Regulatory T Cells Expressing Tumor Necrosis Factor Receptor Type 2 Play a Major Role in CD4+ T-Cell Impairment During Sepsis

Gaborit, Benjamin; Roquilly, Antoine; Louvet, Cédric; Sadek, Abderrahmane; Tessoulin, Benoît; Broquet, Alexis; Jacqueline, Cédric; Vourc’h, Mickaël; Chaumette, Tanguy; Chauveau, Marie; Asquier, Antoine; Bourdiol, Alexandre; Mabecque, Virginie Le; Davieau, Marion; Caillon, Jocelyne; Boutoille, David; Coulpier, Fanny; Lemoine, Sophie; Ronin, Émilie; Poschmann, Jérémie; Salomon, Benoı̂t L.

doi:10.1093/infdis/jiaa225

Cited by 13 publications

(11 citation statements)

References 39 publications

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“…In sepsis, TNFR2 has been shown to associate with CD4 + T-cell impairment and post-septic immunosuppression by activation of Tregs [ 59 ]. In addition to immunosuppression, significant upregulation of TNFR2 in kidney injury was observed on tubular epithelial cells, including both distal convoluted tubules and proximal convoluted tubules [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries

Snyder

Connolly

et al. 2022

Biomedicines

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The novel therapeutic target cytokine LIGHT (TNFSF14) was recently shown to play a major role in COVID-19-induced acute respiratory distress syndrome (ARDS). This study aims to investigate the associations of plasma LIGHT and another potentially targetable cytokine, interleukin-18 (IL-18), with ARDS, acute hypoxic respiratory failure (AHRF), or acute kidney injury (AKI), caused by non-COVID-19 viral or bacterial sepsis. A total of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this cohort study. Day 0 plasma LIGHT and IL-18, as well as 59 other biomarkers (cytokines, chemokines, and acute-phase reactants) were measured by sensitive bead immunoassay and associated with symptom severity. We observed significantly increased LIGHT level in both bacterial sepsis patients (p = 1.80 × 10−5) and patients with sepsis from viral infections (p = 1.78 × 10−3). In bacterial sepsis, increased LIGHT level was associated with ARDS, AKI, and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failure. IL-18 levels were highly variable across individuals and consistently correlated with Apache III scores, mortality, and AKI in both bacterial and viral sepsis. There was no correlation between LIGHT and IL-18. For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failure. The association of plasma LIGHT with AHRF suggests that targeting the pathway warrants exploration, and ongoing trials may soon elucidate whether this is beneficial. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway requires precise application.

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Section: Discussionmentioning

confidence: 99%

Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries

Snyder

Connolly

et al. 2022

Biomedicines

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“…In recent years, TNFR2 has attracted research attentions as an emerging drug target for autoimmune diseases and cancer 57 . In sepsis, TNFR2 has been shown to associate with CD4+ T-cell impairment and post-septic immunosuppression by activation of regulatory T cells (Treg) 58 . Renal-expressed TNFR2 promotes renal monocyte recruitment by the IRF1 and IFN-β autocrine signaling, and may lead to renal injury 59 .…”

Section: Discussionmentioning

confidence: 99%

“…In sepsis, TNFR2 has been shown to associate with CD4+ T-cell impairment and post-septic immunosuppression by activation of Tregs [60]. Besides immunosuppression, significant up-regulation of TNFR2 in kidney injury was observed on tubular epithelial cells, including both distal convoluted tubules and proximal convoluted tubules [61].…”

Section: Light/il-18 Levels and Akimentioning

confidence: 99%

Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries

Jian

Dunn³

et al. 2021

Preprint

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Objective The cytokines, LIGHT (TNFSF14) and Interleukin-18 (IL-18), are two important therapeutic targets due to their central roles in the function of activated T cells and inflammatory injury. LIGHT was recently shown to play a major role in COVID19 induced acute respiratory distress syndrome (ARDS), reducing mortality and hospital stay. This study aims to investigate the associations of LIGHT and IL-18 with non-COVID19 related ARDS, acute hypoxic respiratory failure (AHRF) or acute kidney injury (AKI), secondary to viral or bacterial sepsis. Research Design and Methods A cohort of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this study and compared to healthy controls. Serum LIGHT, IL-18, and 59 other biomarkers (cytokines, chemokines and acute-phase reactants) were measured and associated with symptom severity. Results ARDS was observed in 36% of the patients, with 29% of the total patient cohort developing multi-organ failure (failure of two or more organs). We observed significantly increased LIGHT level (>2SD above mean of healthy subjects) in both bacterial sepsis patients (P=1.80E-05) and patients with sepsis from viral infections (P=1.78E-03). In bacterial sepsis, increased LIGHT level associated with ARDS, AKI and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failures, suggesting LIGHT may be an inflammatory driver. IL-18 levels were highly variable across individuals, and consistently correlated with Apache III scores, mortality, and AKI, in both bacterial and viral sepsis. Conclusions For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failures. LIGHT levels are significantly elevated in non-COVID19 sepsis patients with ARDS and/or multi-organ failures suggesting that anti-LIGHT therapy may be effective therapy in a subset of patients with sepsis. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway raises opportunities that require a precision application.

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“…(59,67,97). The "two-hit" model was used to mimic clinical conditions of secondary infection, but different regimens yielded surprisingly different results (57,70,83,90,97).…”

Section: Limitations Of Treg Models In Sepsismentioning

confidence: 99%

“…Due to their relatively stable genetic uniformity, inbred BALB/c and C57BL/6 mice are most frequently used in sepsisrelated studies (47,59,65,70,83,86,98,118,177). Nevertheless, researchers are beginning to emphasize the importance of using genetically heterogeneous organisms in experiments since they can better simulate the heterozygosity of humans, especially in multi-dimensional heterogeneous syndromes such as sepsis (19,23,67,85,100,135,136).…”

Section: Limitations Of Treg Models In Sepsismentioning

confidence: 99%

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

et al. 2022

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Sepsis is a syndrome characterized by life-threatening organ dysfunction caused by the dysregulated host response to an infection. Sepsis, especially septic shock and multiple organ dysfunction is a medical emergency associated with high morbidity, high mortality, and prolonged after-effects. Over the past 20 years, regulatory T cells (Tregs) have been a key topic of focus in all stages of sepsis research. Tregs play a controversial role in sepsis based on their heterogeneous characteristics, complex organ/tissue-specific patterns in the host, the multi-dimensional heterogeneous syndrome of sepsis, the different types of pathogenic microbiology, and even different types of laboratory research models and clinical research methods. In the context of sepsis, Tregs may be considered both angels and demons. We propose that the symptoms and signs of sepsis can be attenuated by regulating Tregs. This review summarizes the controversial roles and Treg checkpoints in sepsis.

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Regulatory T Cells Expressing Tumor Necrosis Factor Receptor Type 2 Play a Major Role in CD4+ T-Cell Impairment During Sepsis

Cited by 13 publications

References 39 publications

Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries

Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries

Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

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