bims-nastce 2021-10-31 papers

bims-nastce

Biomed News

on NASH and T cells

Issue of 2021–10–31
eight papers selected by
Petra Hirsova, Mayo Clinic College of Medicine

New Insights on CD8+ T Cells in Inflammatory Bowel Disease and Therapeutic Approaches.
Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities.
Synergistic and additive interactions between receptor signaling networks drive the regulatory T cell versus T helper 17 cell fate choice.
Multiplex Immunofluorescence for Detection of Spatial Distributions of Infiltrating T Cells Within Different Regions of Hepatic Lobules During Liver Transplantation Rejection.
Interleukin-10 induces interferon-γ-dependent emergency myelopoiesis.
A novel mouse model of non-alcoholic steatohepatitis suggests that liver fibrosis initiates around lipid-laden macrophages.
The immune niche of the liver.
Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis.

Front Immunol. 2021 ;12 738762

New Insights on CD8+ T Cells in Inflammatory Bowel Disease and Therapeutic Approaches.

Rosaely Casalegno Garduño, Jan Däbritz.

  CD8+ T cells are involved in the pathogenesis of inflammatory bowel disease (IBD), a complex multifactorial chronic disease. Here, we present an overview of the current research with the controversial findings of CD8+ T cell subsets and discuss some possible perspectives on their therapeutic value in IBD. Studies on the role of CD8+ T cells in IBD have contradictory outcomes, which might be related to the heterogeneity of the cells. Recent data suggest that cytotoxic CD8+ T cells (Tc1) and interleukin (IL) 17-producing CD8+ (Tc17) cells contribute to the pathogenesis of IBD. Moreover, subsets of regulatory CD8+ T cells are abundant at sites of inflammation and can exhibit pro-inflammatory features. Some subsets of tissue resident memory CD8+ T cells (Trm) might be immunosuppressant, whereas others might be pro-inflammatory. Lastly, exhausted T cells might indicate a positive outcome for patients. The function and plasticity of different subsets of CD8+ T cells in health and IBD remain to be further investigated in a challenging field due to the limited availability of mucosal samples and adequate controls.

Keywords:  CD8+ Tc1; Crohn´s disease; IBD; T regs; TRM; Tc17; ulcerative colitis

DOI:  https://doi.org/10.3389/fimmu.2021.738762
Nat Rev Endocrinol. 2021 Oct 26.

Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities.

Sara SantaCruz-Calvo, Leena Bharath, Gabriella Pugh, Lucia SantaCruz-Calvo, Raji Rajesh Lenin, Jenny Lutshumba, Rui Liu, Adam D Bachstetter, Beibei Zhu, Barbara S Nikolajczyk.

Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health. In obesity, chronic low-grade inflammation can occur in adipose tissue that can progress to systemic inflammation; this inflammation contributes to the development of insulin resistance, T2DM and other comorbidities. An improved understanding of adaptive immune cell dysregulation that occurs during obesity and its associated metabolic comorbidities, with an appreciation of sex differences, will be critical for repurposing or developing immunomodulatory therapies to treat obesity and/or T2DM-associated inflammation. This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward.

DOI: https://doi.org/10.1038/s41574-021-00575-1
J Biol Chem. 2021 Oct 21. pii: S0021-9258(21)01136-4. [Epub ahead of print] 101330

Synergistic and additive interactions between receptor signaling networks drive the regulatory T cell versus T helper 17 cell fate choice.

Douglas S Prado, Richard T Cattley, Corey W Shipman, Cassandra Happe, Mijoon Lee, William C Boggess, Matthew L MacDonald, William F Hawse.

  CD4+ T cells differentiate into subsets that promote immunity or minimize damage to the host. T helper 17 cells (Th17) are effector cells that function in inflammatory responses. T regulatory cells (Tregs) maintain tolerance and prevent autoimmunity by secreting immunosuppressive cytokines and expressing check point receptors. While the function of Th17 and Treg cells are different, both cell fate trajectories require T cell receptor (TCR) and TGF-β receptor (TGF- βR) signals, and Th17 polarization requires an additional IL-6 receptor (IL-6R) signal. Utilizing high-resolution phosphoproteomics, we identified that both synergistic and additive interactions between TCR, TGF-βR and IL-6R shape kinase signaling networks to differentially regulate key pathways during the early phase of Treg versus Th17 induction. Quantitative biochemical analysis revealed that CD4+ T cells integrate receptor signals via SMAD3, which is a mediator of TGF-βR signaling. Treg induction potentiates the formation of the canonical SMAD3/4 trimer to activate a negative feedback loop through kinases PKA and CSK to suppress TCR signaling, phosphatidylinositol metabolism, and mTOR signaling. IL-6R signaling activates STAT3 to bind SMAD3 and block formation of the SMAD3/4 trimer during the early phase of Th17 induction, which leads to elevated TCR and PI3K signaling. These data provide a biochemical mechanism by which CD4+ T cells integrate TCR, TGF-β, and IL-6 signals via generation of alternate SMAD3 complexes that control the development of early signaling networks to potentiate the choice of Treg versus Th17 cell fate.

Keywords:  C-terminal Src kinase (CSK); SMAD3; STAT3; T cell differentiation; T cell receptor (TCR); T regulatory cell; Th17; Treg; cytokine; immunity; interleukin 6 (IL-6); mTOR; phosphoinositide 3-kinase (PI3K); phospholipid signaling; protein kinase A (PKA); proteomics; transforming growth factor β (TGF-β)

DOI:  https://doi.org/10.1016/j.jbc.2021.101330
Inflammation. 2021 Oct 27.

Multiplex Immunofluorescence for Detection of Spatial Distributions of Infiltrating T Cells Within Different Regions of Hepatic Lobules During Liver Transplantation Rejection.

Shi-Peng Li, Guang-Peng Zhou, Jie Sun, Bin Cui, Hai-Ming Zhang, Lin Wei, Li-Ying Sun, Zhi-Jun Zhu.

  It remains unclear as to whether there are differences that exist in the types and functional status of immune cells within different areas of the liver lobules after rejection of liver transplantation. The composition of infiltrating T cells in liver allografts during liver transplantation rejection is indistinct and difficult to visualize within the same biopsy slide. In an attempt to rectify this problem, we applied multiplex immunofluorescent assays to assess the spatial distribution of various types of infiltrating T cells in different areas of the liver lobules after liver transplantation. In identical areas of the hepatic lobules, the percentage of CD4+ T, CD8+ T, and regulatory T (Treg) cells in the rejection group was greater than that observed in the non-rejection and normal groups. Within all three groups, the percentage of CD4+ T, CD8+ T, and Treg cells from the periportal to perivenous zones initially increased and then decreased. In the rejection group, the percentage of CD8+ T cells gradually increased from the periportal to perivenous zones, with maximal levels in the perivenous as compared with that in the transitional and periportal zones. In conclusion, levels of CD8+ T cells within different regions of liver lobules are closely related to levels of rejection after liver transplantation. Liver transplantation rejection may be linked with increases in CD8+ T cells within the perivenous zone. Although the regional percent of increase in CD4+ T cells may not reflect level of the rejection, the overall numbers of both of CD4+ and CD8+ T cells within different regions were closely related to rejection levels.

Keywords:  hepatic lobule regions; infiltrating T cells; liver transplantation rejection; multiplex immunofluorescence.; spatial distribution

DOI:  https://doi.org/10.1007/s10753-021-01574-0
Cell Rep. 2021 Oct 26. pii: S2211-1247(21)01357-7. [Epub ahead of print]37(4): 109887

Interleukin-10 induces interferon-γ-dependent emergency myelopoiesis.

Ana Cardoso, Ana Catarina Martins, Ana Raquel Maceiras, Wei Liu, Isabel Castro, António G Castro, António Bandeira, James P Di Santo, Ana Cumano, Yan Li, Paulo Vieira, Margarida Saraiva.

  In emergency myelopoiesis (EM), expansion of the myeloid progenitor compartment and increased myeloid cell production are observed and often mediated by the pro-inflammatory cytokine interferon gamma (IFN-γ). Interleukin-10 (IL-10) inhibits IFN-γ secretion, but paradoxically, its therapeutic administration to humans causes hematologic changes similar to those observed in EM. In this work, we use different in vivo systems, including a humanized immune system mouse model, to show that IL-10 triggers EM, with a significant expansion of the myeloid progenitor compartment and production of myeloid cells. Hematopoietic progenitors display a prominent IFN-γ transcriptional signature, and we show that IFN-γ mediates IL-10-driven EM. We also find that IL-10, unexpectedly, reprograms CD4 and CD8 T cells toward an activation state that includes IFN-γ production by these T cell subsets in vivo. Therefore, in addition to its established anti-inflammatory properties, IL-10 can induce IFN-γ production and EM, opening additional perspectives for the design of IL-10-based immunotherapies.

Keywords:  IFN-γ; IL-10; T cells; emergency myelopoiesis

DOI:  https://doi.org/10.1016/j.celrep.2021.109887
Am J Pathol. 2021 Oct 25. pii: S0002-9440(21)00440-5. [Epub ahead of print]

A novel mouse model of non-alcoholic steatohepatitis suggests that liver fibrosis initiates around lipid-laden macrophages.

Mayuko Ichimura-Shimizu, Yosuke Tsuchiyama, Yuki Morimoto, Minoru Matsumoto, Tomoko Kobayashi, Satoshi Sumida, Takumi Kakimoto, Takeshi Oya, Hirohisa Ogawa, Michiko Yamashita, Satoru Matsuda, Katsuhisa Omagari, Shu Taira, Koichi Tsuneyama.

Various cells such as macrophages and hepatic stellate cells interact in the generation of fibrosis in nonalcoholic steatohepatitis (NASH), but the mechanism remains unclear. We employed a high fat/cholesterol/cholate (HFCC) diet to generate a model of NASH-related fibrosis and investigate the pathogenesis of fibrosis. Two mouse strains differing in susceptibility to obesity, the susceptible strain C57BL/6J (B6) and the relatively resistant strain A/J, developed hepatic histological features of NASH including fat deposition, intralobular inflammation, hepatocyte ballooning, and fibrosis after 9 weeks of HFCC diet feeding. The severity of hepatic inflammation and fibrosis was greater in A/J mice than in B6 mice. A/J mice fed the HFCC diet exhibited characteristic CD204-positive lipid-laden macrophage aggregation in hepatic parenchyma. Polarized light visualized the Maltese cross, namely cholesterol crystals within the aggregated macrophages. Moreover, fibrosis developed in a ring-shape from the periphery of the aggregated macrophages, i.e., the starting point of fibrosis could be visualized histologically. Furthermore, matrix assisted laser desorption/ionization mass spectrometry imaging analysis detected a molecule at m/z 772.462, which corresponds to the protonated ion of phosphatidylcholine (P-18:1 (11Z)/18:0) and phosphatidylethanolamine (18:0/20:2 (11Z, 14Z)), in aggregated macrophages in adjacent to the fibrotic lesions. In conclusion, the present HFCC diet-fed A/J model provides an ideal tool to study fibrogenesis and enables novel insights into the pathophysiology of NASH-related fibrosis.

DOI: https://doi.org/10.1016/j.ajpath.2021.10.002
Clin Sci (Lond). 2021 Oct 29. 135(20): 2445-2466

The immune niche of the liver.

Michael L Cheng, Diana Nakib, Catia T Perciani, Sonya A MacParland.

  The liver is an essential organ that is critical for the removal of toxins, the production of proteins, and the maintenance of metabolic homeostasis. Behind each liver functional unit, termed lobules, hides a heterogeneous, complex, and well-orchestrated system. Despite parenchymal cells being most commonly associated with the liver's primary functionality, it has become clear that it is the immune niche of the liver that plays a central role in maintaining both local and systemic homeostasis by propagating hepatic inflammation and orchestrating its resolution. As such, the immunological processes that are at play in healthy and diseased livers are being investigated thoroughly in order to understand the underpinnings of inflammation and the potential avenues for restoring homeostasis. This review highlights recent advances in our understanding of the immune niche of the liver and provides perspectives for how the implementation of new transcriptomic, multimodal, and spatial technologies can uncover the heterogeneity, plasticity, and location of hepatic immune populations. Findings from these technologies will further our understanding of liver biology and create a new framework for the identification of therapeutic targets.

Keywords:  hepatic physiology; immunology; multi-modal technologies; single cell RNA sequencing; spatial transcriptomics

DOI:  https://doi.org/10.1042/CS20190654
Gut. 2021 Oct 26. pii: gutjnl-2021-324546. [Epub ahead of print]

Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis.

Bomi Lee, Hong Namkoong, Yan Yang, Huang Huang, David Heller, Gregory L Szot, Mark M Davis, Sohail Z Husain, Stephen J Pandol, Melena D Bellin, Aida Habtezion.

   OBJECTIVE: Chronic pancreatitis (CP) is a potentially fatal disease of the exocrine pancreas, with no specific or effective approved therapies. Due to difficulty in accessing pancreas tissues, little is known about local immune responses or pathogenesis in human CP. We sought to characterise pancreatic immune responses using tissues derived from patients with different aetiologies of CP and non-CP organ donors in order to identify key signalling molecules associated with human CP.
DESIGN: We performed single-cell level cellular indexing of transcriptomes and epitopes by sequencing and T-cell receptor (TCR) sequencing of pancreatic immune cells isolated from organ donors, hereditary and idiopathic patients with CP who underwent total pancreatectomy. We validated gene expression data by performing flow cytometry and functional assays in a second patient with CP cohort.
RESULTS: Deep single-cell sequencing revealed distinct immune characteristics and significantly enriched CCR6+ CD4+ T cells in hereditary compared with idiopathic CP. In hereditary CP, a reduction in T-cell clonality was observed due to the increased CD4+ T (Th) cells that replaced tissue-resident CD8+ T cells. Shared TCR clonotype analysis among T-cell lineages also unveiled unique interactions between CCR6+ Th and Th1 subsets, and TCR clustering analysis showed unique common antigen binding motifs in hereditary CP. In addition, we observed a significant upregulation of the CCR6 ligand (CCL20) expression among monocytes in hereditary CP as compared with those in idiopathic CP. The functional significance of CCR6 expression in CD4+ T cells was confirmed by flow cytometry and chemotaxis assay.
CONCLUSION: Single-cell sequencing with pancreatic immune cells in human CP highlights pancreas-specific immune crosstalk through the CCR6-CCL20 axis, a signalling pathway that might be leveraged as a potential future target in human hereditary CP.

Keywords:  RNA expression; T-cell receptor; chronic pancreatitis; immunology; pancreatitis

DOI:  https://doi.org/10.1136/gutjnl-2021-324546