bims-nastce Biomed News
on NASH and T cells
Issue of 2022–02–27
eleven papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. Single Cell RNA Sequencing in NASH.
  2. Group 1 ILCs regulate T cell-mediated liver immunopathology by controlling local IL-2 availability.
  3. Th17 cells in the liver: balancing autoimmunity and pathogen defense.
  4. Single-cell atlases: shared and tissue-specific cell types across human organs.
  5. Single-cell eQTL analysis of activated T cell subsets reveals activation and cell type-dependent effects of disease-risk variants.
  6. NAFLD indirectly impairs antigen-specific CD8+ T cell immunity against liver cancer in mice.
  7. Dual roles of B lymphocytes in murine models of diet-induced non-alcoholic fatty liver disease.
  8. Tfh-cell-derived interleukin 21 sustains effector CD8+ T cell responses during chronic viral infection.
  9. A global view of the interplay between non-alcoholic fatty liver disease and diabetes.
  10. Distinguishing activated T regulatory cell and T conventional cells by single cell technologies.
  11. Mechanisms Regulating T Cell-Endothelial Cell Interactions.
  1. Methods Mol Biol. 2022 ;2455 181-202
    Single Cell RNA Sequencing in NASH.
    Jana Hundertmark, Hilmar Berger, Frank Tacke.
      Single cell RNA sequencing (scRNA-seq) allows to uncover cellular heterogeneity and the identification of novel subpopulations. In non-alcoholic steatohepatitis (NASH), scRNA-seq is particularly powerful to understand non-parenchymal cell heterogeneity in the liver, e.g. for inflammatory cells. Myeloid immune cells, particularly macrophages, play a critical role in response of the innate immune system and significantly contribute to the progression of fatty liver disease. Due to their high heterogeneity and complex phenotypes, their functional role in health and disease is difficult to analyze. Here, we describe the isolation and analysis of myeloid cell populations from mouse liver using microdroplet-based scRNA-seq. This approach allows the identification and characterization of different hepatic cell types, exemplified here by hepatic macrophage populations, as well as analyses of differentially expressed genes between samples (e.g., cells from healthy or NASH livers).
    Keywords:  10× Genomics; Fibrosis; Macrophages; Myeloid immune cells; NAFLD; NASH; Single cell RNA sequencing (scRNA-seq); Transcriptomics
    DOI:  https://doi.org/10.1007/978-1-0716-2128-8_15
  2. Sci Immunol. 2022 Feb 25. 7(68): eabi6112
    Group 1 ILCs regulate T cell-mediated liver immunopathology by controlling local IL-2 availability.
    Valeria Fumagalli, Valentina Venzin, Pietro Di Lucia, Federica Moalli, Xenia Ficht, Gioia Ambrosi, Leonardo Giustini, Francesco Andreata, Marta Grillo, Diletta Magini, Micol Ravà, Christin Friedrich, Jason D Fontenot, Philippe Bousso, Sarah A Gilmore, Shahzada Khan, Manuel Baca, Eric Vivier, Georg Gasteiger, Mirela Kuka, Luca G Guidotti, Matteo Iannacone.
      Group 1 innate lymphoid cells (ILCs), which comprise both natural killer (NK) cells and ILC1s, are important innate effectors that can also positively and negatively influence adaptive immune responses. The latter function is generally ascribed to the ability of NK cells to recognize and kill activated T cells. Here, we used multiphoton intravital microscopy in mouse models of hepatitis B to study the intrahepatic behavior of group 1 ILCs and their cross-talk with hepatitis B virus (HBV)-specific CD8+ T cells. We found that hepatocellular antigen recognition by effector CD8+ T cells triggered a prominent increase in the number of hepatic NK cells and ILC1s. Group 1 ILCs colocalized and engaged in prolonged interactions with effector CD8+ T cells undergoing hepatocellular antigen recognition; however, they did not induce T cell apoptosis. Rather, group 1 ILCs constrained CD8+ T cell proliferation by controlling local interleukin-2 (IL-2) availability. Accordingly, group 1 ILC depletion, or genetic removal of their IL-2 receptor a chain, considerably increased the number of intrahepatic HBV-specific effector CD8+ T cells and the attendant immunopathology. Together, these results reveal a role for group 1 ILCs in controlling T cell-mediated liver immunopathology by limiting local IL-2 concentration and have implications for the treatment of chronic HBV infection.
    DOI:  https://doi.org/10.1126/sciimmunol.abi6112
  3. Semin Immunopathol. 2022 Feb 24.
    Th17 cells in the liver: balancing autoimmunity and pathogen defense.
    Nobuhito Taniki, Nobuhiro Nakamoto, Po-Sung Chu, Masataka Ichikawa, Toshiaki Teratani, Takanori Kanai.
      In addition to carcinogenesis, T helper 17 (Th17) cells (a subtype of CD4 + T lymphocytes) are involved in the acute, chronic, and cirrhotic phases of liver diseases; however, their role in the development and progression of liver diseases remains unclear. It is difficult to elucidate the role of Th17 cells in liver diseases due to their dichotomous nature, i.e., plasticity in terms of pathogenic or host protective function depending on environmental and time phase factors. Moreover, insufficient depletion of Th17 cells by inhibiting the cytokines and transcription factors involved in their production causes difficulties in analyzing their specific role in vitro and in vivo murine models, partially due to complex interaction. This review summarizes the recent progress in understanding the plasticity and function of hepatic Th17 cells and type 3 cytokines.
    Keywords:  Gut–liver axis; Hepatitis; IL-17; IL-22; Liver fibrosis; Th17
    DOI:  https://doi.org/10.1007/s00281-022-00917-9
  4. Nat Rev Genet. 2022 Feb 25.
    Single-cell atlases: shared and tissue-specific cell types across human organs.
    Rasa Elmentaite, Cecilia Domínguez Conde, Lu Yang, Sarah A Teichmann.
      The development of single-cell and spatial transcriptomics methods was instrumental in the conception of the Human Cell Atlas initiative, which aims to generate an integrated map of all cells across the human body. These technology advances are bringing increasing depth and resolution to maps of human organs and tissues, as well as our understanding of individual human cell types. Commonalities as well as tissue-specific features of primary and supportive cell types across human organs are beginning to emerge from these human tissue maps. In this Review, we highlight key biological insights obtained from cross-tissue studies into epithelial, fibroblast, vascular and immune cells based on single-cell gene expression data in humans and contrast it with mechanisms reported in mice.
    DOI:  https://doi.org/10.1038/s41576-022-00449-w
  5. Sci Immunol. 2022 Feb 25. 7(68): eabm2508
    Single-cell eQTL analysis of activated T cell subsets reveals activation and cell type-dependent effects of disease-risk variants.
    Benjamin J Schmiedel, Cristian Gonzalez-Colin, Vicente Fajardo, Job Rocha, Ariel Madrigal, Ciro Ramírez-Suástegui, Sourya Bhattacharyya, Hayley Simon, Jason A Greenbaum, Bjoern Peters, Grégory Seumois, Ferhat Ay, Vivek Chandra, Pandurangan Vijayanand.
      The impact of genetic variants on cells challenged in biologically relevant contexts has not been fully explored. Here, we activated CD4+ T cells from 89 healthy donors and performed a single-cell RNA sequencing assay with >1 million cells to examine cell type-specific and activation-dependent effects of genetic variants. Single-cell expression quantitative trait loci (sc-eQTL) analysis of 19 distinct CD4+ T cell subsets showed that the expression of over 4000 genes is significantly associated with common genetic polymorphisms and that most of these genes show their most prominent effects in specific cell types. These genes included many that encode for molecules important for activation, differentiation, and effector functions of T cells. We also found new gene associations for disease-risk variants identified from genome-wide association studies and highlighted the cell types in which their effects are most prominent. We found that biological sex has a major influence on activation-dependent gene expression in CD4+ T cell subsets. Sex-biased transcripts were significantly enriched in several pathways that are essential for the initiation and execution of effector functions by CD4+ T cells like TCR signaling, cytokines, cytokine receptors, costimulatory, apoptosis, and cell-cell adhesion pathways. Overall, this DICE (Database of Immune Cell Expression, eQTLs, and Epigenomics) subproject highlights the power of sc-eQTL studies for simultaneously exploring the activation and cell type-dependent effects of common genetic variants on gene expression (https://dice-database.org).
    DOI:  https://doi.org/10.1126/sciimmunol.abm2508
  6. iScience. 2022 Feb 18. 25(2): 103847
    NAFLD indirectly impairs antigen-specific CD8+ T cell immunity against liver cancer in mice.
    John C McVey, Benjamin L Green, Benjamin Ruf, Justin D McCallen, Simon Wabitsch, Varun Subramanyam, Laurence P Diggs, Bernd Heinrich, Tim F Greten, Chi Ma.
      Non-alcoholic fatty liver disease (NAFLD) has become an important etiology leading to liver cancer. NAFLD alters adaptive T cell immunity and has a profound influence on liver cancer development. However, it is unclear how NAFLD affects tumor antigen-specific T cell response. In this study, we generated a doxycycline-inducible MHC-I and -II antigen-expressing HCC cell line which allowed us to investigate tumor antigen-specific T cell response in two NAFLD mouse models. The system proved to be an effective and efficient way to study tumor antigen-specific T cells. Using this model, it was found that NAFLD impairs antigen-specific CD8+ T cell immunity against HCC. The effect was not due to reduced generation or intrinsic functional changes of tumor antigen-specific CD8+ T cells but caused by accumulated macrophages in the liver environment. The findings suggest that targeting macrophages in NAFLD-driven HCC may improve therapeutic outcomes.
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2022.103847
  7. Hepatology. 2022 Feb 26.
    Dual roles of B lymphocytes in murine models of diet-induced non-alcoholic fatty liver disease.
    Martin Karl, Solveig Hasselwander, Yawen Zhou, Gisela Reifenberg, Yong Ook Kim, Kyoung-Sook Park, Dirk A Ridder, Xiaoyu Wang, Eric Seidel, Nadine Hövelmeyer, Beate K Straub, Huige Li, Detlef Schuppan, Ning Xia.
       BACKGROUND & AIMS: Growing evidence suggests an important role of B cells in the development of non-alcoholic fatty liver disease (NAFLD). However, a detailed functional analysis of B cell subsets in NAFLD pathogenesis is lacking.
    APPROACH & RESULTS: In wildtype mice, 21 weeks of high fat diet (HFD) feeding resulted in NAFLD with massive macrovesicular steatosis, modest hepatic and adipose tissue inflammation, insulin resistance and incipient fibrosis. Remarkably, Bnull (JHT) mice were partially protected whereas B cell harboring but antibody-deficient IgMi mice were completely protected from the development of hepatic steatosis, inflammation and fibrosis. The common feature of JHT and IgMi mice is that they do not secrete antibodies, while HFD feeding in wildtype mice led to increased levels of serum IgG2c. Whereas JHT mice have no B cells at all, regulatory B cells were found in the liver of both wildtype and IgMi mice. HFD reduced the number of regulatory B cells and interleukin 10 production in the liver of wildtype mice, while these increased in IgMi mice. Livers of patients with advanced liver fibrosis showed abundant deposition of IgG, stromal B cells and low numbers of interleukin 10 expressing cells, compatible with our experimental data.
    CONCLUSIONS: B lymphocytes have both detrimental and protective effects in HFD-induced NAFLD. The lack of secreted pathogenic antibodies protects partially from NAFLD, whereas the presence of certain B cell subsets provides additional protection. Interleukin 10-producing regulatory B cells may represent such a protective B cell subset.
    Keywords:  Non-alcoholic steatohepatitis; adipose tissue dysfunction; diet-induced obesity; high fat diet; lipogenesis
    DOI:  https://doi.org/10.1002/hep.32428
  8. Immunity. 2022 Feb 21. pii: S1074-7613(22)00047-4. [Epub ahead of print]
    Tfh-cell-derived interleukin 21 sustains effector CD8+ T cell responses during chronic viral infection.
    Ryan Zander, Moujtaba Y Kasmani, Yao Chen, Paytsar Topchyan, Jian Shen, Shikan Zheng, Robert Burns, Jennifer Ingram, Can Cui, Nikhil Joshi, Joseph Craft, Allan Zajac, Weiguo Cui.
      CD4+ T cell-derived interleukin 21 (IL-21) sustains CD8+ T cell responses during chronic viral infection, but the helper subset that confers this protection remains unclear. Here, we applied scRNA and ATAC-seq approaches to determine the heterogeneity of IL-21+CD4+ T cells during LCMV clone 13 infection. CD4+ T cells were comprised of three transcriptionally and epigenetically distinct populations: Cxcr6+ Th1 cells, Cxcr5+ Tfh cells, and a previously unrecognized Slamf6+ memory-like (Tml) subset. T cell differentiation was specifically redirected toward the Tml subset during chronic, but not acute, LCMV infection. Although this subset displayed an enhanced capacity to accumulate and some developmental plasticity, it remained largely quiescent, which may hinder its helper potential. Conversely, mixed bone marrow chimera experiments revealed that Tfh cell-derived IL-21 was critical to sustain CD8+ T cell responses and viral control. Thus, strategies that bolster IL-21+Tfh cell responses may prove effective in enhancing CD8+ T cell-mediated immunity.
    Keywords:  ATAC-seq; CD4 T cells; IL-21; LCMV Cl13; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.immuni.2022.01.018
  9. Lancet Diabetes Endocrinol. 2022 Feb 17. pii: S2213-8587(22)00003-1. [Epub ahead of print]
    A global view of the interplay between non-alcoholic fatty liver disease and diabetes.
    Norbert Stefan, Kenneth Cusi.
      Non-alcoholic fatty liver disease (NAFLD) has become an epidemic, much like other non-communicable diseases (NCDs), such as cancer, obesity, diabetes, and cardiovascular disease. The pathophysiology of NAFLD, particularly involving insulin resistance and subclinical inflammation, is not only closely linked to that of those NCDs but also to a severe course of the communicable disease COVID-19. Genetics alone cannot explain the large increase in the prevalence of NAFLD during the past 2 decades and the increase that is projected for the next decades. Impairment of glucose and lipid metabolic pathways, which has been propelled by the worldwide increase in the prevalence of obesity and type 2 diabetes, is most likely behind the increase in people with NAFLD. As the prevalence of NAFLD varies among subgroups of patients with diabetes and prediabetes identified by cluster analyses, stratification of people with diabetes and prediabetes by major pathological mechanistic pathways might improve the diagnosis of NAFLD and prediction of its progression. In this Review, we aim to understand how diabetes can affect the development of hepatic steatosis and its progression to advanced liver damage. First, we emphasise the extent to which NAFLD and diabetes jointly occur worldwide. Second, we address the major mechanisms that are involved in the pathogenesis of NAFLD and type 2 diabetes, and we discuss whether these mechanisms place NAFLD in an important position to better understand the pathogenesis of NCDs and communicable diseases, such as COVID-19. Third, we address whether this knowledge can be used for personalised treatment of NAFLD in the future. Finally, we discuss the current treatment strategies for people with type 2 diabetes and their effectiveness in treating the spectrum of hepatic diseases from simple steatosis to non-alcoholic steatohepatitis and hepatic fibrosis.
    DOI:  https://doi.org/10.1016/S2213-8587(22)00003-1
  10. Immunology. 2022 Feb 23.
    Distinguishing activated T regulatory cell and T conventional cells by single cell technologies.
    Julia Reinhardt, Virag Sharma, Antigoni Stavridou, Annett Lindner, Susanne Reinhardt, Andreas Petzold, Mathias Lesche, Fabian Rost, Ezio Bonifacio, Anne Eugster.
       BACKGROUND: Resting conventional T cells (Tconv) can be distinguished from T regulatory cells (Treg) by the canonical markers FOXP3, CD25 and CD127. However, the expression of these proteins alters after T cell activation leading to overlap between Tconv and Treg. The objective of this study was to distinguish resting and antigen-responsive T effector (Tconv) and Treg using single cell technologies.
    METHODS: CD4+ Treg and Tconv cells were stimulated with antigen and responsive and non-responsive populations processed for targeted and non-targeted single cell RNAseq. Machine learning was used to generate a limited set of genes that could distinguish responding and non-responding Treg and Tconv cells and which was used for single cell multiplex qPCR and to design a flow cytometry panel.
    RESULTS: Targeted scRNAseq clearly distinguished the four cell populations. A minimal set of 27 genes was identified by machine learning algorithms to provide discrimination of the four populations at >95% accuracy. Fifteen of the genes were validated to be differentially expressed by single-cell multiplex qPCR. Discrimination of responding Treg from responding Tconv could be achieved by a flow cytometry strategy that included staining for CD25, CD127, FOXP3, IKZF2, ITGA4, and the novel marker TRIM which was strongly expressed in Tconv and weakly expressed in both responding and non-responding Treg.
    CONCLUSION: A minimal set of genes was identified that discriminates responding and non-responding CD4+ Treg and Tconv cells and, which have identified TRIM as a marker to distinguish Treg by flow cytometry.
    DOI:  https://doi.org/10.1111/imm.13460
  11. Cold Spring Harb Perspect Med. 2022 Feb 22. pii: a041170. [Epub ahead of print]
    Mechanisms Regulating T Cell-Endothelial Cell Interactions.
    Pilar Alcaide.
      T-cell interaction with the endothelial cells lining the vessel wall is a necessary step in the inflammatory response that allows T cells to extravasate from the circulation and migrate to sites of infectious or sterile inflammation. On one hand, the vascular endothelium is activated and, as a result, switches from an anti-adhesive to a pro-adhesive state, allowing adhesion of T cells and other leukocytes. On the other hand, T cells express ligands of endothelial adhesion molecules to sustain these interactions that eventually result in T-cell extravasation into sites of inflammation. A better understanding of the central players mediating these interactions may help develop novel therapeutics that modulate this process by preventing T-cell migration and inflammation. Here, I summarize current knowledge on the nature of these interactions in the context of inflammation and cancer immunotherapy.
    DOI:  https://doi.org/10.1101/cshperspect.a041170
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