Indeterminate pediatric acute liver failure is uniquely characterized by a CD103+CD8+ T‐cell infiltrate

Chapin, Catherine A.; Burn, Thomas N.; Meijome, Tomas E.; Loomes, Kathleen M.; Melín-Aldana, Héctor; Kreiger, Portia A.; Whitington, Peter F.; Behrens, Edward M.; Alonso, Estella M.

doi:10.1002/hep.29901

Cited by 60 publications

(60 citation statements)

References 35 publications

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“…In this study, we confirm in all the sHLH or MAS patient livers analysed the infiltration from CD8-positive T cells. Interestingly, biopsies from children with acute liver failure of unknown causes are characterized by a dense infiltrate of perforin expressing CD8-positive T cells [19]. Infiltration from CD8-positive T cells has been proposed as a biomarker able to differentiate acute liver failure of unknown causes from acute liver failure with known aetiology (e.g.…”

Section: Discussionmentioning

confidence: 99%

The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis

et al. 2019

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Aim of this study was to investigate the activation of the IFNγ pathway in the affected liver and in the blood of patients with secondary hemophagocytic lymphohistiocytosis (sHLH). To this purpose, the mRNA expression levels of IFNG and IFNγ-inducible genes as well as Tyrosine (701)-phosphorylated signal transducer and activator of transcription 1 (STAT1) protein levels were evaluated in the liver and in peripheral blood mononuclear cells (PBMCs) of three patients with sHLH with predominant liver involvement. The mRNA expression levels of IFNG and IFNγ-inducible genes were markedly higher in patient livers compared to control livers and to one disease control liver. Conversely, slight differences in the expression levels of Type I IFN-inducible genes and other classical inflammatory cytokine genes were found. Further supporting the activation of the IFNγ pathway, higher protein levels of phosphorylated and total STAT1 were detected in patient livers compared to control livers. When the expression of the same genes analysed in liver tissues was evaluated in PBMCs collected from 2 out of 3 patients before the liver biopsy, we found that mRNA levels of IFNγ-inducible genes were markedly increased. Accordingly, high circulating levels of IFNγ-inducible CXCL9 were observed in patients. Altogether, these data demonstrate the selective and marked up-regulation of the IFNγ pathway in the liver tissue and blood of patients with active sHLH. Finally, we show that measurement of circulating CXCL9 levels and evaluation of IFNγ–inducible gene expression levels in PBMCs may represent a new valid tool to better identify patients with suspected HLH with predominant liver involvement.

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Section: Discussionmentioning

confidence: 99%

The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis

et al. 2019

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“…However, the function of liver T RM cells under nonimmunized or uninfected conditions has not been elucidated. It was recently reported that CD8 + T cells with T RM ‐like features are accumulated in liver of iPALF patients, suggesting that liver CD8 + T RM cells might be involved in the immunopathogenesis that leads to liver failure. On the other hand, the CD8 + T RM cell population was also expanded in livers of Cic f/f ;Vav1‐Cre mice (Supporting Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although hepatic CD8 + T RM cells are known to contribute to protective immunity against liver‐stage malarial infection, it has not been appreciated how important the maintenance of the CD8 + T RM cell population at physiological levels is. Moreover, although it was observed that frequency of CD8 + T RM ‐like cells are increased in liver of iPALF patients, it remains unclear that this causes liver failure. Our study suggests that enhanced formation of liver CD8 + T RM cells is detrimental to the liver.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that liver CD8 + T RM cells exert protective immune responses directed against liver‐stage malarial infections . Recently, it was also reported that the number of CD8 + T cells with T RM characteristics is increased in liver tissues from indeterminate pediatric acute liver failure (iPALF) patients, implicating the pathogenic role of liver CD8 + T RM cells in liver failure and related liver diseases.…”

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confidence: 99%

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The Capicua/ETS Translocation Variant 5 Axis Regulates Liver‐Resident Memory CD8+ T‐Cell Development and the Pathogenesis of Liver Injury

Park

Kim

et al. 2019

Hepatology

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Liver‐resident memory T (liver TRM) cells exert protective immune responses following liver infection by malaria parasites. However, how these TRM cells are developed and what the consequence is if they are not properly maintained remain poorly understood. Here, we show that the transcriptional repressor, Capicua (CIC), controls liver CD8+ TRM cell development to maintain normal liver function. Cic‐deficient mice have a greater number of liver CD8+ TRM cells and liver injury phenotypes accompanied by increased levels of proinflammatory cytokine genes in liver tissues. Excessive formation of CD69+CD8+ TRM‐like cells was also observed in mice with acetaminophen‐induced liver injury (AILI). Moreover, expansion of liver CD8+ TRM cell population and liver injury phenotypes in T‐cell–specific Cic null mice were rescued by codeletion of ETS translocation variant [Etv]5 alleles, indicating that Etv5 is a CIC target gene responsible for regulation of CD8+ TRM cell development and liver function. We also discovered that ETV5 directly regulates expression of Hobit, a master transcription factor for TRM cell development, in CD8+ T cells. Conclusion: Our findings suggest the CIC‐ETV5 axis as a key molecular module that controls CD8+ TRM cell development, indicating a pathogenic role for CD8+ TRM cells in liver injury.

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“…Importantly, an inverse correlation between liver T RM frequencies and viral titers was observed, indicating that high numbers of specific liver T RM cells were associated with viral control [58]. However, accumulation of intrahepatic CD8 + CD103 + perforin + T cells has been observed in cases of autoimmune hepatitis, particularly in indetermined pediatric acute liver failure [106]. These findings suggest that liver T RM cells could also have a pathogenic function.…”

Section: Liver T Rm Cell Immune Responses To Infectionmentioning

confidence: 95%

Resident Memory T Cells and Their Role within the Liver

Ghilas

Valencia-Hernandez

Enders

et al. 2020

IJMS

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Immunological memory is fundamental to maintain immunity against re-invading pathogens. It is the basis for prolonged protection induced by vaccines and can be mediated by humoral or cellular responses—the latter largely mediated by T cells. Memory T cells belong to different subsets with specialized functions and distributions within the body. They can be broadly separated into circulating memory cells, which pace the entire body through the lymphatics and blood, and tissue-resident memory T (TRM) cells, which are constrained to peripheral tissues. Retained in the tissues where they form, TRM cells provide a frontline defense against reinfection. Here, we review this population of cells with specific attention to the liver, where TRM cells have been found to protect against infections, in particular those by Plasmodium species that cause malaria.

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Indeterminate pediatric acute liver failure is uniquely characterized by a CD103+CD8+ T‐cell infiltrate

Abstract: Indeterminate PALF is characterized by a dense CD8 T-cell hepatic infiltrate consistent with expansion of a tissue resident memory T-cell phenotype; CD8 T-cells are a biomarker of immune dysregulation in iPALF and may be used to better identify and define this group. (Hepatology 2018).

Cited by 60 publications

References 35 publications

The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis

The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis

The Capicua/ETS Translocation Variant 5 Axis Regulates Liver‐Resident Memory CD8+ T‐Cell Development and the Pathogenesis of Liver Injury

Resident Memory T Cells and Their Role within the Liver

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