bims-nastce Biomed News
on NASH and T cells
Issue of 2021–07–25
six papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells.
  2. Pathophysiological Communication between Hepatocytes and Non-Parenchymal Cells in Liver Injury from NAFLD to Liver Fibrosis.
  3. Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism.
  4. Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease.
  5. A multilayered immune system through the lens of unconventional T cells.
  6. Volume control: Turning the dial on regulatory T cells.
  1. Nat Commun. 2021 07 22. 12(1): 4474
    CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells.
    Yuzo Koda, Toshiaki Teratani, Po-Sung Chu, Yuya Hagihara, Yohei Mikami, Yosuke Harada, Hanako Tsujikawa, Kentaro Miyamoto, Takahiro Suzuki, Nobuhito Taniki, Tomohisa Sujino, Michiie Sakamoto, Takanori Kanai, Nobuhiro Nakamoto.
      Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103-CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.
    DOI:  https://doi.org/10.1038/s41467-021-24734-0
  2. Adv Drug Deliv Rev. 2021 Jul 16. pii: S0169-409X(21)00261-1. [Epub ahead of print] 113869
    Pathophysiological Communication between Hepatocytes and Non-Parenchymal Cells in Liver Injury from NAFLD to Liver Fibrosis.
    Santosh Kumar, Qihua Duan, Rongxue Wu, Edward Harris, Qiaozhu Su.
      Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease that encompasses a spectrum of pathological conditions, ranging from simple steatosis (NAFL), nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis which can further progress to hepatocellular carcinoma and liver failure. The progression of NAFL to NASH and liver fibrosis is closely associated with a series of liver injury resulting from lipotoxicity, oxidative stress, redox imbalance (excessive nitric oxide), ER stress, inflammation and apoptosis that occur sequentially in different liver cells which ultimately leads to the activation of liver regeneration and fibrogenesis, augmenting collagen and extracellular matrix deposition and promoting liver fibrosis and cirrhosis. Type 2 diabetes is a significant risk factor in NAFLD development by accelerating liver damage. Here, we overview recent findings from human study and animal models on the pathophysiological communication among hepatocytes (HCs), Kupffer cells (KCs), hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) during the disease development. The mechanisms of crucial signaling pathways, including Toll-like receptor, TGFβ and hedgehog mediated hepatic injury are also discussed. We further highlight the potentials of precisely targeting hepatic individual cell-type using nanotechnology as therapeutic strategy for the treatment of NASH and liver fibrosis.
    Keywords:  ER stress; Hedgehog and TGFβ; NAFLD; NASH; TLRs; lipotoxicity; liver fibrosis; metabolic inflammation; nitric oxide; oxidative stress
    DOI:  https://doi.org/10.1016/j.addr.2021.113869
  3. Nat Commun. 2021 07 22. 12(1): 4462
    Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism.
    Zheng Fu, Joseph W Dean, Lifeng Xiong, Michael W Dougherty, Kristen N Oliff, Zong-Ming E Chen, Christian Jobin, Timothy J Garrett, Liang Zhou.
      RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.
    DOI:  https://doi.org/10.1038/s41467-021-24755-9
  4. Dig Liver Dis. 2021 Jul 19. pii: S1590-8658(21)00337-6. [Epub ahead of print]
    Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease.
    Luca Valenti, Federica Pedica, Massimo Colombo.
      Hepatocellular carcinoma (HCC) is on the rise globally, causing more than 800 thousand deaths annually, with an estimated annual percent change of 0.51 for causes other than viral hepatitis, including nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD-related HCC is peaking in several Far East regions (6-12% vs. 2-3% in Western Europe and USA), HCC risk being mainly driven by the epidemic of obesity and diabetes, both favored by an unhealthy diet and sedentary lifestyle. Under inherited susceptibility outlined by such genetic markers as variants in PNPLA3, TM6SF2 and MBOAT7, neoplastic transformation of NAFLD is driven by sublethal lipotoxicity consequent to hepatocyte lipid overload, whereas a myriad of factors spanning from subverted circadian homeostasis and gut dysbiosis to alcohol abuse and tobacco may interact as risk modifiers. At variance with viral HCC, NAFLD-HCC shows a frequent association with cardiovascular co-morbidities, absence of cirrhosis in up to half of patients and an association with persistently normal transaminase values. All these misleading features of NAFLD-related HCC account for the low uptake of surveillance and linkage to curative treatments that has been reported in patients with this cancer, a downside that could be attenuated when scores for cost-effective risk stratification become available.
    Keywords:  Diabetes; HCC; NAFLD; NASH; Obesity
    DOI:  https://doi.org/10.1016/j.dld.2021.06.023
  5. Nature. 2021 Jul;595(7868): 501-510
    A multilayered immune system through the lens of unconventional T cells.
    Toufic Mayassi, Luis B Barreiro, Jamie Rossjohn, Bana Jabri.
      The unconventional T cell compartment encompasses a variety of cell subsets that straddle the line between innate and adaptive immunity, often reside at mucosal surfaces and can recognize a wide range of non-polymorphic ligands. Recent advances have highlighted the role of unconventional T cells in tissue homeostasis and disease. In this Review, we recast unconventional T cell subsets according to the class of ligand that they recognize; their expression of semi-invariant or diverse T cell receptors; the structural features that underlie ligand recognition; their acquisition of effector functions in the thymus or periphery; and their distinct functional properties. Unconventional T cells follow specific selection rules and are poised to recognize self or evolutionarily conserved microbial antigens. We discuss these features from an evolutionary perspective to provide insights into the development and function of unconventional T cells. Finally, we elaborate on the functional redundancy of unconventional T cells and their relationship to subsets of innate and adaptive lymphoid cells, and propose that the unconventional T cell compartment has a critical role in our survival by expanding and complementing the role of the conventional T cell compartment in protective immunity, tissue healing and barrier function.
    DOI:  https://doi.org/10.1038/s41586-021-03578-0
  6. Cell. 2021 Jul 22. pii: S0092-8674(21)00750-9. [Epub ahead of print]184(15): 3847-3849
    Volume control: Turning the dial on regulatory T cells.
    Chrysothemis C Brown, Rachel A Gottschalk.
      Treg-mediated immunosuppression must be tightly regulated to support immunity while limiting tissue damage. In this issue of Cell, Wong et al. and Marangoni et al. use high-resolution imaging to define feedback circuits that quantitatively control local Treg expansion and function.
    DOI:  https://doi.org/10.1016/j.cell.2021.06.015
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