Abstract
ContextSepsis is characterized by the development of adaptive immune cell alterations, which intensity and duration are associated with increased risk of health-care associated infections and mortality. However, pathophysiological mechanisms leading to such lymphocyte dysfunctions are not completely understood, although both intrinsic lymphocyte alterations and antigen-presenting cells (APCs) dysfunctions are most likely involved.StudyThe aim of the current study was to evaluate whether lipopolysaccharide (LPS, mimicking initial Gram negative bacterial challenge) could directly impact lymphocyte function after sepsis. Therefore, we explored ex-vivo the effect of LPS priming on human T lymphocyte proliferation induced by different stimuli.ResultsWe showed that LPS priming of PBMCs reduced T cell proliferative response and altered IFNγ secretion after stimulation with OKT3 but not with phytohaemagglutinin or anti-CD2/CD3/CD28-coated beads stimulations. Interestingly only LPS priming of monocytes led to decreased T cell proliferative response as opposed to LPS priming of lymphocytes. Importantly, LPS priming was associated with reduced expression of HLA-DR, CD86 and CD64 on monocytes but not with the modification of CD3, CTLA4, PD-1 and CD28 expressions on lymphocytes. Finally, IFNγ stimulation restored monocytes accessory functions and T cell proliferative response to OKT3.ConclusionWe conclude that LPS priming does not directly impact lymphocyte functions but reduces APC’s capacity to activate T cells. This recapitulates ex vivo indirect mechanisms participating in sepsis-induced lymphocyte alterations and suggests that monocyte-targeting immunoadjuvant therapies in sepsis may also help to improve adaptive immune dysfunctions. Direct mechanisms impacting lymphocytes being also at play during sepsis, the respective parts of direct versus indirect sepsis-induced lymphocyte alterations remain to be evaluated in clinic.
Highlights
Septic syndromes represent a major healthcare problem worldwide accounting for a high number of deaths every year [1,2].Sepsis is characterized by the development of a phase of immunosuppression affecting both innate and adaptive immunity
We showed that LPS priming of PBMCs reduced T cell proliferative response and altered IFNγ secretion after stimulation with OKT3 but not with phytohaemagglutinin or anti-CD2/ CD3/CD28-coated beads stimulations
Only LPS priming of monocytes led to decreased T cell proliferative response as opposed to LPS priming of lymphocytes
Summary
Septic syndromes represent a major healthcare problem worldwide accounting for a high number of deaths every year [1,2].Sepsis is characterized by the development of a phase of immunosuppression affecting both innate and adaptive immunity. Circulating lymphocytes in septic patients present an exhausted phenotype, characterized by lower levels of CD3 and co-stimulatory molecule, increased expression of co-inhibitory receptors such as PD-1 (programmed cell death receptor-1) or CTLA-4 (cytotoxic T lymphocyte associated protein 4) [3,4]. Many studies have demonstrated an association between intensity and length of sepsis-induced T cell anergy and/or lymphopenia and increased risk of HAI (healthcare associated infections) and mortality [5,6]. This constitutes the rational for innovative therapeutic interventions (such as rhIL-7 (recombinant human interleukin-7) or anti-PD-1/PD-L1 (PD-1 ligand) antibodies) targeting these lymphocyte alterations that are considered in the treatment of septic patients [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
