Similar Datasets
Project description:Mice engrafted with components of a human immune system have become widely-used models for studying aspects of human immunity and disease. However, a defined methodology to objectively measure and compare the quality of the human immune response in different models is lacking. Here, by taking advantage of the highly immunogenic live-attenuated yellow fever virus vaccine YFV-17D, we provide an in-depth comparison of immune responses in human vaccinees, conventional humanized mice, and second generation humanized mice. We demonstrate that selective expansion of human myeloid and natural killer cells promotes transcriptomic responses akin to those of human vaccinees. These enhanced transcriptomic profiles correlate with the development of an antigen-specific cellular and humoral response to YFV-17D. Altogether, our approach provides a robust scoring of the quality of the human immune response in humanized mice and highlights a rational path towards developing better pre-clinical models for studying the human immune response and disease.
| S-EPMC6262001 | biostudies-literature
Project description:By taking advantage of the highly immunogenic live-attenuated yellow fever virus vaccine YFV-17D, we performed an in-depth comparison of transcriptomic responses in human vaccinees, conventional humanized mice, and second generation humanized mice. We demonstrate that selective expansion of human myeloid and natural killer cells in humanized mice promotes transcriptomic responses akin to those of human vaccinees
2018-11-28 | GSE119749 | GEO
Project description:We performed an in-depth characterization and comparison of the immune system diversity and complexity in the spleen of conventional NRG-HIS mice and NFA2-HIS/Ftl3LG mice upon YFV-17D infection, a live-attenuated virus that induce that induce potent protective immunity in human. To do so, we employed Seq-Well, a recently developed platform for massively parallel single-cell RNA-Seq (scRNA-Seq), on splenocytes from NRG-HIS mice and NFA2-HIS/Flt3LG mice at six-weeks post YFV-17D infection. Our data provide an in-depth view of the cellular composition of the HIS in conventional and second-generation humanized mice. They also highlight the enhanced engraftment and functionality of the critical role of the myeloid and NK cell compartment in NFA2-HIS/Flt3LG mice, which is likely critical in promoting an enhanced transcriptomic, cellular and humoral response to YFV-17D.
2018-11-28 | GSE119750 | GEO
Project description:Selective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses
| PRJNA490175 | ENA
Project description:Selective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses (Experiment 2: scRNA-seq)
| PRJNA490177 | ENA
Project description:Selective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses (Experiment 1: RNA-seq)
| PRJNA490176 | ENA
Project description:Lupus susceptibility results from the combined effects of numerous genetic loci, but the contribution of these loci to disease pathogenesis has been difficult to study due to the large cellular heterogeneity of the autoimmune immune response. We performed single-cell RNA, BCR, and TCR sequencing of splenocytes from mice with multiple polymorphic lupus susceptibility loci. We not only observed lymphocyte and myeloid expansion, but we also characterized changes in subset frequencies and gene expression, such as decreased CD8 and marginal zone B cells and increased Fcrl5- and Cd5l-expressing macrophages. Clonotypic analyses revealed expansion of B and CD4 clones, and TCR repertoires from lupus-prone mice were distinguishable by algorithmic specificity prediction and unsupervised machine learning classification. Myeloid differential gene expression, metabolism, and altered ligand-receptor interaction were associated with decreased Ag presentation. This dataset provides novel mechanistic insight into the pathophysiology of a spontaneous model of lupus, highlighting potential therapeutic targets for autoantibody-mediated disease.
| S-EPMC9254690 | biostudies-literature
Project description:Emerging data suggest that hypercholesterolemia has stimulatory effects on adaptive immunity and that these effects can promote atherosclerosis and perhaps other inflammatory diseases. However, research in this area has relied primarily on inbred strains of mice whose adaptive immune system can differ substantially from that of humans. Moreover, the genetically induced hypercholesterolemia in these models typically results in plasma cholesterol levels that are much higher than those in most humans. To overcome these obstacles, we studied human immune system-reconstituted mice (hu-mice) rendered hypercholesterolemic by treatment with adeno-associated virus 8-proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and a high-fat/high-cholesterol Western-type diet (WD). These mice had a high percentage of human T cells and moderate hypercholesterolemia. Compared with hu-mice that had lower plasma cholesterol, the PCSK9-WD mice developed a T cell-mediated inflammatory response in the lung and liver. Human CD4+ and CD8+ T cells bearing an effector memory phenotype were significantly elevated in the blood, spleen, and lungs of PCSK9-WD hu-mice, whereas splenic and circulating regulatory T cells were reduced. These data show that moderately high plasma cholesterol can disrupt human T cell homeostasis in vivo. This process may not only exacerbate atherosclerosis, but also contribute to T cell-mediated inflammatory diseases in the hypercholesterolemia setting.
| S-EPMC5983331 | biostudies-literature
Project description:To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics that recapitulate antigen-specific T cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent antiviral activities. Intravenous injection of HIV- or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens. Notably, these expanded HIV- or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections in the humanized mice, providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.
| S-EPMC8631598 | biostudies-literature
Project description:The role of NK cells against HIV-1 infections remains to be elucidated in vivo. While humanized mouse models potentially could be used to directly evaluate human NK cell responses during HIV-1 infection, improved functional development of human NK cells in these hosts is needed. Here, we report the humanized MISTRG-6-15 mouse model, in which NK cells were quick to expand and exhibit degranulation, cytotoxicity, and proinflammatory cytokine production in nonlymphoid organs upon HIV-1 infection but had reduced functionality in lymphoid organs. Although HIV-1 infection induced functional impairment of NK cells, antiretroviral therapy reinvigorated NK cells in response to HIV-1 rebound after analytic treatment interruption. Moreover, a broadly neutralizing antibody, PGT121, enhanced NK cell function in vivo, consistent with antibody-dependent cellular cytotoxicity. Monoclonal antibody depletion of NK cells resulted in higher viral loads in multiple nonlymphoid organs. Overall, our results in humanized MISTRG-6-15 mice demonstrated that NK cells provided direct anti-HIV-1 responses in vivo but were limited in their responses in lymphoid organs.
| S-EPMC9753998 | biostudies-literature