (CLP) method. Expression of TCF7 and LEF-1 in sepsis was investigated using bioinformatics analysis and molecular experiments. We then constructed TCF7 and LEF-1 overexpression cell lines to investigate their effects on proliferation, apoptosis, effector activation, and immunosuppressive molecules of CD4⁺ T cells in sepsis.

TCF7 and LEF-1 were downregulated in sepsis. As the duration of sepsis induction increased, the levels of TCF7 and LEF-1 gradually decreased, as did the number of CD4⁺ T cells. Cell experiments showed that overexpression of TCF7 and LEF-1 enhanced proliferation and effector activation of CD4⁺ T cells, reduced apoptosis, decreased PD-1 and LAG3 expression, and promoted immune response in sepsis.

In conclusion, this study confirmed that downregulation of TCF7 and LEF-1 expression in sepsis inhibited proliferation of CD4⁺ T cells, leading to immune suppression. This finding suggested that TCF7 and LEF-1 were potential biological targets for sepsis and indicated that immunotherapy aimed at improving CD4⁺ T cell proliferation may be a new strategy for immune therapy in sepsis patients.