Ontology highlight
ABSTRACT:
PROVIDER: PRJNA572597 | ENA |
REPOSITORIES: ENA
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Project description:The mitogen activated kinases ERK1/2 are activated by antigen receptor engagement and control T cell differentiation. We have used mass spectrometry to explore how ERK1/2 control antigen receptor driven cell growth and proteome restructuring in CD8 T cells. Quantitative analysis of >8000 proteins provides new understanding of the highly selective role of ERK1/2 in controlling T cell protein systems. The data reveal that ERK signalling is not a dominant regulator of the metabolic and biosynthetic programs that drive T cell growth. Rather, the dominant function of ERK1/2 is to control the repertoire of transcription factors, cytokines and cytokine receptors expressed by activated T cells. This study provides a comprehensive map of how T cell phenotypes are selectively shaped by ERK1/2 and reveals that ERK1/2 controls the transcriptional reprogramming of activated T cells that is pivotal for T cell differentiation and acquisition of effector function.
2020-12-23 | PXD023256 | Pride
Project description:Antibodies are central to the immune response against microbes. We have previously generated an opsonic IgG1 monoclonal antibody, Ab25, targeting the M protein of Streptococcus pyogenes. Here, we engineered Ab25 into the IgG2-4 subclasses. Despite reduced binding, the IgG3 version demonstrated enhanced opsonic function. Molecular dynamics (MD) simulations showed that IgG3s Fc exhibits extensive mobility in 3D space relative to the antigen due to its extended hinge region. The MD simulations also showed altered Fab-antigen interactions, in line with IgG3s diminished affinity. We explored the impact of hinge-engineering by generating a panel of IgG antibodies, IgGhxx, containing the CH1-3 domains of IgG1 and different segments of IgG3s hinge. Hinge-engineering enhanced opsonic function, with the most potent hinge having 47 amino acids. IgGh47 exceeded the parent IgG1 and, in some instances, the IgG3 version. The IgGh47 was protective against Streptococcus pyogenes in a systemic infection mouse model, contrary to parent IgG3 and IgG1. The in vitro phenotype of IgGh47 was generalizable to clinical isolates with different emm types. Finally, we generated IgGh47 versions of anti-SARS-CoV-2 mAbs, which exhibited strongly enhanced in vitro opsonic function compared to the original IgG1s. The improved function of the IgGh47 subclass in two distant biological systems provides new insights into antibody function and how to enhance it for opsonic function.
2024-03-10 | MSV000094287 | MassIVE
Project description:Chimeric antigen receptor (CAR)-T cell-based immunotherapy for cancer and immunological diseases has made great strides, but it still faces multiple hurdles. Finding the right molecular targets to engineer T cells toward a desired function has broad implications for the armamentarium of T cell-centered therapies. Here, we developed a dead-guide RNA (dgRNA)-based CRISPR activation screen in primary CD8+ T cells, and identified gain-of-function (GOF) targets for CAR-T engineering. Targeted knock-in or overexpression of a lead target, PRODH2, enhanced CAR-T-based killing and in vivo efficacy in multiple cancer models. Transcriptomics and metabolomics in CAR-T cells revealed that augmenting PRODH2 expression re-shaped broad and distinct gene expression and metabolic programs. Mitochondrial, metabolic and immunological analyses showed that PRODH2 engineering enhances the metabolic and immune functions of CAR-T cells against cancer. Together these findings provide a system for identification of GOF immune boosters, and demonstrate PRODH2 as a target to enhance CAR-T efficacy.
2022-02-14 | ST002084 | MetabolomicsWorkbench
Project description:Chimeric antigen receptor (CAR)-T cell-based immunotherapy for cancer and immunological diseases has made great strides, but it still faces multiple hurdles. Finding the right molecular targets to engineer T cells toward a desired function has broad implications for the armamentarium of T cell-centered therapies. Here, we developed a dead-guide RNA (dgRNA)-based CRISPR activation screen in primary CD8+ T cells, and identified gain-of-function (GOF) targets for CAR-T engineering. Targeted knock-in or overexpression of a lead target, PRODH2, enhanced CAR-T-based killing and in vivo efficacy in multiple cancer models. Transcriptomics and metabolomics in CAR-T cells revealed that augmenting PRODH2 expression re-shaped broad and distinct gene expression and metabolic programs. Mitochondrial, metabolic and immunological analyses showed that PRODH2 engineering enhances the metabolic and immune functions of CAR-T cells against cancer. Together these findings provide a system for identification of GOF immune boosters, and demonstrate PRODH2 as a target to enhance CAR-T efficacy.
2022-02-12 | ST002085 | MetabolomicsWorkbench
Project description:<p>Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood is able to escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-specific CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. While all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly among different individuals. A genetic influence was seen for the sharing of individual TCR sequences from antigen-specific cells, but not for repertoire richness or the selection of clonal dominance. VZV vaccination favored the expansion of infrequent VZV-specific TCRs including those from naïve T cells while leaving dominant T cell clones mostly unaffected.</p>
| phs001082 | dbGaP
Project description:Here we provide a framework to qualtitatively evaluate the tyrosine phosphorylation-mediated signaling pathways triggered by antigen-independent antibody and antigen-specific OVA peptide-MHC using Jurkat T cells expressing OT-1 T cell receptors. Our data suggest that pTyr-mediated regulatory axis triggered by OVA antigen-specific activation of TCR closely resembled that of antigen-independent stimulation using anti-TCR antibody, albeit OVA could likely induce a relatively stronger signaling effect. While data from this study do not invalidate previous studies of T cell signaling using antibody-based stimulation, our data revealed potential advantages of using peptide-MHC tetramers in studying T cell signaling. Antigen-specific activation of the OT-1 TCR using a panel of peptide-MHC tetramers (OVA, T4 and G4) generated data that correlates well with the corresponding binding affinity of the peptide-MHC, consistent with predicted signaling strength. Importantly, the apparent correlation between signaling strength and peptide-MHC affinity enables us to fine-tune the signaling strength of T cell stimulation in future studies, allowing a more precise control of the experimental parameter instead of a more binary antibody-based activation. Overall, we demonstrate the utility of BOOST to reveal new biological insights in the immune system.
2021-04-27 | PXD024579 | Pride
Project description:We define a network of protein interactions engaged by chimeric antigen receptors following target binding, and show that the magnitude of network activation correlates with IL-2 secretion, a proxy measure for CAR T cell function.
2023-08-18 | MSV000092691 | MassIVE
Project description:Myeloid-derived cells comprising the tumor stroma represent a heterogeneous population of cells critical to the structure, function and growth of established cancers. We have recently found that engineering tumor-specific CD8+ T cells to secrete IL-12 (IL-12TD) can lead to striking improvements in T-cell activity against established melanomas in murine models. Surprisingly, IL-12-dependent enhancement of CD8+ T-cell anti-tumor function did not occur through direct ligation of receptors on lymphocytes or NK cells. Instead, IL-12 sensitized host bone marrow-derived tumor-stromal cells, partly through interferon-gamma, to indirectly enhance the effects of adoptively-transferred T cells. Direct presentation of antigen by tumor was not necessary, but MHC class I expression on endogenous cells was essential for IL-12 mediated anti-tumor enhancements. Upon successful treatment with IL-12TD cells, we observed the selective elimination of tumor-infiltrating CD11b+ F4/80+ macrophages, CD11b+/ClassII+/CD11c+ dendritic cells and CD11b+/Ly6C+/Ly6G- but not CD11b+/Ly6C+/Ly6G+ myeloid-derived suppressor cells within regressing lesions. These results are consistent with a model whereby IL-12 triggers the maturation of myeloid-derived cells into competent antigen cross-presenting cells. Licensed recognition of these antigens by effector T cells may in turn trigger the collapse of the tumor stroma and aid in the regression of large vascularized lesions. Samples were collected at 3 days and 7 days from tumors treated in-vivo with no treatment, Mock pmel-1 CD8+ cell treatment, or IL-12 pmel-1 CD8+ cell treatment. There were 4 biological replicates of each sample type. There were a total of 24 samples.
2012-04-22 | E-GEOD-29164 | biostudies-arrayexpress
Project description:A longstanding goal has been to find an antigen-specific preventive therapy, i.e., a vaccine, for autoimmune diseases. Major hindrances have so far been to select natural regulatory antigen targets and side-effects induced by clustering the T cell receptor (TCR) or activating the costimulatory signals. Here we show that the administration of a mouse major histocompatibility complex class II protein binding a unique galactosylated collagen type II (COL2) peptide (Aq-galCOL2) directly interacts with the antigen specific TCR, and expands peripheral regulatory T cells, displaying a potent dominant suppressive effect and protection of collagen induced arthritis. The therapeutic effect is dominant and tissue specific as it is possible to transfer the effect with induced regulatory T cells and downregulate autoimmune arthritis induced by other antigens than COL2 or by passive transfer of antibodies. Thus, the here described tolerogenic approach may be a promising dominant antigen-specific therapy for RA, and in principle, for autoimmune diseases in general.
2023-06-15 | PXD034792 | Pride
Project description:While dendritic cells (DCs) are known to play a major role in the process of vaccination, the mechanisms by which vaccines induce protective immunity in humans remain elusive. Herein, we used gene microarrays to characterize the transcriptional programs induced over time in human monocyte-derived DCs (moDCs) in vitro in response to influenza H1N1 Brisbane, Salmonella enterica and Staphylococcus aureus. We built a data-driven modular analytical framework focused on 204 pathogen-induced gene clusters. The expression of these modules was analyzed in response to 16 well-defined ligands, targeting TLRs, cytoplasmic PAMP receptors and cytokine receptors. This multi-dimensional framework covers the major biological functions of APC, including the IFN response, inflammation, DC maturation, T cell activation, antigen processing, cell motility and histone regulation. This framework was used to characterize the response of monocytes and moDCs to 14 commercially available vaccines. These vaccines displayed quantitatively and qualitatively distinct modular signatures in monocytes and DCs, in particular Fluzone and Pneumovax, highlighting the functional and phenotypic differences between APC subsets. This modular framework allows the application of systems immunology approaches to study early transcriptional changes in human APC subsets in response to pathogens and vaccines, which might guide the development of improved vaccines. 38 samples of IFNa DC and 39 samples of IL4 DC stimulated by CL097, CpG 2006, CpG 2216, Flagellin, IFNa, IL10, IL15, IL1b, LPS, MDP, PAM3, Poly I:C, Poly I:C-LMW-Lyovec, R837 or TNFa
2014-10-22 | E-GEOD-44719 | biostudies-arrayexpress