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Generation of antigen-specific mature T cells from RAG1−/−RAG2−/−B2M−/− stem cells by engineering their microenvironment

ABSTRACT: Pluripotent stem cells (PSCs) present promising engineering opportunities as sources of allogeneic T cells for off-the-shelf immunotherapies. However, the complex in vitro process of differentiation required to generate mature T cells from genetically engineered PSCs introduces unique challenges, as positive selection is dependent on the same molecular machinery that must be removed to prevent alloreactivity. We report an organoid-based method in which engineering of the stromal microenvironment induced generation of antigen-restricted, mature, conventional T cells from PSCs which lacked all endogenous TCR and Class I MHC expression. Transgenic signals required to rescue positive selection were supplied by separate cellular sources; T cell precursors from edited PSC expressed a single TCR, and a murine stromal line provided cognate human MHC and other critical T cell development signals. Edited T cells exhibited superior tumour control in vivo likely due to the absence of TCR mispairing. This in vitro method overcomes key biological impediments inherent to developing T cell immunotherapies from allogeneic PSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237780 | GEO | 2023/12/07

REPOSITORIES: GEO

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Parthenogenetic stem cells for tissue-engineered heart repair

Project description:Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenogenetic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar fundamental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics. Haploidentity of major histocompatibility complexes (MHCs) in PSCs is particularly attractive for allogeneic cell-based therapies. Accordingly, we confirmed acceptance of PSCs in MHC-matched allotransplantation. Cardiomyocyte derivation from PSCs and ESCs was equally effective. The use of cardiomyocyte-restricted GFP enabled cell sorting and documentation of advanced structural and functional maturation in vitro and in vivo. This included seamless electrical integration of PSC-derived cardiomyocytes into recipient myocardium. Finally, we enriched cardiomyocytes to facilitate engineering of force-generating myocardium and demonstrated the utility of this technique in enhancing regional myocardial function after myocardial infarction. Collectively, our data demonstrate pluripotency, with unrestricted cardiogenicity in PSCs, and introduce this unique cell type as an attractive source for tissue-engineered heart repair. 8 samples in total. Parthenogenetic stem cells (PSC): - PSC_1 - PSC_2 - PSC_3 Embryoid body (EB) assays of parthenogenetic stem cells: - EB_PSC_1 - EB_PSC_2 Embryonic stem cells (ESC): - ESC_1 - ESC_2 - ESC_3

2013-02-23 | E-GEOD-30868 | biostudies-arrayexpress

Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [VDJ-seq]

Project description:While T cell-based immunotherapies have shown promising clinical responses, current cancer treatments are restricted to autologous cellular products due to the risk of graft-versus-host disease (GvHD) by allogeneic cell transfer. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing off-the-shelf allogeneic cellular therapy because they are powerful immune cells targeting a broad range of cancers without causing GvHD. However, current immunotherapies using iNKT cells are impeded by their extremely low number in cancer patients. In this study, we aimed to overcome this limitation by generating a large number of iNKT cells through TCR engineering of human hematopoietic stem cells (HSCs) and differentiation of HSCs to iNKT cells in an in vitro cultured system. Additionally, Chimeric antigen receptor (CAR) engineering and the CRISPR-Cas9 gene editing tool were utilized to enhance the tumor killing efficacy of iNKT cells and eliminate HLA molecules on their surface, making the cellular product suitable for cancer therapy and allogeneic adoptive transfer. Our results demonstrated successful generation of the promising off-the-shelf B cell maturation antigen (BCMA)-CAR engineered iNKT cells for treating multiple myeloma, and the same strategy will be applied to multiple cellular products for treating other cancers.

2021-12-01 | GSE164500 | GEO

Generation of Allogeneic Hematopoietic Stem Cell-Engineered Invariant Natural Killer T cells for Off-the-Shelf Immunotherapy [RNA-seq]

2021-12-01 | GSE164425 | GEO

Parthenogenetic stem cells for tissue-engineered heart repair

2013-02-23 | GSE30868 | GEO

Proteome analysis of transgenic 1D1a mice

Project description:T cells specifically recognize an antigen with a T cell receptor (TCR) consisting of α- and β-chain. The transgenic 1D1a mice were generated on the genetic background of the B10.D2(R101) line and expressed in their T cells the α-chain TCR (TCRα) specific to the allogeneic MHC molecule Н2-Kb. To evaluate effects of TCRα transgenesis on the qualitative and quantitative composition of plasma proteins, comparative proteome analysis was performed for both female and male transgenic 1D1a and wild-type B10.D2(R101) mice aged 3-, 6-, and 12-months.

2023-05-10 | PXD034188 | Pride

Uterine transcriptome in b2m KO mice

Project description:Natural killer (NK) cell function is enhanced by interaction of inhibitory NK receptors with MHC class I molecules. NK cell function is critical during placentation, where these cells mediate adaptations to pregnancy in concert with other cells at the maternal/fetal interface. The aim of this experiment was to determine the downstream consequences on the uterine transcriptome that arise from lack of NK interaction with MHC class I molecules. This was done in mice lacking beta-2-microglobulin, thus not having correctly folded surface MHC class I. Biopsies were obtained from the mesometrial poles of the implantation chamber in gestation day (gd) 10.5 pregnant mice.

2018-11-01 | E-MTAB-4727 | biostudies-arrayexpress

Induction of regulatory M2 macrophage-like immunosuppressive cells from mouse ES cells that contribute to prolong allogeneic immune rejection

Project description:A promise of cell replacement therapy using pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) as donor source has been increased. However, particularly when ESCs were used, immune suppression should be required because the donor-recipient combination would be allogeneic. In this study, we examined a concept that some immunosuppressive cells could be induced from PSCs and those cells could prevent allogeneic immune rejection of the PSCs-based transplantation. In fact, we successfully induced immunosuppressive cells that resemble M2 macrophages in terms of cell surface molecule and gene expressions. They efficiently suppressed allogeneic T cell proliferative responses, at least partly, in nitric oxide dependent manner. We applied these cells to in vivoallogeneic transplantation and found that they substantially prolonged ESCs-derived graft survival. These results open a new insight for development of a practical immune-regulatory strategy in cell replacement therapy using PSCs. Difference of the gene expression between ESdSC and ESdDC was analyzed. Two independent experiment were performed.

2014-03-28 | E-GEOD-56302 | biostudies-arrayexpress

Loss of B cell Tolerance is TCR Dependent [amplicon-seq]

Project description:We tested orphan TCR autoreactivity using the peptide MHC-TCR chimeric receptor (MCR) co-culture system. In this system, cognate antigen recognition leads to TCR specific NFAT activation in MCR reporter cells expressing a mouse I-Ab MHC class II extracellular domain covalently linked to candidate peptides and an intracellular TCR signaling domain. We used mixed autoimmune bone marrow chimera spleens and kidneys as sources of cDNA to generate a transcriptome-wide library of natural autoantigen peptides . We cloned this cDNA-derived peptide (CDP) autoantigen library into the MCR retroviral backbone and transduced NFAT reporter cells to make a murine autoantigen MCR reporter library (MCR-Lib). We then used this library to screen orphan TCRs identified by scTCR-seq for autoreactivity.

2023-12-29 | GSE229921 | GEO

Induction of regulatory M2 macrophage-like immunosuppressive cells from mouse ES cells that contribute to prolong allogeneic immune rejection

2014-03-28 | GSE56302 | GEO

Differential expression of immune privilege genes in human pluripotent stem cells and their derivatives

Project description:Pluripotent stem cells, including human embryonic stem (hES) and human induced pluripotent stem (hiPS) cells, have been regarded as potential sources for cell-based transplantation therapy. However, the immunogenicity of these cells remains the major determinant for successful clinical application. We therefore studied multiple hES and hiPS cell lines for MHC expression, HLA haplotyping, expression of immune-related genes and T cell activation. The data showed lower levels of MHC class I (MHC-I), b2-microglobulin and HLA-E in undifferentiated stem cells, but the levels were increased to near the levels of somatic cells after co-treatment with interferon gamma. However, the percentages of cells expressing antigen presenting cell markers and MHC-II molecules remained consistently low. Activation of responder lymphocytes by the pluripotent stem cells was significantly lower than by allogeneic lymphocytes in mixed lymphocyte reactions. Finally, the data showed significant differential expression of immune privilege genes (TGF-beta2, Arginase 2, Indo1, GATA3, POMC, VIP, CACLA, CACLB, IL-1RN, CD95L, CR1L, Serpine 1, HMOX1, IL6, LGALS3, HEBP1, THBS1, CD59 and LGALS1) between pluripotent stem cells/derivatives and somatic cells. We concluded that pluripotent stem cell progeny may retain some level of immune privilege and will likely behave in a way different from those of somatic cells after transplantation. Confirmed hiPSC cells and their parental cells were selected for RNA extraction and Affymetrix array analysis. To minimize the clone variation, we selected two clones from each type of iPSC.

2012-12-31 | E-GEOD-28406 | biostudies-arrayexpress

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