Abstract
BackgroundSepsis is the leading cause of mortality for critically ill patients worldwide. Patients develop T lymphocyte dysfunctions leading to T-cell exhaustion associated with increased risk of death. As interleukin-7 (IL-7) is currently tested in clinical trials to reverse these dysfunctions, it is important to evaluate the expression of its specific CD127 receptor on the T-cell surface of patients with septic shock. Moreover, the CD127lowPD-1high phenotype has been proposed as a T-cell exhaustion marker in chronic viral infections but has never been evaluated in sepsis. The objective of this study was first to evaluate CD127 and CD127lowPD-1high phenotype in septic shock in parallel with functional T-cell alterations. Second, we aimed to reproduce septic shock–induced T-cell alterations in an ex vivo model.MethodsCD127 expression was followed at the protein and mRNA levels in patients with septic shock and healthy volunteers. CD127lowPD-1high phenotype was also evaluated in parallel with T-cell functional alterations after ex vivo activation. To reproduce T-cell alterations observed in patients, purified T cells from healthy volunteers were activated ex vivo and their phenotype and function were evaluated.ResultsIn patients, neither CD127 expression nor its corresponding mRNA transcript level was modified compared with normal values. However, the percentage of CD127lowPD-1high T cells was increased while T cells also presented functional alterations. CD127lowPD-1high T cells co-expressed HLA-DR, an activation marker, suggesting a role for T-cell activation in the development of this phenotype. Indeed, T-cell receptor (TCR) activation of normal T lymphocytes ex vivo reproduced the increase of CD127lowPD-1high T cells and functional alterations following a second stimulation, as observed in patients. Finally, in this model, as observed in patients, IL-7 could improve T-cell proliferation.ConclusionsThe proportion of CD127lowPD-1high T cells in patients was increased compared with healthy volunteers, although no global CD127 regulation was observed. Our results suggest that TCR activation participates in the occurrence of this T-cell population and in the development of T-cell alterations in septic shock. Furthermore, we provide an ex vivo model for the investigation of the pathophysiology of sepsis-induced T-cell immunosuppression and the testing of innovative immunostimulant treatments.
Highlights
Sepsis is the leading cause of mortality for critically ill patients worldwide
We aimed to evaluate the effect of T-cell activation through T-cell receptors (TCRs) on the development of these phenotypic and functional alterations in an ex vivo model
We show that a complete ex vivo TCR activation of purified T cells from healthy donors led to the induction of CD127lowPD-1high T cells and HLA-DR expression, as observed in patients with septic shock
Summary
Sepsis is the leading cause of mortality for critically ill patients worldwide. Patients develop T lymphocyte dysfunctions leading to T-cell exhaustion associated with increased risk of death. Sepsis has recently been re-defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. It represents a major health-care challenge with high incidence and mortality [2, 3]. Most patients with sepsis are lymphopenic [9], and the remaining T lymphocytes show a poor functional status This includes decreased proliferation and cytokine production ex vivo and increased apoptosis [8, 10, 11] along with an increased expression of co-inhibitory receptors such as PD-1 [12, 13]. Clinical trials evaluating immuno-adjuvant therapies to target T-cell alterations are ongoing in sepsis
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