Single-cell RNA sequencing identifies a population of human liver-type ILC1s

Krämer, Benjamin; Nalin, Ansel P.; Ma, Feiyang; Eickhoff, Sarah; Lutz, Philipp; Goeser, Felix; Finnemann, Claudia; Hack, Gudrun; Raabe, Jan; ToVinh, Michael; Ahmad, Sarah; Hoffmeister, Christoph; Kaiser, Kim M; Manekeller, Steffen; Branchi, Vittorio; Bald, Tobias; Hölzel, Michael; Hüneburg, Robert; Nischalke, Hans Dieter; Semaan, Alexander; Langhans, Bettina; Kaczmarek, Dominik J.; Benner, Brooke; Lordo, Matthew R.; Kowalski, Jesse; Gerhardt, Adam; Timm, Jörg; Toma, Marieta; Mohr, Raphael; Türler, Andreas; Charpentier, Arthur; Bremen, Tobias Van; Feldmann, Georg; Sattler, Arne; Kotsch, Katja; Abdallah, Ali T.; Strassburg, Christian P.; Spengler, Ulrich; Carson, William E.; Mundy-Bosse, Bethany L.; Pellegrini, Matteo; O’Sullivan, Timothy E.; Freud, Aharon G.; Nattermann, Jacob

doi:10.1016/j.celrep.2022.111937

Cited by 17 publications

(9 citation statements)

References 56 publications

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“…These were related to enterocytes and not stem cells, goblet, or Paneth cells. Prior studies of scRNA seq have shown lower stem cell fractions in the liver in patients with cirrhosis, however, our findings of a similar pattern in the terminal ileum are novel [ 8 , 9 ]. This is striking because unlike inflammation, which was more significant in decompensated patients, relatively low proportion of stem cells were found even in the compensated patient.…”

Section: Discussionsupporting

confidence: 55%

“…These changes have been associated with the development and progression of complications such as hepatic encephalopathy (HE), and spontaneous bacterial peritonitis (SBP) [ 5 – 7 ]. While there have been recent single-cell studies focusing on the liver in early-stage cirrhosis and compared to colon in healthy individuals, the impact of later stages of cirrhosis on the intestinal mucosa needs to be explored in humans [ 8 , 9 ]. This is particularly relevant in the small intestine, where there is a high potential for bacterial translocation and worsening of systemic inflammation [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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Single nuclear RNA sequencing of terminal ileum in patients with cirrhosis demonstrates multi-faceted alterations in the intestinal barrier

Jiang,

Xu,

Fagan

et al. 2024

Cell Biosci

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Patients with cirrhosis have intestinal barrier dysfunction but the role of the individual cell types in human small intestine is unclear. We performed single-nuclear RNA sequencing (snRNAseq) in the pinch biopsies of terminal ileum of four age-matched men [56 years, healthy control, compensated, early (ascites and lactulose use) and advanced decompensated cirrhosis (ascites and rifaximin use)]. Cell type proportions, differential gene expressions, cell-type specific pathway analysis using IPA, and cellular crosstalk dynamics were compared. Stem cells, enterocytes and Paneth cells were lowest in advanced decompensation. Immune cells like naive CD4 + T cells were lowest while ITGAE + cells were highest in advanced decompensation patients. MECOM had lowest expression in stem cells in advanced decompensation. Defensin and mucin sulfation gene (PAPSS2) which can stabilize the mucus barrier expression were lowest while IL1, IL6 and TNF-related genes were significantly upregulated in the enterocytes, goblet, and Paneth cells in decompensated subjects. IPA analysis showed higher inflammatory pathways in enterocytes, stem, goblet, and Paneth cells in decompensated patients. Cellular crosstalk analysis showed that desmosome, protease-activated receptors, and cadherin-catenin complex interactions were most perturbed in decompensated patients. In summary, the snRNAseq of the human terminal ileum in 4 subjects (1 control and three cirrhosis) identified multidimensional alteration in the intestinal barrier with lower stem cells and altered gene expression focused on inflammation, mucin sulfation and cell–cell interactions with cirrhosis decompensation.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Single nuclear RNA sequencing of terminal ileum in patients with cirrhosis demonstrates multi-faceted alterations in the intestinal barrier

Jiang,

Xu,

Fagan

et al. 2024

Cell Biosci

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“…113 As ILC1 have been recovered from all mouse peripheral organs analyzed, in addition to certain human tissues, they likely represent the first critical line of nonspecific lymphocyte defense in response to myeloidderived inflammation during infection and tissue injury. 113,114,[118][119][120] Current evidence from mouse studies in the salivary gland and uterus supports the hypothesis that trNK cells are derived from circulating NK cells and are likely epigenetically imprinted based on tissue-specific factors. 121 Because the developmental and phenotypic differences between group 1 ILCs have been reviewed previously, 117 we will focus our discussion on studies detailing the impact of epigenetic modifications on the survival of distinct subsets of group 1 ILCs.…”

Section: Trafficking and Tissue-residencymentioning

confidence: 98%

“…For instance, ILC1s represent long‐term tissue‐resident group 1 ILCs that are the first lymphocytes to produce IFN‐γ in response to IL‐12 and IL‐18 in initially infected tissues of naïve mice 113 . As ILC1 have been recovered from all mouse peripheral organs analyzed, in addition to certain human tissues, they likely represent the first critical line of nonspecific lymphocyte defense in response to myeloid‐derived inflammation during infection and tissue injury 113,114,118–120 . Current evidence from mouse studies in the salivary gland and uterus supports the hypothesis that trNK cells are derived from circulating NK cells and are likely epigenetically imprinted based on tissue‐specific factors 121 .…”

Section: Nk Cell‐intrinsic Epigenetic Regulation Of Survivalmentioning

confidence: 99%

No time to die: Epigenetic regulation of natural killer cell survival

Hermans,

O'Sullivan

2024

Immunological Reviews

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SummaryNK cells are short‐lived innate lymphocytes that can mediate antigen‐independent responses to infection and cancer. However, studies from the past two decades have shown that NK cells can acquire transcriptional and epigenetic modifications during inflammation that result in increased survival and lifespan. These findings blur the lines between the innate and adaptive arms of the immune system, and suggest that the homeostatic mechanisms that govern the persistence of innate immune cells are malleable. Indeed, recent studies have shown that NK cells undergo continuous and strictly regulated adaptations controlling their survival during development, tissue residency, and following inflammation. In this review, we summarize our current understanding of the critical factors regulating NK cell survival throughout their lifespan, with a specific emphasis on the epigenetic modifications that regulate the survival of NK cells in various contexts. A precise understanding of the molecular mechanisms that govern NK cell survival will be important to enhance therapies for cancer and infectious diseases.

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“…These paradigm-shifting studies demonstrate that CD8 EXP alloreactive T cells are able to persist in solid organ allograft target tissue and adjacent biofluids, acquire markers associated with tissue residence and memory formation, and are resistant to treatment with anti-rejection protocols currently in use (37,38). Although many high-quality single cell RNA sequencing studies have shown various T cell and macrophage subsets in the human liver primarily using freshly processed liver tissue (39)(40)(41)(42)(43)(44)(45)(46)(47)(48), no studies have been performed to date specifically on pediatric liver transplant rejection or with cryopreserved specimens. Moreover, the dynamics of these populations following rejection therapy have also not been explored.…”

Section: Introductionmentioning

confidence: 99%

Defining the T cell transcriptional landscape in pediatric liver transplant rejection at single cell resolution

Peters,

DePasquale,

Begum

et al. 2024

Preprint

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Acute cellular rejection (ACR) affects >80% of pediatric liver transplant recipients within 5 years, and late ACR is associated with graft failure. Traditional anti-rejection therapy for late ACR is ineffective and has remained unchanged for six decades. Although CD8+ T cells promote late ACR, little has been done to define their specificity and gene expression. Here, we used single-cell sequencing and immune repertoire profiling (10X Genomics) on 30 cryopreserved 16G liver biopsies from 14 patients (5 pre-transplant or with no ACR, 9 with ACR). We identified expanded intragraft CD8+ T cell clonotypes (CD8EXP) and their gene expression profiles in response to anti-rejection treatment. Notably, we found that expanded CD8+ clonotypes (CD8EXP) bore markers of effector and CD56hiCD161- 'NK-like' T cells, retaining their clonotype identity and phenotype in subsequent biopsies from the same patients despite histologic ACR resolution. CD8EXP clonotypes localized to portal infiltrates during active ACR, and persisted in the lobule after histologic ACR resolution. CellPhoneDB analysis revealed differential crosstalk between KC and CD8EXP during late ACR, with activation of the LTB-LTBR pathway and downregulation of TGFβ signaling. Therefore, persistently-detected intragraft CD8EXP clones remain active despite ACR treatment and may contribute to long-term allograft fibrosis and failure of operational tolerance.

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Single-cell RNA sequencing identifies a population of human liver-type ILC1s

Cited by 17 publications

References 56 publications

Single nuclear RNA sequencing of terminal ileum in patients with cirrhosis demonstrates multi-faceted alterations in the intestinal barrier

Single nuclear RNA sequencing of terminal ileum in patients with cirrhosis demonstrates multi-faceted alterations in the intestinal barrier

No time to die: Epigenetic regulation of natural killer cell survival

Defining the T cell transcriptional landscape in pediatric liver transplant rejection at single cell resolution

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