Soluble B and T Lymphocyte Attenuator Correlates to Disease Severity in Sepsis and High Levels Are Associated with an Increased Risk of Mortality

Lange, A.; Sundén-Cullberg, Jonas; Magnuson, Anders; Hultgren, Olof

doi:10.1371/journal.pone.0169176

Cited by 38 publications

(35 citation statements)

References 49 publications

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“…We did not find any significant differences in sPD-1 or sPD-L1 levels between patients with sepsis and controls; of note, levels were towards the lower limit of detection in the majority of subjects. Previous studies measuring serum sPD-1/L levels in sepsis have yielded inconsistent results [ 21 – 23 ] (Additional file 17 : Table S6). Importantly, concurrent cell surface expression was not measured in any of these studies.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, concurrent cell surface expression was not measured in any of these studies. Timing of measurement may contribute to the differences; we measured sPD-1/PD-L1 within 12 h of ICU admission whereas the others varied from time of presentation to the emergency department [ 21 ] to within 24 h of ICU admission [ 22 , 23 ]. Our pilot study results suggest that sPD-1 or sPD-L1 levels within 12 h of ICU admission do not identify patients with high cell surface PD-1/L expression [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

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Lymphocyte subset expression and serum concentrations of PD-1/PD-L1 in sepsis - pilot study

et al. 2018

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BackgroundSepsis remains a major cause of mortality in critical care, for which specific treatments are lacking. The dysregulated response to infection seen in sepsis includes features of lymphocyte dysfunction and exhaustion, suggesting that immune-stimulatory therapy may improve outcomes in certain patient groups. Monoclonal antibodies targeting checkpoint molecules, such as programmed-death 1 protein (PD-1) and its ligand PD-L1, have shown success in stimulating the immune response in patients with cancer, and are being considered for future sepsis trials. The aims of this pilot study were to compare lymphocyte subset expression of PD-1 and its ligands between patients with sepsis and controls; to characterize serum levels of PD-1 and PD-L1 in patients with sepsis and controls, and determine if serum concentrations correlated with cell surface expression.MethodsExpression levels of PD-1, PD-L1 and PD-L2 on four lymphocyte subsets (CD27 + CD19+ B cells, CD27-CD19+ B cells, CD27 + CD4+ T cells and CD27-CD4+ T cells) were compared between 22 patients with sepsis (including 11 survivors and 11 non-survivors) and 11 healthy controls using flow cytometry. Levels of soluble PD-1 and PD-L1 were also compared using commercially available ELISA kits.ResultsExpression of PD-1 and PD-L1 was higher on all lymphocyte subsets in patients with sepsis compared to controls (p < 0.05). PD-L2 expression on CD27+ B cells was also higher in patients with sepsis (p = 0.0317). There was differential expression of PD-1 by CD27 status, with expression being higher in the B and T cell subsets associated with memory status (CD27+ and CD27-, respectively; p < 0.001). Higher PD-1 and PD-L1 expression was not associated with mortality or with a higher risk of nosocomial infection. There were no differences in levels of soluble PD-1 or PD-L1 between patients with sepsis and controls.ConclusionsHigher expression of PD-1 by memory subpopulations of B cells and CD4+ T cells, with normal soluble PD-1 and PD-L1 in patients with sepsis, are novel findings. This information may be useful to enrich sepsis populations for trials of PD-1/PD-L1 blockade.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2020-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lymphocyte subset expression and serum concentrations of PD-1/PD-L1 in sepsis - pilot study

et al. 2018

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“…These results demonstrate that anti-BTLA actually further potentiated BTLA actions in this model of sepsis. In an interesting study by Lange et al soluble BTLA (sBTLA) levels in the plasma were founds to be significantly higher among sepsis patients as compared to controls and the levels also correlated with clinical severity of the disease [ 61 ]. Moreover, the relative risk of 28-day mortality among septic patients was five-fold higher among patients with baseline sBTLA levels of greater than 21 ng/mL, as compared to those with a level below this threshold, suggesting that sBTLA may be explored as a prognostic marker in sepsis [ 61 ].…”

Section: B and T Lymphocyte Attenuator (Btla)mentioning

confidence: 99%

“…In an interesting study by Lange et al soluble BTLA (sBTLA) levels in the plasma were founds to be significantly higher among sepsis patients as compared to controls and the levels also correlated with clinical severity of the disease [ 61 ]. Moreover, the relative risk of 28-day mortality among septic patients was five-fold higher among patients with baseline sBTLA levels of greater than 21 ng/mL, as compared to those with a level below this threshold, suggesting that sBTLA may be explored as a prognostic marker in sepsis [ 61 ]. This study has some major drawbacks as noted by the authors including limited plasma samples in certain later phases of the study period, due to missing samples or patients being transferred from the intensive care unit, leading to limitations on conclusions that could be drawn on dynamics of immune markers studied, and varied time points of sepsis onset among different subjects studied.…”

Section: B and T Lymphocyte Attenuator (Btla)mentioning

confidence: 99%

Targeting Immune Cell Checkpoints during Sepsis

Patil

Guo

Luan

et al. 2017

IJMS

129

104

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Immunosuppression is increasingly being recognized as one of the causes of increased morbidity and mortality during sepsis. Both innate and adaptive immune system dysfunction have been shown to cause an impaired ability to eradicate the primary infection and also lead to frequent occurrence of secondary opportunistic infections. Pre-clinical and clinical studies have shown that inhibitory immune checkpoint molecules, including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell membrane protein-3 (TIM-3), Lymphocyte activation-gene-3 (LAG-3) and 2B4, are upregulated during the course of sepsis. Engagement of these inhibitory molecules on various immune cells has been consistently shown to inhibit innate immune cell functions (e.g., phagocytosis, cytokine production and pathogen clearance) and also lead to impaired T cell competence. In numerous pre-clinical models of sepsis, therapeutic agents aimed at blocking engagement of inhibitory immune checkpoints on immune cells have been shown to improve innate and adaptive immune cell functions, increase host resistance to infection and significantly improve survival. Therefore, immunotherapy with immune cell checkpoint inhibitors holds significant potential for the future of sepsis therapy and merits further investigation.

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“…The splicing of BTLA-202 leads to loss of the transmembrane helix domain, resulting in a soluble BTLA product compared with the canonical isoform. This soluble isoform was confirmed and found to increase in the early stages of sepsis(51, 52) and was able to enhance antitumor activity in a melanoma pulmonary metastasis model in combination of HSP70 vaccine(53). Thus, the enrichment of T BTLA 202 cells in CD8+ exhausted T cells may suggest a new mechanism for the induction of immunosuppressive tumor microenvironment.…”

Section: Resultsmentioning

confidence: 81%

Landscape of transcript isoforms in single T cells infiltrating in non-small cell lung cancer

Zhang

Ren

2020

Preprint

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11Single cell RNA-seq has enabled high-resolution characterization of molecular signatures of tumor-12 infiltrating lymphocytes. However, analyses at the transcript isoform level are rarely reported. As 13 alternative splicing is critical to T cell differentiation and activation, here we proposed a computational 14 method named as IDEA to comprehensively detect and annotate differentially used isoforms across 15 cell subtypes. We applied IDEA on a scRNA-seq dataset of 12,346 T cells from non-small cell lung 16 cancer. We found most genes tend to dominantly express one isoform in single T cells, enabling 17 typing T cells according to the isotypes given a gene. Isotype analysis suggested that tumor-infiltrating 18 T cells significantly preferred specific isotypes for 245 genes in CD8+ T cells and 456 genes in CD4+ 19 T cells. Functional annotation suggests that the preferred isoforms involved in coding/non-coding 20 switches, transcription start site changes, gains/losses of domains and subcellular translocation. 21 Clonal analysis revealed that isoform switching occurred during T cell activation/differentiation. Our 22 analysis provides precise characterization of the molecular events in tumor-infiltrating T cells and 23 sheds new lights into the regulatory mechanisms of tumor-infiltrating T cells. 24 25 65 Altogether, our work provides a comprehensive analysis of the transcript isoform landscape of tumor-66 infiltrating T cells in non-small cell lung cancer at the single-cell resolution. The abundant isoform 67 switching events identified among tumor-infiltrating T cell subtypes may serve as a rich data resource 68for precisely analyzing the mechanisms underlying T cell-based antitumor immunity. Our analysis also 69 highlights the necessity of splicing analysis at the single-cell resolution, which can be applied to a 70 wide range of biological questions.

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Soluble B and T Lymphocyte Attenuator Correlates to Disease Severity in Sepsis and High Levels Are Associated with an Increased Risk of Mortality

Cited by 38 publications

References 49 publications

Lymphocyte subset expression and serum concentrations of PD-1/PD-L1 in sepsis - pilot study

Lymphocyte subset expression and serum concentrations of PD-1/PD-L1 in sepsis - pilot study

Targeting Immune Cell Checkpoints during Sepsis

Landscape of transcript isoforms in single T cells infiltrating in non-small cell lung cancer

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