bims-nastce Biomed News
on NASH and T cells
Issue of 2021–08–15
eleven papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. Multiprotein Particles from T Cells Deliver Cytotoxic Cargo to Targets.
  2. Regulatory T cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis.
  3. How the immune system shapes atherosclerosis: roles of innate and adaptive immunity.
  4. Non-alcoholic fatty liver disease Stratification by Liver Lipidomics.
  5. Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component.
  6. Targeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma.
  7. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death.
  8. Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome.
  9. Repertoire Remodeling through CD4+ T-cell Depletion.
  10. Single-Cell Proteomics Reveals the Defined Heterogeneity of Resident Macrophages in White Adipose Tissue.
  11. Targetable CD4+ T-cell TGFβ Signaling Suppresses Antitumor Immunity.
  1. Cancer Discov. 2020 Jul;10(7): 899
    Multiprotein Particles from T Cells Deliver Cytotoxic Cargo to Targets.
      CD8+ T cells produced supramolecular complexes containing cytotoxic proteins GZMB and PRF1.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-072
  2. J Hepatol. 2021 Aug 04. pii: S0168-8278(21)01962-0. [Epub ahead of print]
    Regulatory T cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis.
    Han Wang, Hongji Zhang, Yu Wang, Zachary J Brown, Yujia Xia, Zheng Huang, Chengli Shen, Zhiwei Hu, Joal Beane, Ephraim A Ansa-Addo, Hai Huang, Dean Tian, Allan Tsung.
       INTRODUCTION: Regulatory T cells (Tregs) impair cancer immunosurveillance by creating an immunosuppressive environment fostering tumor cell survival. Our previous finding demonstrated that neutrophil extracellular traps (NETs), which are involved both in innate and adaptive immunity, are abundant in the NASH liver. However, how NETs can interact with Tregs in the development of nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is not known.
    METHODS: Stelic Animal Model, choline-deficient, high-fat diet + diethylnitrosamine mouse model, and western diet mouse model were utilized for NASH-HCC or NASH development. Treg depletion was achieved using FoxP3-DTR mice. RNA sequencing was used to explore the mechanism of NETs on Treg differentiation. Bioenergetic analyses of naïve CD4+ T cells were assessed by Seahorse.
    RESULTS: Although the absolute number of CD4+ T cells is decreased in NASH livers, the Treg subpopulation is selectively increased. Depleting Tregs dramatically inhibits HCC initiation and progression in NASH. There is a positive correlation between increased NET and hepatic Treg levels. RNA-seq data reveals that NETs impact gene profiles in naive CD4+ T cells and tilt the balance toward Tregs with most differential differentially expressed genes enriched in mitochondrial oxidative phosphorylation (OXPHOS). NETs through facilitating mitochondrial respiration can promote Treg differentiation. The metabolic reprogramming in naïve CD4+ T cells by NETs requires toll-like receptor 4 (TLR4). The blockade of NETs in vivo using PAD4-/- mice or DNase I treatment reduces the activity of Tregs.
    CONCLUSIONS: Tregs can suppress immunosurveillance in the premalignant stages of NASH. NETs facilitate the crosstalk between innate and adaptive immunity in NASH by promoting Treg activity through metabolic reprogramming. Therapies targeting NETs and Treg interactions can offer a potential strategy for preventing HCC in NASH.
    LAY SUMMARY: Regulatory T cells (Tregs) can promote tumor development by suppressing cancer immunosurveillance, but their role in carcinogenesis during NASH progression is unknown. Herein, we discovered that selectively increased intrahepatic Tregs can promote an immunosuppressive environment in NASH livers. Neutrophil extracellular traps (NETs) link innate and adaptive immunity by promoting Treg differentiation via metabolic reprogramming of naïve CD4+ T cells, which exposes a potential therapeutic intervention to prevent HCC in NASH.
    Keywords:  Carcinogenesis; Hepatocellular carcinoma (HCC); Metabolic reprogramming; Neutrophils extracellular traps (NETs); Nonalcoholic steatohepatitis (NASH); Oxidative phosphorylation (OXPHOS); Regulatory T cell (Treg)
    DOI:  https://doi.org/10.1016/j.jhep.2021.07.032
  3. Nat Rev Immunol. 2021 Aug 13.
    How the immune system shapes atherosclerosis: roles of innate and adaptive immunity.
    Payel Roy, Marco Orecchioni, Klaus Ley.
      Atherosclerosis is the root cause of many cardiovascular diseases. Extensive research in preclinical models and emerging evidence in humans have established the crucial roles of the innate and adaptive immune systems in driving atherosclerosis-associated chronic inflammation in arterial blood vessels. New techniques have highlighted the enormous heterogeneity of leukocyte subsets in the arterial wall that have pro-inflammatory or regulatory roles in atherogenesis. Understanding the homing and activation pathways of these immune cells, their disease-associated dynamics and their regulation by microbial and metabolic factors will be crucial for the development of clinical interventions for atherosclerosis, including potentially vaccination-based therapeutic strategies. Here, we review key molecular mechanisms of immune cell activation implicated in modulating atherogenesis and provide an update on the contributions of innate and adaptive immune cell subsets in atherosclerosis.
    DOI:  https://doi.org/10.1038/s41577-021-00584-1
  4. J Lipid Res. 2021 Aug 09. pii: S0022-2275(21)00086-9. [Epub ahead of print] 100104
    Non-alcoholic fatty liver disease Stratification by Liver Lipidomics.
    Olga Vvedenskaya, Tim Daniel Rose, Oskar Knittelfelder, Alessandra Palladini, Judith Andrea Heidrun Wodke, Kai Schumann, Jacobo Miranda Ackerman, Yuting Wang, Canan Has, Mario Brosch, Veera Raghavan Thangapandi, Stephan Buch, Thomas Züllig, Jürgen Hartler, Harald C Köfeler, Christoph Röcken, Ünal Coskun, Edda Klipp, Witigo von Schoenfels, Justus Gross, Clemens Schafmayer, Jochen Hampe, Josch Konstantin Pauling, Andrej Shevchenko.
      Non-alcoholic fatty liver disease (NAFLD) is a common metabolic dysfunction leading to hepatic steatosis. However, NAFLD's global impact on the liver lipidome is poorly understood. Using high-resolution shotgun mass spectrometry, we quantified the molar abundance of 316 species from 22 major lipid classes in liver biopsies of 365 patients, including non-steatotic patients with normal or excessive weight, patients diagnosed with NAFL (non-alcoholic fatty liver) or NASH (non-alcoholic steatohepatitis), and patients bearing common mutations of NAFLD-related protein factors. We confirmed the progressive accumulation of di- and tri- acylglycerols and cholesteryl esters in the liver of NAFL and NASH patients, while the bulk composition of glycerophospho- and sphingolipids remained unchanged. Further stratification by biclustering analysis identified sphingomyelin species comprising n24:2 fatty acid moieties as membrane lipid markers of NAFLD. Normalized relative abundance of sphingomyelins SM 43:3;2 and SM 43:1;2 containing n24:2 and n24:0 fatty acid moieties, respectively, showed opposite trends during NAFLD progression and distinguished NAFL and NASH lipidomes from the lipidome of non-steatoic livers. Together with several glycerophospholipids containing a C22:6 fatty acid moiety, these lipids serve as markers of early and advanced stages of NAFL.
    Keywords:  NAFL; NAFLD; NASH; biclustering analysis; lipid biomarkers; liver biopsies; liver lipidome; shotgun lipidomics; sphingomyelins; steatosis
    DOI:  https://doi.org/10.1016/j.jlr.2021.100104
  5. Front Immunol. 2021 ;12 674016
    Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component.
    Lauren Daniel, Marion Tassery, Clara Lateur, Antoine Thierry, André Herbelin, Jean-Marc Gombert, Alice Barbarin.
      Immunosenescence is a physiological process that is associated with changes in the immune system, particularly among CD8 T-cells. Recent studies have hypothesized that senescent CD8 T-cells are produced with chronologic age by chronic stimulation, leading to the acquisition of hallmarks of innate-like T-cells. While conventional CD8 T-cells are quite well characterized, CD8 T-cells sharing features of NK cells and memory CD8 T-cells, are a newly described immune cell population. They can be distinguished from conventional CD8 T-cells by their combined expression of panKIR/NKG2A and Eomesodermin (E), a unique phenotype closely associated with IFN-γ production in response to innate stimulation. Here, we first provided new evidence in favor of the innate character of panKIR/NKG2A(+) E(+) CD8 T-cells in normal subjects, documenting their position at an intermediate level in the innateness gradient in terms of both innate IFN-γ production and diminished mitochondrial mass. We also revealed that CD8 E(+) panKIR/NKG2A(+) T-cells, hereafter referred to as Innate E(+) CD8 T-cells, exhibit increased senescent (CD27(-) CD28(-)) phenotype, compared to their conventional memory counterparts. Surprisingly, this phenomenon was not dependent on age. Given that inflammation related to chronic viral infection is known to induce NK-like marker expression and a senescence phenotype among CD8 T-cells, we hypothesized that innate E(+) CD8 T-cells will be preferentially associated with exacerbated cellular senescence in response to chronic alloantigen exposure or CMV infection. Accordingly, in a pilot cohort of stable kidney allotransplant recipients, we observed an increased frequency of the Innate E(+) CD8 T-cell subset, together with an exacerbated senescent phenotype. Importantly, this phenotype cannot be explained by age alone, in clear contrast to their conventional memory counterparts. The senescent phenotype in CD8 T-cells was further increased in cytomegalovirus (CMV) positive serology transplant recipients, suggesting that transplantation and CMV, rather than aging by itself, may promote an exacerbated senescent phenotype of innate CD8 T-cells. In conclusion, we proposed that kidney transplantation, via the setting of inflammatory stimuli of alloantigen exposure and CMV infection, may exogenously age the CD8 T-cell compartment, especially its innate component. The physiopathological consequences of this change in the immune system remain to be elucidated.
    Keywords:  NK-like T-cells; allotransplantation; immune memory; innate memory CD8(+) T-cells; innateness gradient; senescence
    DOI:  https://doi.org/10.3389/fimmu.2021.674016
  6. Nat Commun. 2021 08 12. 12(1): 4878
    Targeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma.
    Alessandra Scagliola, Annarita Miluzio, Gabriele Ventura, Stefania Oliveto, Chiara Cordiglieri, Nicola Manfrini, Delia Cirino, Sara Ricciardi, Luca Valenti, Guido Baselli, Roberta D'Ambrosio, Marco Maggioni, Daniela Brina, Alberto Bresciani, Stefano Biffo.
      A postprandial increase of translation mediated by eukaryotic Initiation Factor 6 (eIF6) occurs in the liver. Its contribution to steatosis and disease is unknown. In this study we address whether eIF6-driven translation contributes to disease progression. eIF6 levels increase throughout the progression from Non-Alcoholic Fatty Liver Disease (NAFLD) to hepatocellular carcinoma. Reduction of eIF6 levels protects the liver from disease progression. eIF6 depletion blunts lipid accumulation, increases fatty acid oxidation (FAO) and reduces oncogenic transformation in vitro. In addition, eIF6 depletion delays the progression from NAFLD to hepatocellular carcinoma, in vivo. Mechanistically, eIF6 depletion reduces the translation of transcription factor C/EBPβ, leading to a drop in biomarkers associated with NAFLD progression to hepatocellular carcinoma and preserves mitochondrial respiration due to the maintenance of an alternative mTORC1-eIF4F translational branch that increases the expression of transcription factor YY1. We provide proof-of-concept that in vitro pharmacological inhibition of eIF6 activity recapitulates the protective effects of eIF6 depletion. We hypothesize the existence of a targetable, evolutionarily conserved translation circuit optimized for lipid accumulation and tumor progression.
    DOI:  https://doi.org/10.1038/s41467-021-25195-1
  7. Cell. 2021 Aug 03. pii: S0092-8674(21)00885-0. [Epub ahead of print]
    Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death.
    Justin Taft, Michael Markson, Diana Legarda, Roosheel Patel, Mark Chan, Louise Malle, Ashley Richardson, Conor Gruber, Marta Martín-Fernández, Grazia M S Mancini, Jan A M van Laar, Philomine van Pelt, Sofija Buta, Beatrijs H A Wokke, Ira K D Sabli, Vanessa Sancho-Shimizu, Pallavi Pimpale Chavan, Oskar Schnappauf, Raju Khubchandani, Müşerref Kasap Cüceoğlu, Seza Özen, Daniel L Kastner, Adrian T Ting, Ivona Aksentijevich, Iris H I M Hollink, Dusan Bogunovic.
      TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.
    Keywords:  IKKE; IRF3; RIPK1; TBK1 deficiency; TNF alpha; autoinflammation; interferon type I; viral susceptibility
    DOI:  https://doi.org/10.1016/j.cell.2021.07.026
  8. Elife. 2021 Aug 11. pii: e68371. [Epub ahead of print]10
    Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome.
    Isabelle J Marie, Lara Brambilla, Doua Azzouz, Ze Chen, Gisele V Baracho, Azlann Arnett, Haiyan S Li, Weiguo Liu, Lluisa Cimmino, Pratip Chattopadhyay, Gregg Silverman, Stephanie S Watowich, Bernard Khor, David Levy.
      Maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls responses to acute microbial infection, through engagement of the STAT1 transcription factor. However, the contribution of tonic levels of IFN to immune homeostasis in absence of acute infection remains largely unexplored. We report that STAT1 KO mice spontaneously developed an inflammatory disease marked by myeloid hyperplasia and splenic accumulation of hematopoietic stem cells. Moreover, these animals developed inflammatory bowel disease. Profiling gut bacteria revealed a profound dysbiosis in absence of tonic IFN signaling, which triggered expansion of TH17 cells and loss of splenic Treg cells. Reduction of bacterial load by antibiotic treatment averted the TH17 bias, and blocking IL17 signaling prevented myeloid expansion and splenic stem cell accumulation. Thus, tonic IFNs regulate gut microbial ecology, which is crucial for maintaining physiologic immune homeostasis and preventing inflammation.
    Keywords:  immunology; infectious disease; inflammation; microbiology; mouse
    DOI:  https://doi.org/10.7554/eLife.68371
  9. Cancer Immunol Res. 2021 Jun;9(6): 601
    Repertoire Remodeling through CD4+ T-cell Depletion.
    Winnie Yao, Ansuman T Satpathy.
      Understanding the cellular regulation of tumor-specific CD8+ T-cell responses is critical to designing improved clinical strategies for cancer immunotherapy. In this issue, Aoki and colleagues deepen our knowledge of this topic by demonstrating that transient depletion of CD4+ T cells in patients with gastrointestinal cancer induces remodeling of the T-cell repertoire, including clonal replacement and expansion of CD8+ T-cell clones shared between the blood and tumor.See article by Aoki et al., p. 624.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-21-0301
  10. Front Immunol. 2021 ;12 719979
    Single-Cell Proteomics Reveals the Defined Heterogeneity of Resident Macrophages in White Adipose Tissue.
    Inês Félix, Heli Jokela, Joonas Karhula, Noora Kotaja, Eriika Savontaus, Marko Salmi, Pia Rantakari.
      Adipose tissue macrophages (ATMs) regulate homeostasis and contribute to the metabolically harmful chronic inflammation in obese individuals. While evident heterogeneity of resident ATMs has been described previously, their phenotype, developmental origin, and functionality remain inconsistent. We analyzed white adipose tissue (WAT) during homeostasis and diet interventions using comprehensive and unbiased single-cell mass cytometry and genetic lineage tracking models. We now provide a uniform definition of individual subsets of resident ATMs. We show that in lean mice, WAT co-harbors eight kinetically evolving CD206+ macrophage subpopulations (defined by TIM4, CD163, and MHC II) and two CD206- macrophage subpopulations. TIM4-CD163+, TIM4-CD163- and CD206- macrophage populations are largely bone marrow-derived, while the proliferating TIM4+CD163+ subpopulation is of embryonic origin. All macrophage subtypes are active in phagocytosis, endocytosis, and antigen processing in vitro, whereas TIM4+CD163+ cells are superior in scavenging in vivo. A high-fat diet induces massive infiltration of CD206- macrophages and selective down-regulation of MHC II on TIM4+ macrophages. These changes are reversed by dietary intervention. Thus, the developmental origin and environment jointly regulate the functional malleability of resident ATMs.
    Keywords:  adipose tissue; developmental origin; macrophage; mass cytometry (CyTOF); obesity
    DOI:  https://doi.org/10.3389/fimmu.2021.719979
  11. Cancer Discov. 2020 Dec;10(12): 1785
    Targetable CD4+ T-cell TGFβ Signaling Suppresses Antitumor Immunity.
      Ablating TGFβ signaling by CD4+ T cells remodeled tumor vasculature to cause cancer-cell death.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-158
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