Impaired CD4⁺ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis

Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to alterations in myeloid cell function; however, the effect of severe sepsis on subsequent CD4⁺ T-cell responses remains unclear. In the present study, CD4 ⁺ T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro. CD4 ⁺CD62L⁺ T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4 ⁺CD62L⁺ T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing with exogenous cytokines, indicating a decreased capability of these cells to commit to either the T_H1 or T_H2 lineage. Repressive histone methylation marks were also evident at promoter regions for the T_H1 cytokine IFN-γ and the T _H2 transcription factor GATA-3 in naïve CD4⁺ T cells from CLP mice. These results provide evidence that CD4⁺ T-cell subsets from post-septic mice exhibit defects in activation and effector function, possibly due to chromatin remodeling proximal to genes involved in cytokine production or gene transcription.