Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells

Jensen, Isaac J.; Li, Xiang; McGonagill, Patrick W.; Shan, Qiang; Fosdick, Micaela G.; Tremblay, Mikaela M.; Houtman, Jon C. D.; Xue, Hai-Hui; Griffith, Thomas S.; Peng, Weiqun; Badovinac, Vladimir P.

doi:10.7554/elife.70989

Cited by 27 publications

(22 citation statements)

References 86 publications

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“…10 Multiple cytokines, including IFN-γ, IL-2 and TNF-α, have been identified as key regulators in T-cell activation, with the ability to trigger T-cell activation response in a TCR-independent manner. 29 Studies have revealed that the transcriptional profile and chromatin accessibility are altered in memory T cells from sepsis survivors, leading to decreased T-cell cytokine secretion and reduced infection control, 30 which is consistent with our results. We found that the level of IL-2 released by memory CD8 + T cells and the level of IFN-γ released by memory CD4 + T cells of nonsurvivors were significantly decreased, which may abrogate the response of T cells to infection.…”

Section: Discussionsupporting

confidence: 91%

Expression of PD-1 on Memory T Lymphocytes Predicts 28-Day Mortality of Patients with Sepsis: A Prospective Observational Study

Liu¹,

Xue²,

Song³

et al. 2022

JIR

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Background PD-1 is an important immune checkpoint expressed on T lymphocytes and is associated with T-cell function in sepsis. However, the role of PD-1 in naive and memory T-cell responses in sepsis is not well understood. We aimed to determine the expression of PD-1 induced on naive and memory T lymphocytes in patients with sepsis and its association with clinical outcome. Methods A prospective observational study was conducted at a general intensive care unit (ICU). Whole blood samples were collected from patients within 48 h after sepsis diagnosis. PD-1 expression on naive and memory T cells was measured by flow cytometry. The levels of IFN-γ, IL-2 and TNF-α released by memory T cells were also determined. All patients were followed up to 28 days, and 28-day mortality was recorded. Results PD-1 expression showed no difference in naive CD4 + T cells ( P =0.617) or naive CD8 + T cells ( P =0.079) between survivors (n = 21) and nonsurvivors (n = 9). Increased PD-1 expression on memory CD4 + T cells was found in nonsurvivors ( P =0.030) and memory CD8 + T cells ( P =0.006) in comparison with survivors. According to the cutoff value of the percentage of PD-1 on memory CD8 + T cells in predicting 28-day mortality of patients with sepsis, patients were divided into two groups. The 28-day mortality rates between the two groups were significantly different ( P =0.009). A Kaplan Meier curve was constructed to derive a hazard ratio of 9.33 (95% CI: 2.52–34.60) for the percentage of PD-1 on memory CD8 + T cells regarding 28-day mortality. In addition, the IFN-γ secretion of memory CD4 + T cells ( P =0.046) and IL-2 secretion of memory CD8 + T cells ( P =0.014) were significantly greater in survivors than nonsurvivors. Conclusion Flow cytometric assessment of PD-1 expression on memory CD8 + T cells identifies patients with poor outcomes during sepsis.

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Section: Discussionsupporting

confidence: 91%

Expression of PD-1 on Memory T Lymphocytes Predicts 28-Day Mortality of Patients with Sepsis: A Prospective Observational Study

Liu¹,

Xue²,

Song³

et al. 2022

JIR

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“…The sepsis-induced changes in the composition of the memory CD8 T-cell pool and transcriptional landscape culminated in an altered T-cell function and reduced capacity to control L. monocytogenes infection. This may change the host’s capacity to respond to reinfection ( 29 ). In a prospective cohort study, B cells and follicular T cells were linked.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Predictive Values of Ferroptosis-Related Genes in Child Sepsis

Zhang²,

Liu³

et al. 2022

Front. Immunol.

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BackgroundEarly diagnosis of sepsis in children was essential to reducing mortality. This study aimed to explore the value of ferroptosis-related genes in children with sepsis.MethodsWe screened the septic children microarray dataset from the GEO database and analyzed the ferroptosis-related differentially expressed genes (DEGs). A functional analysis of ferroptosis-related DEGs was performed. The protein–protein interaction network was used to identify hub genes. We explored the immune landscape of sepsis and controls. The value of hub genes in diagnosing sepsis was tested in the training (GSE26440) and validation sets (GSE13904), and ELISA was used to verify their diagnostic value in children with sepsis in our hospital.ResultsA total of 2,103 DEGs in GSE26440 were obtained, of which ferroptosis-related DEGs were 34. Enrichment analysis showed significant enrichment in the ferroptosis and hypoxia pathways (i.e., HIF-1 pathway). The top three genes (HMOX1, MAPK14, TLR4) were selected as hub genes. Immunological analysis suggested that 10 cell types (i.e., CD8/CD4 T cells) were lower in sepsis. Immune checkpoint-related genes CD274 (PD-L1), HAVCR2 (TIM3), and SIGLEC15 were overexpressed in sepsis. The AUROC for the diagnosis of sepsis for HMOX1 and TLR4 ranged from 0.77 to 0.81, while the AUROC of MAPK14 reached 0.935 and 0.941 in the training and validation sets. Serum ELISA results of HMOX1 and TLR4 showed no significant difference in differentiating sepsis. The AUROC of MAPK14 was 0.877. When the diagnostic threshold was 74.852 ng/ml, the sensitivity and specificity were 0.906 and 0.719, respectively.ConclusionFerroptosis-related gene MAPK14 is of considerable value in the early diagnosis of sepsis in children.

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“…B cells are considered to have protective functions in sepsis, including antibody-dependent and non-dependent mechanisms ( Kelly-Scumpia et al, 2011 ). However, B cells of sepsis undergo massive apoptosis, and release PAMP and DAMP ( Hotchkiss et al, 2002 ; Jensen et al, 2021 ). Some researches found that serum IgM and IgG antibody concentrations are elevated under sepsis induction ( Nicolai et al, 2020b ).…”

Section: Discussionmentioning

confidence: 99%

Screening of ferroptosis-related genes in sepsis-induced liver failure and analysis of immune correlation

Chen

Liu

2022

PeerJ

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Purpose Sepsis-induced liver failure is a kind of liver injury with a high mortality, and ferroptosis plays a key role in this disease. Our research aims to screen ferroptosis-related genes in sepsis-induced liver failure as targeted therapy for patients with liver failure. Methods Using the limma software, we analyzed the differentially expressed genes (DEGs) in the GSE60088 dataset downloaded from the Gene Expression Omnibus (GEO) database. Clusterprofiler was applied for enrichment analysis of DEGs enrichment function. Then, the ferroptosis-related genes of the mice in the FerrDb database were crossed with DEGs. Sepsis mice model were prepared by cecal ligation and perforation (CLP). ALT and AST in the serum of mice were measured using detection kit. The pathological changes of the liver tissues in mice were observed by hematoxylin-eosin (H & E) staining. We detected the apoptosis of mice liver tissues using TUNEL. The expression of Hmox1, Epas1, Sirt1, Slc3a2, Jun, Plin2 and Zfp36 were detected by qRT-PCR. Results DEGs analysis showed 136 up-regulated and 45 down-regulated DEGs. Meanwhile, we found that the up-regulated DEGs were enriched in pathways including the cytokine biosynthesis process while the down-regulated DEGs were enriched in pathways such as organic hydroxy compound metabolic process. In this study, seven genes (Hmox1, Epas1, Sirt1, Slc3a2, Jun, Plin2 and Zfp36) were obtained through the intersection of FerrDb database and DEGs. However, immune infiltration analysis revealed that ferroptosis-related genes may promote the development of liver failure through B cells and natural killer (NK) cells. Finally, it was confirmed by the construction of septic liver failure mice model that ferroptosis-related genes of Hmox1, Slc3a2, Jun and Zfp36 were significantly correlated with liver failure and were highly expressed. Conclusion The identification of ferroptosis-related genes Hmox1, Slc3a2, Jun and Zfp36 in the present study contribute to our understanding of the molecular mechanism of sepsis-induced liver failure, and provide candidate targets for the diagnosis and treatment of the disease.

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Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells

Cited by 27 publications

References 86 publications

Expression of PD-1 on Memory T Lymphocytes Predicts 28-Day Mortality of Patients with Sepsis: A Prospective Observational Study

Expression of PD-1 on Memory T Lymphocytes Predicts 28-Day Mortality of Patients with Sepsis: A Prospective Observational Study

Diagnostic and Predictive Values of Ferroptosis-Related Genes in Child Sepsis

Screening of ferroptosis-related genes in sepsis-induced liver failure and analysis of immune correlation

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