Severe inflammatory diseases, including sepsis, are characterized by an impaired host adaptive and innate immunity which results in immunosuppression, responsible for secondary infections and increased morbidity and mortality in critically ill patients. T cells are major actors of the immune system. During post-aggressive immunosuppression, lymphopenia, reduction of innate T cells, changes in T helper cell polarization and regulatory T cell increase are observed. The main mechanisms involved in T cell dysregulation are T cell apoptosis, autophagy deficiency, T cell anergy, T cell exhaustion and T cell metabolic reprogramming. In this review, we describe the alterations of T cell regulation, their mechanisms, and their association with clinical outcomes in severe inflammatory diseases, foremost of which is the sepsis.

Histones are widely recognized as pro-inflammatory mediators upon their release from the nucleus into the extracellular space. However, their impact on endothelial cell immunogenicity is unknown. Endothelial cells, Human Microvascular Endothelial cells 1 (HMEC1), have been exposed to recombinant histones in order to study their effect on the endothelial phenotype. We then studied the differentiation of CD4+-T lymphocytes subpopulations after three days of interaction with endothelial cells in vitro and observed that histone-treated endothelial cells differentiate a suppressive FoxP3+ T regulator subpopulation that expressed Human Leucocyte Antigen DR (HLA-DR) and Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA4). Toll-Like Receptor 4 (TLR4) inhibition significantly decreased the expansion of these Treg cells. Moreover, blockade of Interleukin (IL)-6 and Intercellular Adhesion Molecule (ICAM)-1 in cocultures significantly decreased the expansion of Tregs, suggesting an IL-6 and ICAM-1 dependent pathway. Thus, beyond their inflammatory effects, extracellular histones may induce an increase of immunosuppressive Treg population via their action on endothelial cells. Further studies are needed to evaluate the impact on immunosuppression of an increase of peripheral suppressive Treg via endothelial cell activation by histones in vivo.