bims-nastce Biomed News
on NASH and T cells
Issue of 2021–07–18
six papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. Hepatic T helper 17 cells implicated in NAFLD.
  2. High Fat Diet-Induced CD8+ T Cells in Adipose Tissue Mediate Macrophages to Sustain Low-Grade Chronic Inflammation.
  3. T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model.
  4. CD8+ T cell differentiation and dysfunction in cancer.
  5. The impact of alteration in gut microbiome in the pathogenesis of nonalcoholic fatty liver disease.
  6. Interferon-α-producing plasmacytoid dendritic cells drive the loss of adipose tissue regulatory T cells during obesity.
  1. Nat Rev Endocrinol. 2021 Aug;17(8): 449
    Hepatic T helper 17 cells implicated in NAFLD.
    Claire Greenhill.
      
    DOI:  https://doi.org/10.1038/s41574-021-00525-x
  2. Front Immunol. 2021 ;12 680944
    High Fat Diet-Induced CD8+ T Cells in Adipose Tissue Mediate Macrophages to Sustain Low-Grade Chronic Inflammation.
    Sonia Kiran, Vijay Kumar, E Angela Murphy, Reilly T Enos, Udai P Singh.
      Obesity in the United States and worldwide reached epidemic proportions within the last 20 years. Obesity is a very powerful health determinant or indicator that facilitates the development and progression of several metabolic diseases, insulin resistance, and low-grade chronic inflammation. Low-grade chronic inflammation in adipose tissue (AT) is marked by the accumulation of T cells, macrophages, and other immune cells and increased production of proinflammatory cytokines. During the onset of obesity but before the influx of macrophages, the AT is infiltrated by T cells that are strongly implicated in the initiation of obesity-associated inflammation. In comparing mice fed a high-fat diet (HFD) with those fed a normal diet (ND), we observed in HFD epididymal AT induction and infiltration of activated T cells, an accumulation and polarization of macrophages, and an increase in populations of activated CD4+ T cells and CD8+ T cells that express CXCR3 or killer cell lectin-like receptor subfamily G member 1 (KLRG1). Levels of inflammatory cytokines and leptin and the results of in vitro co-culture experiments revealed interactions among HFD- and ND-induced CD8+ T cells, macrophages, and adipocytes. Our findings suggest that obese tissues activate and induce both CD4+ and CD8+ CD69+ T cells and augment the expression of CXCR3 receptors, which promotes the recruitment and numbers of pro-inflammatory M1 macrophages to maintain low-grade chronic inflammation. The results support the hypothesis that CXCR3-expressing CD8+T cells play an essential role in the initiation and maintenance of adipose tissue inflammation.
    Keywords:  CD8+ T cells; chemokine; inflammation; macrophages; obesity
    DOI:  https://doi.org/10.3389/fimmu.2021.680944
  3. J Hepatol. 2021 Jul 06. pii: S0168-8278(21)01887-0. [Epub ahead of print]
    T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model.
    Heather P Llewellyn, Seda Arat, Jingjin Gao, Ji Wen, Shuhua Xia, Dalia Kalabat, Elias Oziolor, Richard Virgen-Slane, Timothy Affolter, Changhua Ji.
       BACKGROUND & AIMS: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. We aim to use a mouse model to elucidate the immune related molecular mechanisms of hepatitis, one of the common ICI irAEs.
    METHODS: Immune phenotyping and molecular profiling were performed on PD1-/- mice treated with anti-CTLA4 and/or the IDO1 inhibitor, epacadostat, or a 4-1BB agonist antibody.
    RESULTS: ICI combination-induced hepatitis and the 4-1BB agonist mediated hepatitis share similar features yet maintain distinct immune signatures. Both were characterized by an expansion of peri-portal infiltrates and pan-zonal inflammation albeit with different morphologic characteristics. In both cases, infiltrates were predominantly CD4+ and CD8+ T cells with upregulated T cell activation markers ICOS and CD44. Depletion of CD8+ T cells abolished the ICI-mediated hepatitis. Single cell transcriptomics revealed that the hepatitis induced by combination of ICIs is associated with a robust immune activation signature in all subtypes of T cells and Th1 skewing. Expression profiling revealed a central role for IFNγ and liver monocyte-derived macrophages in promoting a pro-inflammatory T cell response to ICI combination and 4-1BB agonism.
    CONCLUSION: We developed a novel mouse model which offers significant value in yielding deeper mechanistic insight into immune-mediated liver toxicity associated with various immunotherapies.
    LAY SUMMARY: Hepatitis is one of the common immune-related adverse events in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. The mechanisms of ICI-induced hepatitis are not well understood. In this paper, we identify key molecular mechanisms mediating immune intracellular crosstalk between liver T cells and macrophages in response to ICI in a mouse model.
    Keywords:  4-1BB; CTLA4; IDO1; Immune-related adverse events; Ipilimumab; Liver injury; Nivolumab; PD-1
    DOI:  https://doi.org/10.1016/j.jhep.2021.06.037
  4. Nat Rev Immunol. 2021 Jul 12.
    CD8+ T cell differentiation and dysfunction in cancer.
    Mary Philip, Andrea Schietinger.
      CD8+ T cells specific for cancer cells are detected within tumours. However, despite their presence, tumours progress. The clinical success of immune checkpoint blockade and adoptive T cell therapy demonstrates the potential of CD8+ T cells to mediate antitumour responses; however, most patients with cancer fail to achieve long-term responses to immunotherapy. Here we review CD8+ T cell differentiation to dysfunctional states during tumorigenesis. We highlight similarities and differences between T cell dysfunction and other hyporesponsive T cell states and discuss the spatio-temporal factors contributing to T cell state heterogeneity in tumours. An important challenge is predicting which patients will respond to immunotherapeutic interventions and understanding which T cell subsets mediate the clinical response. We explore our current understanding of what determines T cell responsiveness and resistance to immunotherapy and point out the outstanding research questions.
    DOI:  https://doi.org/10.1038/s41577-021-00574-3
  5. Curr Opin Infect Dis. 2021 Jul 15.
    The impact of alteration in gut microbiome in the pathogenesis of nonalcoholic fatty liver disease.
    Jake S Jacob, Aijaz Ahmed, George Cholankeril.
       PURPOSE OF REVIEW: We have increasing evidence that alterations of the intestinal microbiome have a strong influence on human health. Previous work has demonstrated the association between changes in the microbiome and metabolic risk factors. One related area of interest is the relationship between dysbiosis and nonalcoholic fatty liver disease (NAFLD), as the global prevalence of NAFLD, and its resultant complications, increases.
    RECENT FINDINGS: In this review, we summarize the hypothesized pathophysiology of dysbiosis-mediated progression of NAFLD, including promotion of an inflammatory intestinal environment, increased intestinal permeability, endogenous ethanol production, short-chain fatty acid production, secondary bile acid metabolism, and choline depletion. We also review potential therapeutic interventions of the microbiome to slow or prevent NAFLD progression, including antibiotics, probiotics, prebiotics, fecal microbiota transplant, and farnesoid × receptor agonism.
    SUMMARY: Much of the evidence supporting dysbiosis-mediated NAFLD progression has been gathered in high-quality animal trials. There remains a need for additional observational and randomized controlled trials in humans to establish causality between the suspected factors and pathogenesis of NAFLD.
    DOI:  https://doi.org/10.1097/QCO.0000000000000759
  6. Cell Metab. 2021 Jul 08. pii: S1550-4131(21)00277-1. [Epub ahead of print]
    Interferon-α-producing plasmacytoid dendritic cells drive the loss of adipose tissue regulatory T cells during obesity.
    Chaoran Li, Gang Wang, Pulavendran Sivasami, Ricardo N Ramirez, Yanbo Zhang, Christophe Benoist, Diane Mathis.
      The visceral adipose tissue (VAT) of lean mice hosts a unique population of regulatory T cells (Tregs) that have a distinct transcriptome and T cell receptor (TCR) repertoire and regulate local and systemic inflammation and metabolism. Perplexingly, this population disappears in obese mice, limiting the promise of Treg-based therapies for metabolic disorders. We exploited the power of a VAT-Treg TCR-transgenic mouse model to follow the dynamics of, and phenotypic changes in, the VAT-Treg population throughout the development of diet-induced obesity. Our results show that VAT-Tregs are lost under obesogenic conditions due to downregulation of their defining transcription factor, PPARγ, coupled with their strikingly enhanced responses to pro-inflammatory cytokines. In particular, the VAT from obese mice (and reportedly humans) was strongly enriched in plasmacytoid dendritic cells that actively express interferon-alpha. These cells were directly toxic to PPARγ+ VAT-Tregs. Blocking this pathway in obese mice by multiple approaches substantially restored the VAT-Treg population and enhanced insulin sensitivity.
    Keywords:  CRISPR-Cas9; Tregs; adipose tissue; immunometabolism; inflammatory cytokine; interferon; obesity; pDC
    DOI:  https://doi.org/10.1016/j.cmet.2021.06.007
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