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

Abstract

Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from lifethreatening 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 CD41 T-cell responses remains unclear. In the present study, CD4 1 T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro. CD4 1 CD62L 1 T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4 1 CD62L 1 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 H 1 or T H 2 lineage. Repressive histone methylation marks were also evident at promoter regions for the T H 1 cytokine IFN-c and the T H 2 transcription factor GATA-3 in naïve CD4 1 T cells from CLP mice. These results provide evidence that CD4 1 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.

Differential alterations of tissue T-cell subsets after sepsis

“…It has also been indicated that sepsis induces anergic state in CD4 + T cells with defects in proliferation and dysregulated Th1 and Th2 cytokine production attributed to chromatin remodeling [52]. Therefore, a future study is granted to identify the change of cytokine production and cellular function of T cell subsets in various organs after sepsis.…”

Immune Cell Dysfunction as a Consequence of Severe Sepsis

“…One of the hallmarks of CD4+ T cells from septic patients is the development of anergy, or unresponsives to antigen stimulation (Heidecke et al, 1999). CD4+ T cells from septic animals also exhibit this anergic phenotype, and the proliferative capacity of these cells is not recovered by the addition of exogenous cytokines, such as the potent T cell proliferative factor IL-2 (W. F. Carson et al, 2010). In addition, their gene expression is drastically altered as compared to CD4+ T cells from healthy animals.…”

“…Concurrently, these cells downregulate mRNA for cell surface receptors critical for T cell activation, including CD4 and CD28. As these differences in gene expression are observed following optimized polyclonal stimulus in the absence of accessory cells such as DCs, it appears that the changes in gene expression are due to cellintrinsic factors (W. F. Carson et al, 2010). This modulated cytokine response by post-septic CD4+ T cells becomes even more apparent once these cells are tasked with committing to specific T-helper lineages.…”

“…For example, when expanded in an optimized T H 1-promoting environment (including exogenous IL-12 and blocking antibodies to IL-4), post-septic CD4+ T cells produce significantly less IFN in recall responses, as compared to CD4+ T cells from control animals. If these same cells are expanded in a T H 2 culture (exogenous IL-4 and blocking antibodies to IL-12 and IFN ), postseptic CD4+ T cells produce both T H 1 and T H 2 cytokines upon recall, whereas CD4+ T cells from control animals only make T H 2 cytokines (W. F. Carson et al, 2010). This modulation in T-helper subtype cytokine responses represents an inability of post-septic CD4+ T cells to properly commit to either the T H 1 or T H 2 effector lineage.…”

“…In addition, these same cells exhibit increased levels of H3K27me in the promoter region of Gata3, a transcription factor critical for the development of T H 2 T cells. This increase in repressive histone methylation correlates with the reduced capacity of post-septic T cells to fully commit to the T H 2 lineage, as evidenced by the continued production of IFN in T H 2 inflammatory contexts both in vitro and in vivo (W. F. Carson et al, 2010;. In addition to modulations in histone methylation, histone acetylation is also modulated in post-septic CD4+ T cells, in particular the CD4+ CD25-T cell subset that is thought to consist primarily of effector cells.…”