bims-nastce Biomed News
on NASH and T cells
Issue of 2021‒09‒26
sixteen papers selected by
Petra Hirsova
Mayo Clinic College of Medicine
  1. NAFLD-driven HCC: Safety and efficacy of current and emerging treatment options.
  2. Role of Cholesterol-Associated Steatohepatitis in the Development of NASH.
  3. Editorial: CD4+ T Cells in Cancer Immunotherapies.
  4. Five-in-One: Simultaneous isolation of multiple major liver cell types from livers of normal and NASH mice.
  5. The human liver microenvironment shapes the homing and function of CD4+ T-cell populations.
  6. Integrin-based therapy in IBD.
  7. Role for exosomes in insulin sensitivity.
  8. A Cre-driven allele-conditioning line to interrogate CD4+ conventional T cells.
  9. Cutting Edge: Intestinal IL-17A Receptor Signaling Specifically Regulates High-Fat Diet-Mediated, Microbiota-Driven Metabolic Disorders.
  10. Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity.
  11. Repositioning TH cell polarization from single cytokines to complex help.
  12. Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice.
  13. Western Diet Changes Gut Microbiota and Ameliorates Liver Injury in a Mouse Model with Human-Like Bile Acid Composition.
  14. Secret messengers: Extracellular RNA communication in the immune system.
  15. Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis.
  16. Interferon-γ-Producing CD4+ T Cells Drive Monocyte Activation in the Bone Marrow During Experimental Leishmania donovani Infection.
  1. J Hepatol. 2021 Sep 20. pii: S0168-8278(21)02037-7. [Epub ahead of print]
    NAFLD-driven HCC: Safety and efficacy of current and emerging treatment options.
    Friedrich Foerster, Simon Johannes Gairing, Lukas Müller, Peter Robert Galle.
      In light of a global rise in obesity and type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) represent an increasingly important underlying etiology of hepatocellular carcinoma (HCC). HCCs arising from lipotoxicity-mediated chronic inflammation due to excessive accumulation of neutral lipids in the liver are characterized by several unique features: In contrast to viral-driven HCC, up to 50% of NAFLD-HCC occurs in patients without cirrhosis, and annual HCC incidence is comparatively low, complicating current surveillance strategies. On average, patients are older and diagnosis occurs more frequently at an advanced stage. Locoregional treatments are probably equally effective regardless of HCC etiology. For systemic therapy the picture is less clear. Tyrosine kinase inhibitors are probably equally effective, while there have been first signals that immune checkpoint inhibitors may be less effective in NAFLD-HCC than in viral HCC. To date, treatment recommendations for HCC by international guidelines do not take the underlying etiology into consideration. This review article summarizes the currently available evidence for the efficacy and safety of the various treatment modalities for HCC. There are insufficient data to draw any conclusion and to modify the current management of HCC patients with regard to etiology. However, in light of the growing relevance of NAFLD-HCC, future clinical trials should assess whether HCC etiology - and NAFLD/NASH in particular - influence the safety and efficacy of a given treatment.
    Keywords:  Ablation; Hepatocellular carcinoma; Immunotherapy; Liver cirrhosis; Metabolic syndrome; NAFLD; NASH; SBRT; SIRT; Surgery; Systemic treatment; TACE; Transplant
    DOI:  https://doi.org/10.1016/j.jhep.2021.09.007
  2. Hepatol Commun. 2021 Aug 24.
    Role of Cholesterol-Associated Steatohepatitis in the Development of NASH.
    Christian L Horn, Amilcar L Morales, Christopher Savard, Geoffrey C Farrell, George N Ioannou.
      The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol-associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH-cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH.
    DOI:  https://doi.org/10.1002/hep4.1801
  3. Front Immunol. 2021 ;12 737615
    Editorial: CD4+ T Cells in Cancer Immunotherapies.
    José M González-Navajas, Eyad Elkord, Jongdae Lee.
      
    Keywords:  CD4; T lymphocyte; cancer; immune checkpoint inhibitor (ICI); immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2021.737615
  4. J Cell Mol Med. 2021 Sep 23.
    Five-in-One: Simultaneous isolation of multiple major liver cell types from livers of normal and NASH mice.
    Ye Zhou, Funmilola Adewale, Sun Kim, Qi Su, David Glass, Mark W Sleeman, Andrew J Murphy, Xiping Cheng.
      NASH is a chronic liver disease that affects 3%-6% of individuals and requires urgent therapeutic developments. Isolating the key cell types in the liver is a necessary step towards understanding their function and roles in disease pathogenesis. However, traditional isolation methods through gradient centrifugation can only collect one or a few cell types simultaneously and pose technical difficulties when applied to NASH livers. Taking advantage of identified cell surface markers from liver single-cell RNAseq, here we established the combination of gradient centrifugation and antibody-based cell sorting techniques to isolate five key liver cell types (hepatocytes, endothelial cells, stellate cells, macrophages and other immune cells) from a single mouse liver. This method yielded high purity of each cell type from healthy and NASH livers. Our five-in-one protocol simultaneously isolates key liver cell types with high purity under normal and NASH conditions, enabling for systematic and accurate exploratory experiments such as RNA sequencing.
    Keywords:  cell isolation; fluorescence-activated cell sorting; liver; non-alcoholic steatohepatitis
    DOI:  https://doi.org/10.1111/jcmm.16933
  5. Gut. 2021 Sep 21. pii: gutjnl-2020-323771. [Epub ahead of print]
    The human liver microenvironment shapes the homing and function of CD4+ T-cell populations.
    Benjamin G Wiggins, Laura J Pallett, Xiaoyan Li, Scott P Davies, Oliver E Amin, Upkar S Gill, Stephanie Kucykowicz, Arzoo M Patel, Konstantinos Aliazis, Yuxin S Liu, Gary M Reynolds, Brian R Davidson, Amir Gander, Tu Vinh Luong, Gideon M Hirschfield, Patrick T F Kennedy, Yuehua Huang, Mala K Maini, Zania Stamataki.
      OBJECTIVE: Tissue-resident memory T cells (TRM) are vital immune sentinels that provide protective immunity. While hepatic CD8+ TRM have been well described, little is known about the location, phenotype and function of CD4+ TRM.DESIGN: We used multiparametric flow cytometry, histological assessment and novel human tissue coculture systems to interrogate the ex vivo phenotype, function and generation of the intrahepatic CD4+ T-cell compartment. We also used leukocytes isolated from human leukocyte antigen (HLA)-disparate liver allografts to assess long-term retention.
    RESULTS: Hepatic CD4+ T cells were delineated into three distinct populations based on CD69 expression: CD69-, CD69INT and CD69HI. CD69HICD4+ cells were identified as tissue-resident CD4+ T cells on the basis of their exclusion from the circulation, phenotypical profile (CXCR6+CD49a+S1PR1-PD-1+) and long-term persistence within the pool of donor-derived leukcoocytes in HLA-disparate liver allografts. CD69HICD4+ T cells produced robust type 1 polyfunctional cytokine responses on stimulation. Conversely, CD69INTCD4+ T cells represented a more heterogenous population containing cells with a more activated phenotype, a distinct chemokine receptor profile (CX3CR1+CXCR3+CXCR1+) and a bias towards interleukin-4 production. While CD69INTCD4+ T cells could be found in the circulation and lymph nodes, these cells also formed part of the long-term resident pool, persisting in HLA-mismatched allografts. Notably, frequencies of CD69INTCD4+ T cells correlated with necroinflammatory scores in chronic hepatitis B infection. Finally, we demonstrated that interaction with hepatic epithelia was sufficient to generate CD69INTCD4+ T cells, while additional signals from the liver microenvironment were required to generate liver-resident CD69HICD4+ T cells.
    CONCLUSIONS: High and intermediate CD69 expressions mark human hepatic CD4+ TRM and a novel functionally distinct recirculating population, respectively, both shaped by the liver microenvironment to achieve diverse immunosurveillance.
    Keywords:  T lymphocytes; cellular immunity; hepatitis B; immunology; liver immunology
    DOI:  https://doi.org/10.1136/gutjnl-2020-323771
  6. Nat Rev Gastroenterol Hepatol. 2021 Sep 23.
    Integrin-based therapy in IBD.
    Eleni Kotsiliti.
      
    DOI:  https://doi.org/10.1038/s41575-021-00526-1
  7. Nat Rev Endocrinol. 2021 Sep 20.
    Role for exosomes in insulin sensitivity.
    Claire Greenhill.
      
    DOI:  https://doi.org/10.1038/s41574-021-00570-6
  8. Immunity. 2021 Sep 15. pii: S1074-7613(21)00363-0. [Epub ahead of print]
    A Cre-driven allele-conditioning line to interrogate CD4+ conventional T cells.
    Lawrence P Andrews, Kate M Vignali, Andrea L Szymczak-Workman, Amanda R Burton, Erin A Brunazzi, Shin Foong Ngiow, Akihito Harusato, Arlene H Sharpe, E John Wherry, Ichiro Taniuchi, Creg J Workman, Dario A A Vignali.
      CD4+ T cells share common developmental pathways with CD8+ T cells, and upon maturation, CD4+ T conventional T (Tconv) cells lack phenotypic markers that distinguish these cells from FoxP3+ T regulatory cells. We developed a tamoxifen-inducible ThPOKCreERT2.hCD2 line with Frt sites inserted on either side of the CreERT2-hCD2 cassette, and a Foxp3Ametrine-FlpO strain, expressing Ametrine and FlpO in Foxp3+ cells. Breeding these mice resulted in a CD4conviCreERT2-hCD2 line that allows for the specific manipulation of a gene in CD4+ Tconv cells. As FlpO removes the CreERT2-hCD2 cassette, CD4+ Treg cells are spared from Cre activity, which we refer to as allele conditioning. Comparison with an E8IiCreERT2.GFP mouse that enables inducible targeting of CD8+ T cells, and deletion of two inhibitory receptors, PD-1 and LAG-3, in a melanoma model, support the fidelity of these lines. These engineered mouse strains present a resource for the temporal manipulation of genes in CD4+ T cells and CD4+ Tconv cells.
    Keywords:  CD4; CD8; T cells; Treg; allele-conditioning; gene editing
    DOI:  https://doi.org/10.1016/j.immuni.2021.08.029
  9. J Immunol. 2021 Sep 20. pii: ji2000986. [Epub ahead of print]
    Cutting Edge: Intestinal IL-17A Receptor Signaling Specifically Regulates High-Fat Diet-Mediated, Microbiota-Driven Metabolic Disorders.
    Stephen J Gaudino, Huakang Huang, Makheni Jean-Pierre, Preet Joshi, Michael Beaupre, Cody Kempen, Hoi Tong Wong, Pawan Kumar.
      Previous studies indicate that IL-17A plays an important role in mediating the intestinal microbiota and systemic metabolic functions. However, it is not known where IL-17RA signaling occurs to mediate these effects. To investigate this question, we used intestinal epithelial-specific (Il17raIEC ) and liver-specific (Il17raLiver ) IL-17RA knockout mice as well as littermate control mice. Our results indicate that intestinal IL-17RA signaling helps mediate systemic metabolic functions upon exposure to prolonged high-fat diet. Il17raIEC mice display impaired glucose metabolism, altered hormone and adipokine levels, increased visceral adiposity, and greater hepatic lipid deposition when compared with their littermate controls. We show that IL-17RA-driven changes in microbiota composition are responsible for regulating systemic glucose metabolism. Altogether, our data elucidate the importance of intestinal IL-17RA signaling in regulating high-fat diet-mediated systemic glucose and lipid metabolism.
    DOI:  https://doi.org/10.4049/jimmunol.2000986
  10. Nat Metab. 2021 Sep;3(9): 1175-1188
    Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity.
    Enyuan Cao, Matthew J Watt, Cameron J Nowell, Tim Quach, Jamie S Simpson, Vilena De Melo Ferreira, Sonya Agarwal, Hannah Chu, Anubhav Srivastava, Dovile Anderson, Gracia Gracia, Alina Lam, Gabriela Segal, Jiwon Hong, Luojuan Hu, Kian Liun Phang, Alistair B J Escott, John A Windsor, Anthony R J Phillips, Darren J Creek, Natasha L Harvey, Christopher J H Porter, Natalie L Trevaskis.
      Visceral adipose tissue (VAT) encases mesenteric lymphatic vessels and lymph nodes through which lymph is transported from the intestine and mesentery. Whether mesenteric lymphatics contribute to adipose tissue inflammation and metabolism and insulin resistance is unclear. Here we show that obesity is associated with profound and progressive dysfunction of the mesenteric lymphatic system in mice and humans. We find that lymph from mice and humans consuming a high-fat diet (HFD) stimulates lymphatic vessel growth, leading to the formation of highly branched mesenteric lymphatic vessels that 'leak' HFD-lymph into VAT and, thereby, promote insulin resistance. Mesenteric lymphatic dysfunction is regulated by cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF)-C-VEGF receptor (R)3 signalling. Lymph-targeted inhibition of COX-2 using a glyceride prodrug approach reverses mesenteric lymphatic dysfunction, visceral obesity and inflammation and restores glycaemic control in mice. Targeting obesity-associated mesenteric lymphatic dysfunction thus represents a potential therapeutic option to treat metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-021-00457-w
  11. Nat Immunol. 2021 Sep 20.
    Repositioning TH cell polarization from single cytokines to complex help.
    Selma Tuzlak, Anne S Dejean, Matteo Iannacone, Francisco J Quintana, Ari Waisman, Florent Ginhoux, Thomas Korn, Burkhard Becher.
      When helper T (TH) cell polarization was initially described three decades ago, the TH cell universe grew dramatically. New subsets were described based on their expression of few specific cytokines. Beyond TH1 and TH2 cells, this led to the coining of various TH17 and regulatory (Treg) cell subsets as well as TH22, TH25, follicular helper (TFH), TH3, TH5 and TH9 cells. High-dimensional single-cell analysis revealed that a categorization of TH cells into a single-cytokine-based nomenclature fails to capture the complexity and diversity of TH cells. Similar to the simple nomenclature used to describe innate lymphoid cells (ILCs), we propose that TH cell polarization should be categorized in terms of the help they provide to phagocytes (type 1), to B cells, eosinophils and mast cells (type 2) and to non-immune tissue cells, including the stroma and epithelium (type 3). Studying TH cells based on their helper function and the cells they help, rather than phenotypic features such as individual analyzed cytokines or transcription factors, better captures TH cell plasticity and conversion as well as the breadth of immune responses in vivo.
    DOI:  https://doi.org/10.1038/s41590-021-01009-w
  12. Nat Metab. 2021 Sep;3(9): 1202-1216
    Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice.
    Alexandra Aliluev, Sophie Tritschler, Michael Sterr, Lena Oppenländer, Julia Hinterdobler, Tobias Greisle, Martin Irmler, Johannes Beckers, Na Sun, Axel Walch, Kerstin Stemmer, Alida Kindt, Jan Krumsiek, Matthias H Tschöp, Malte D Luecken, Fabian J Theis, Heiko Lickert, Anika Böttcher.
      Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr-Igf1r-Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.
    DOI:  https://doi.org/10.1038/s42255-021-00458-9
  13. Hepatol Commun. 2021 Aug 24.
    Western Diet Changes Gut Microbiota and Ameliorates Liver Injury in a Mouse Model with Human-Like Bile Acid Composition.
    Junichi Iwamoto, Akira Honda, Teruo Miyazaki, Tadakuni Monma, Hajime Ueda, Yukio Morishita, Sho-Ichiro Yara, Takeshi Hirayama, Tadashi Ikegami.
      Western-style high-fat/high-sucrose diet (HFHSD) changes gut microbiota and bile acid (BA) profiles. Because gut microbiota and BAs could influence each other, the mechanism of changes in both by HFHSD is complicated and remains unclear. We first aimed to clarify the roles of BAs in the HFHSD-induced change of gut microbiota. Then, we studied the effects of the changed gut microbiota on BA composition and liver function. Male wild-type (WT) and human-like Cyp2a12/Cyp2c70 double knockout (DKO) mice derived from C57BL/6J were fed with normal chow or HFHSD for 4 weeks. Gut microbiomes were analyzed by fecal 16S ribosomal RNA gene sequencing, and BA composition was determined by liquid chromatography-tandem mass spectrometry. The DKO mice exhibited significantly reduced fecal BA concentration, lacked muricholic acids, and increased proportions of chenodeoxycholic and lithocholic acids. Despite the marked difference in the fecal BA composition, the profiles of gut microbiota in the two mouse models were quite similar. An HFHSD resulted in a significant increase in the BA pool and fecal BA excretion in WT mice but not in DKO mice. However, microbial composition in the two mouse models was drastically but similarly changed by the HFHSD. In addition, the HFHSD-induced change of gut microbiota inhibited BA deconjugation and 7α-dehydroxylation in both types of mice, which improved chronic liver injury observed in DKO mice. Conclusion: The HFHSD itself causes the change of gut microbiota due to HFHSD, and the altered composition or concentration of BAs by HFHSD is not the primary factor. On the contrary, the gut microbiota formed by HFHSD affects BA composition and ameliorates liver injury in the mouse model with human-like hydrophobic BA composition.
    DOI:  https://doi.org/10.1002/hep4.1778
  14. Immunol Rev. 2021 Sep 20.
    Secret messengers: Extracellular RNA communication in the immune system.
    Grant K Nation, Cherie E Saffold, Heather H Pua.
      One of the hallmarks of the immune system is a dynamic landscape of cellular communication through the secretion of soluble factors, production of cell-bound ligands, and expression of surface receptors. This communication affects all aspects of immune cell behavior, integrates the responses of immune cells in tissues, and is fundamental to orchestrating effective immunity. Recent pioneering work has shown that the transfer of ribonucleic acids (RNAs) constitutes a novel mode of cellular communication. This communication involves diverse RNA species, with short noncoding RNAs especially enriched in the extracellular space. These RNAs are highly stable and selectively packaged for secretion. Transferred RNAs have functions in target cells that both mirror their cell-intrinsic roles and adopt novel mechanisms of action. These extracellular RNAs both impact the behavior of individual immune cells and participate in local and systemic immune responses. The impacts of RNA communication on immune cells and disease states have important implications for the development of novel clinical biomarkers and innovative therapeutic designs in immune-related disease. In this review, we will discuss the foundation of knowledge that is establishing RNA communication as an active and functional process in the immune system.
    Keywords:  Argonaute; B cell; EV; T cell; YRNA; dendritic cell; exRNA; exomere; exosome; extracellular RNA; extracellular vesicles; immune; inflammation; macrophage; miRNA; microvesicle; snoRNA; tRNA; vtRNA
    DOI:  https://doi.org/10.1111/imr.13027
  15. Proc Natl Acad Sci U S A. 2021 09 28. pii: e2102715118. [Epub ahead of print]118(39):
    Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis.
    Moeed Akbar, Lindsay A N Crowe, Michael McLean, Emma Garcia-Melchor, Lucy MacDonald, Kristyn Carter, Umberto G Fazzi, David Martin, Angus Arthur, James H Reilly, Iain B McInnes, Neal L Millar.
      Frozen shoulder is a common fibroproliferative disease characterized by the insidious onset of pain and restricted range of shoulder movement with a significant socioeconomic impact. The pathophysiological mechanisms responsible for chronic inflammation and matrix remodeling in this prevalent fibrotic disorder remain unclear; however, increasing evidence implicates dysregulated immunobiology. IL-17A is a key cytokine associated with inflammation and tissue remodeling in numerous musculoskeletal diseases, and thus, we sought to determine the role of IL-17A in the immunopathogenesis of frozen shoulder. We demonstrate an immune cell landscape that switches from a predominantly macrophage population in nondiseased tissue to a T cell-rich environment in disease. Furthermore, we observed a subpopulation of IL-17A-producing T cells capable of inducing profibrotic and inflammatory responses in diseased fibroblasts through enhanced expression of the signaling receptor IL-17RA, rendering diseased cells more sensitive to IL-17A. We further established that the effects of IL-17A on diseased fibroblasts was TRAF-6/NF-κB dependent and could be inhibited by treatment with an IKKβ inhibitor or anti-IL-17A antibody. Accordingly, targeting of the IL-17A pathway may provide future therapeutic approaches to the management of this common, debilitating disease.
    Keywords:  IL-17A; T cell; adhesive capsulitis; frozen shoulder; inflammation
    DOI:  https://doi.org/10.1073/pnas.2102715118
  16. Front Immunol. 2021 ;12 700501
    Interferon-γ-Producing CD4+ T Cells Drive Monocyte Activation in the Bone Marrow During Experimental Leishmania donovani Infection.
    Audrey Romano, Najmeeyah Brown, Helen Ashwin, Johannes S P Doehl, Jonathan Hamp, Mohamed Osman, Nidhi Dey, Gulab Fatima Rani, Tiago Rodrigues Ferreira, Paul M Kaye.
      Ly6Chi inflammatory monocytes develop in the bone marrow and migrate to the site of infection during inflammation. Upon recruitment, Ly6Chi monocytes can differentiate into dendritic cells or macrophages. According to the tissue environment they can also acquire different functions. Several studies have described pre-activation of Ly6Chi monocytes in the bone marrow during parasitic infection, but whether this process occurs during experimental visceral leishmaniasis and, if so, the mechanisms contributing to their activation are yet to be established. In wild type C57BL/6 (B6) mice infected with Leishmania donovani, the number of bone marrow Ly6Chi monocytes increased over time. Ly6Chi monocytes displayed a highly activated phenotype from 28 days to 5 months post infection (p.i), with >90% expressing MHCII and >20% expressing iNOS. In comparison, in B6.Rag2 -/- mice <10% of bone marrow monocytes were MHCII+ at day 28 p.i., an activation deficiency that was reversed by adoptive transfer of CD4+ T cells. Depletion of CD4+ T cells in B6 mice and the use of mixed bone marrow chimeras further indicated that monocyte activation was driven by IFNγ produced by CD4+ T cells. In B6.Il10 -/- mice, L. donovani infection induced a faster but transient activation of bone marrow monocytes, which correlated with the magnitude of CD4+ T cell production of IFNγ and resolution of the infection. Under all of the above conditions, monocyte activation was associated with greater control of parasite load in the bone marrow. Through reinfection studies in B6.Il10 -/- mice and drug (AmBisome®) treatment of B6 mice, we also show the dependence of monocyte activation on parasite load. In summary, these data demonstrate that during L. donovani infection, Ly6Chi monocytes are primed in the bone marrow in a process driven by CD4+ T cells and whereby IFNγ promotes and IL-10 limits monocyte activation and that the presence of parasites/parasite antigen plays a crucial role in maintaining bone marrow monocyte activation.
    Keywords:  CD4+ T cells; IL-10; bone marrow; interferon-gamma; monocytes; mouse models; visceral leishmaniasis
    DOI:  https://doi.org/10.3389/fimmu.2021.700501
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