bims-nastce Biomed News
on NASH and T cells
Issue of 2021–11–14
seven papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. Quantitative genome-scale metabolic modeling of human CD4+ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways.
  2. IFN-γ facilitates liver fibrogenesis by CD161+CD4+ T cells through a regenerative IL-23/IL-17 axis in chronic hepatitis B virus infection.
  3. Single-cell spatial transcriptomics.
  4. Single-cell RNA transcriptome landscape of hepatocytes and non-parenchymal cells in healthy and NAFLD mouse liver.
  5. SPICA: Swiss portal for immune cell analysis.
  6. Survivin expression is essential for early activation of hepatic stellate cells and fibrosis progression in chronic liver injury.
  7. The small intestine epithelium exempts Foxp3+ Tregs from their IL-2 requirement for homeostasis and effector function.
  1. Cell Rep. 2021 Nov 09. pii: S2211-1247(21)01452-2. [Epub ahead of print]37(6): 109973
    Quantitative genome-scale metabolic modeling of human CD4+ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways.
    Partho Sen, Syed Bilal Ahmad Andrabi, Tanja Buchacher, Mohd Moin Khan, Ubaid Ullah Kalim, Tuomas Mikael Lindeman, Marina Amaral Alves, Victoria Hinkkanen, Esko Kemppainen, Alex M Dickens, Omid Rasool, Tuulia Hyötyläinen, Riitta Lahesmaa, Matej Orešič.
      T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, proteins, and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T cell subsets (T helper [Th]1, Th2, Th17, and induced regulatory T [iTreg] cells). Here, we combine genome-scale metabolic modeling, gene expression data, and targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments, and show that human CD4+ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiate the requirement of serine palmitoyltransferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokines (interleukin [IL]-17A and IL17F) by Th17 cells. Our findings provide a comprehensive resource for selective manipulation of CD4+ T cells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.
    Keywords:  CD4(+) T cells; ceramides; gene expression; genome-scale metabolic modeling; glycosphingolipid metabolism; lipid metabolism; lipidomics; metabolic pathways; sphingolipids; type 1 diabetes
    DOI:  https://doi.org/10.1016/j.celrep.2021.109973
  2. Clin Transl Immunology. 2021 ;10(11): e1353
    IFN-γ facilitates liver fibrogenesis by CD161+CD4+ T cells through a regenerative IL-23/IL-17 axis in chronic hepatitis B virus infection.
    Jing Li, Lisha Cheng, Haoyu Jia, Chun Liu, Siqi Wang, Yun Liu, Yue Shen, Shengdi Wu, Fanli Meng, Beishi Zheng, Changqing Yang, Wei Jiang.
       Objectives: This study aimed to determine the role of CD161+CD4+ T cells in chronic hepatitis B virus (HBV) infection.
    Methods: A total of 94 patients with chronic hepatitis B (CHB), 73 with liver cirrhosis (LC) and 28 healthy controls were enrolled to determine frequency, cytokine production and chemokine receptor expression of circulating CD161+CD4+ T cells. Among these, 50 CHB and 34 LC patients were followed up for a period of 52-week entecavir monotherapy to assess the association of CD161+CD4+ T cells with seroconversion of HBV e antigen (HBeAg). In addition, 15 patients with hepatocellular carcinoma (HCC) and 15 with hepatic haemangioma (HHA) were enrolled to compare the paired circulating and intrahepatic CD161+CD4+ T cells.
    Results: CD161+CD4+ T cells were found to accumulate in the circulation of HBV cohorts, which showed a significant correlation with the clinical parameters of disease progression. In addition, higher numbers of circulating CD161+CD4+ T cells were associated with an improved serological response of HBeAg to antiviral treatment. Moreover, CD161+CD4+ T cells as compared to homologous CD161-CD4+ T cells produced more pro-inflammatory cytokines including interleukin (IL)-17 and interferon (IFN)-γ and expressed higher levels of liver-homing chemokine receptors including CCR6, CXCR6 and CX3CR1. Notably, a significant enrichment of CD161+CD4+ T cell subsets co-expressing IFN-γ and IL-17 was observed in HBV-associated cirrhotic livers. During in vitro co-cultures, circulating CD161+CD4+ T cells in the chronic HBV setting exhibited prominent pro-fibrogenic effects by regulating primary hepatic stellate cells through a regenerative IFN-γ/IL-23/IL-17 axis.
    Conclusions: In chronic HBV infection, CD161+CD4+ T cells play antiviral, pro-inflammatory and pro-fibrogenic roles.
    Keywords:  CD161+CD4+ T cells; HBV; interferon‐γ; interleukin 17; liver fibrosis
    DOI:  https://doi.org/10.1002/cti2.1353
  3. Nat Cell Biol. 2021 Nov;23(11): 1108
    Single-cell spatial transcriptomics.
    Christine Weber.
      
    DOI:  https://doi.org/10.1038/s41556-021-00778-8
  4. iScience. 2021 Nov 19. 24(11): 103233
    Single-cell RNA transcriptome landscape of hepatocytes and non-parenchymal cells in healthy and NAFLD mouse liver.
    Qi Su, Sun Y Kim, Funmi Adewale, Ye Zhou, Christina Aldler, Min Ni, Yi Wei, Michael E Burczynski, Gurinder S Atwal, Mark W Sleeman, Andrew J Murphy, Yurong Xin, Xiping Cheng.
      Nonalcoholic fatty liver disease (NAFLD) is a global health-care problem with limited therapeutic options. To obtain a cellular resolution of pathogenesis, 82,168 single-cell transcriptomes (scRNA-seq) across different NAFLD stages were profiled, identifying hepatocytes and 12 other non-parenchymal cell (NPC) types. scRNA-seq revealed insights into the cellular and molecular mechanisms of the disease. We discovered a dual role for hepatic stellate cells in gene expression regulation and in the potential to trans-differentiate into myofibroblasts. We uncovered distinct expression profiles of Kupffer cells versus monocyte-derived macrophages during NAFLD progression. Kupffer cells showed stronger immune responses, while monocyte-derived macrophages demonstrated a capability for differentiation. Three chimeric NPCs were identified including endothelial-chimeric stellate cells, hepatocyte-chimeric endothelial cells, and endothelial-chimeric Kupffer cells. Our work identified unanticipated aspects of mouse with NAFLD at the single-cell level and advanced the understanding of cellular heterogeneity in NAFLD livers.
    Keywords:  Animal physiology; Cell biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2021.103233
  5. Nucleic Acids Res. 2021 Nov 08. pii: gkab1055. [Epub ahead of print]
    SPICA: Swiss portal for immune cell analysis.
    Massimo Andreatta, Fabrice P A David, Christian Iseli, Nicolas Guex, Santiago J Carmona.
      Single-cell transcriptomics allows the study of immune cell heterogeneity at an unprecedented level of resolution. The Swiss portal for immune cell analysis (SPICA) is a web resource dedicated to the exploration and analysis of single-cell RNA-seq data of immune cells. In contrast to other single-cell databases, SPICA hosts curated, cell type-specific reference atlases that describe immune cell states at high resolution, and published single-cell datasets analysed in the context of these atlases. Additionally, users can privately analyse their own data in the context of existing atlases and contribute to the SPICA database. SPICA is available at https://spica.unil.ch.
    DOI:  https://doi.org/10.1093/nar/gkab1055
  6. Life Sci. 2021 Nov 04. pii: S0024-3205(21)01106-1. [Epub ahead of print] 120119
    Survivin expression is essential for early activation of hepatic stellate cells and fibrosis progression in chronic liver injury.
    Sachin Sharma, Shaikh Maryam Ghufran, Basundhara Das, Bornika Roy, Sampa Ghose, Subhrajit Biswas.
       AIM: Hepatic fibrosis in injured liver is characterized by the activation of hepatic stellate cells (HSCs) from their quiescent state. Survivin (BIRC5) is one of the key genes that are upregulated during activation of HSCs but their role in HSC activation and fibrosis progression is unknown. Here, we have investigated the role of survivin protein in early fibrogenic activation of HSCs and fibrosis progression in chronic liver injury.
    MATERIALS & METHODS: Primary quiescent HSCs were isolated from healthy mice liver through perfusion and cultured for fibrogenic activation. Survivin expression was suppressed by its pharmacological suppressant, YM155. We developed chronic liver injury induced fibrotic mice model through administrating repeated dose of CCl4 for 2 weeks and 4 weeks. Mice were pre-treated with YM155 a week before CCl4 administration till 2nd week of dosing and then discontinued. Hepatic parameters were characterized and underlying mechanisms were investigated.
    KEY FINDINGS: Survivin expression gradually increased along with the expression of αSMA, collagen I activation maker in HSCs during their activation from quiescent state. Survivin suppression through YM155 downregulated αSMA, collagen I. Pre-treatment of YM155 in mice ceased the early activation of HSCs and onset of fibrosis in injured liver. However, discontinuation of YM155 initiated the activation of HSCs and fibrosis progression that shows survivin expression in HSCs is essential for their early activation and onset of liver fibrosis.
    SIGNIFICANCE: Survivin expression induces with activation of HSCs and drives onset of liver fibrosis in injured liver. Targeting survivin protein in activated HSCs could be a potential anti-fibrotic therapeutic approach in chronic liver injury.
    Keywords:  Chronic liver injury; Hepatic stellate cells; Liver fibrosis; Survivin (BIRC5)
    DOI:  https://doi.org/10.1016/j.lfs.2021.120119
  7. JCI Insight. 2021 Nov 08. pii: e149656. [Epub ahead of print]6(21):
    The small intestine epithelium exempts Foxp3+ Tregs from their IL-2 requirement for homeostasis and effector function.
    Praveen Prakhar, Jaylene Alvarez-DelValle, Hilary Keller, Assiatu Crossman, Xuguang Tai, Yoo Kyoung Park, Jung-Hyun Park.
      Foxp3+ Tregs are potent immunosuppressive CD4+ T cells that are critical to maintain immune quiescence and prevent autoimmunity. Both the generation and maintenance of Foxp3+ Tregs depend on the cytokine IL-2. Hence, the expression of the IL-2 receptor α-chain (CD25) is not only considered a specific marker, but also a nonredundant requirement for Tregs. Here, we report that Foxp3+ Tregs in the small intestine (SI) epithelium, a critical barrier tissue, are exempt from such an IL-2 requirement, since they had dramatically downregulated CD25 expression, showed minimal STAT5 phosphorylation ex vivo, and were unable to respond to IL-2 in vitro. Nonetheless, SI epithelial Tregs survived and were present at the same frequency as in other lymphoid organs, and they retained potent suppressor function that was associated with high levels of CTLA-4 expression and the production of copious amounts of IL-10. Moreover, adoptive transfer experiments of Foxp3+ Tregs revealed that such IL-2-independent survival and effector functions were imposed by the SI epithelial tissue, suggesting that tissue adaptation is a mechanism that tailors the effector function and survival requirements of Foxp3+ Tregs specific to the tissue environment.
    Keywords:  Adaptive immunity; Autoimmunity; Cytokines; Immunology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.149656
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