Chronic Critical Illness from Sepsis Is Associated with an Enhanced TCR Response

Borken, Farina; Markwart, Robby; Requardt, Robert P.; Schubert, Katja; Špaček, M.; Verner, Miroslav; Rückriem, Stefan; Scherag, André; Oehmichen, Frank; Brunkhorst, Frank M.; Rubio, Ignacio

doi:10.4049/jimmunol.1700142

Cited by 15 publications

(12 citation statements)

References 72 publications

(95 reference statements)

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“…41 Besides the numerical loss or clonal shift, multiple dysfunctions in T cells' metabolism and activation in sepsis have been reported. 44 Nonetheless, the extent to which these cell-intrinsic impairments contribute to post-sepsis immunosuppression has now been challenged, 45,46 implying a prominent role of T cells' extrinsic cues in the post-sepsis environment (eg, defective antigen presentation). Also, the impact of sepsis on non-conventional, but biologically potent T-cell subsets such natural killer T cells or γδ T cells deserves more attention.…”

Section: Immunological Gaps During Sepsismentioning

confidence: 99%

Current gaps in sepsis immunology: new opportunities for translational research

Rubio

Osuchowski

Shankar-Hari

et al. 2019

The Lancet Infectious Diseases

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Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care.

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Section: Immunological Gaps During Sepsismentioning

confidence: 99%

Current gaps in sepsis immunology: new opportunities for translational research

Rubio

Osuchowski

Shankar-Hari

et al. 2019

The Lancet Infectious Diseases

Self Cite

257

207

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“…T cells were eluted into the cell culture medium (RPMI 1,640 medium supplemented with penicillin and streptomycin and 10% heat-inactivated fetal calf serum (FCS) and kept in a humidified atmosphere at 37 °C and 5% CO 2 for 24 h before stimulation. Peripheral T cells from a donor and patient blood were isolated and cultured in the same way out of PBMCs, except that a step of erythrocyte lysis was included before magnetic sorting 15 .…”

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confidence: 99%

Cytokine production in patients with recurrent acute tonsillitis: analysis of tonsil samples and blood

Geißler

Weigel

Schubert

et al. 2020

Sci Rep

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the aim of this study was to examine t cell function in tonsils of patients with recurrent acute tonsillitis (RAT) or peritonsillar abscess (PTA) by analyzing the cytokine production following T cell receptor (TCR) and co-receptor stimulation with a combination of anti-CD3 and anti-CD28 antibodies. The release of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10 and IL-17A from isolated, stimulated T cells of 27 palatine tonsils (10 RAT, 7 PTA, 10 tonsils without inflammation) was measured via a bead-based flow cytometric analysis. The results were compared with the cytokine release of isolated peripheral T cells in a subset of the same patients (6 PTA, 4 patients without signs of inflammation in the blood). tcR stimulation increased the concentration of released cytokines in tonsil and blood as well as in different forms of inflammation and tissue with no inflammation. Stimulation increased the proinflammatory cytokines TNF-α, IFN-γ, and IL-2 more than the anti-inflammatory cytokines IL-4 and IL-10 in tonsil and blood samples in RAT, PTA, and samples without inflammation. Blood of patients with PTA showed a higher pro-inflammatory cytokine level compared to the samples of patients without inflammation. T cells in tonsils are fully responsive and competent for antigen-induced cytokine production in RAT and PTA. One should be aware that tonsillectomy, if indicated, might remove a functioning immune organ. Tonsillotomy might be an alternative even in adults to maintain immunological function. The palatine tonsils as paired lymphatic organs are located at the beginning of the upper aerodigestive tract and are responsible for immune protection against ingested and inhaled pathogens. In this context, innate and adaptive immune reactions interact, whereby tonsillar T cells located primarily in the extra-follicular spaces, in particular, play a dominant role 1. Cytokines are produced in the context of inflammatory reactions by immunecompetent cells. A distinction is made between genuine pro-inflammatory, e. g. tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-6, IL17-A, and mostly anti-inflammatory cytokines like IL-4 and IL-10 2-4. Furthermore, depending on the inflammatory scenario, T-cells can differentiate into differently primed states, including Th1, Th2, and Th17. Briefly, Th1 helper cells produce large amounts of IFN-γ, IL-2, and TNF-β, which trigger macrophages and are important for cell-mediated immunity and phagocyte-dependent immune responses. Th2 cells produce IL-4, IL-5, IL-10, and IL-13, which promote antibody production, eosinophil activation, and inhibition of several macrophage functions 5. Th17 cells and their effector cytokines IL-17A, IL-17F, IL-21, and IL-22 mediate host defense mechanisms to a variety of infections, especially of bacterial origin, and are furthermore involved in the pathogenesis of many autoimmune diseases 6. Recurrent acute tonsillitis (RAT) is a common chronic inflammation of the palatine tonsils, which often needs surgical excision 7 .

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“…The co-expression of a late activation marker in parallel with a characteristic phenotype of T-cell exhaustion suggests a potential role for T-cell activation in the development of T-cell alterations following septic shock. Similarly, it has been shown that T cells from patients with sepsis present an activated phenotype [46, 47]. Furthermore, this potential role for T-cell activation is supported by ex vivo data.…”

Section: Discussionmentioning

confidence: 70%

TCR activation mimics CD127lowPD-1high phenotype and functional alterations of T lymphocytes from septic shock patients

et al. 2019

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Background 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. 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 CD127 low PD-1 high 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 CD127 low PD-1 high 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. Methods CD127 expression was followed at the protein and mRNA levels in patients with septic shock and healthy volunteers. CD127 low PD-1 high 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. Results In patients, neither CD127 expression nor its corresponding mRNA transcript level was modified compared with normal values. However, the percentage of CD127 low PD-1 high T cells was increased while T cells also presented functional alterations. CD127 low PD-1 high 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 CD127 low PD-1 high 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. Conclusions The proportion of CD127 low PD-1 high 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 t...

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Chronic Critical Illness from Sepsis Is Associated with an Enhanced TCR Response

Cited by 15 publications

References 72 publications

Current gaps in sepsis immunology: new opportunities for translational research

Current gaps in sepsis immunology: new opportunities for translational research

Cytokine production in patients with recurrent acute tonsillitis: analysis of tonsil samples and blood

TCR activation mimics CD127lowPD-1high phenotype and functional alterations of T lymphocytes from septic shock patients

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