Fig. 1.

T cells dysregulation in critical illnesses. T cell alterations include lymphopenia with polarization of Th cells towards Th2, increase of Th17 cells, increase of Tregs and reduction of innate T cells (MAIT cells and γδT cells). The main mechanisms responsible for these alterations are: lymphocyte apoptosis, autophagy deficiency, lymphocyte metabolic reprogramming and T cell anergy and exhaustion. Lymphocyte apoptosis: in the mitochondrial pathway, caspase-9 serves as an initiator caspase. The activation of the initiator caspase, caspase-9 (mitochondrial pathway) is responsible for increased apoptosis. Autophagy deficiency results in reduced lymphocyte apoptosis inhibition. Lymphocyte metabolic reprogramming: during sepsis or burns, the increase of arginase activity induces a decrease of arginine with a subsequent reduction of mitochondrial activity and glycolysis. Exhaustion and anergy: in critical inflammatory diseases, T cells express exhaustion markers on their surface and have reduced capacity to proliferate and activate. They produce less pro-inflammatory cytokines and more anti-inflammatory cytokines, such as IL-10. Finally, alterations of innate immune response contribute to T lymphocytes dysfunction. Monocytes and dendritic cells express less HLA-DR and have therefore, reduced capacities of antigen presentation, thus contributing to T cells anergy and exhaustion. NK cells produce less INFγ. The increase in MDSC is involved in the Treg increase, as well as in the Th2 cells polarization, in the inhibition of T cell proliferation and in the inhibition of NK cells cytokines production. ATP: adenosine triphosphate; Th2: T helper 2 cells; Th17: Th17 cells, Casp-9: caspase 9, OCR: oxygen consumption rate, DC: dendritic cells, HLA-DR: human leukocyte antigen-DR isotype, CTLA-4: cytotoxic T-lymphocyte-associated protein 4, TIM-3: T-cell immunoglobulin and mucin containing protein-3, LAG-3: lymphocyte-activation gene 3, PD-1: programmed death protein 1, INFγ: interferon γ, TNFα: tumor necrosis factor α, IL-6: interleukin 6, IL-10: interleukin 10, TGF-β: transforming growth factor β, Th2: Th2 cells, Th17: Th17 cells, MDSC: myeloid-derived suppressor cells