Microarray expression data from human TCRVg9-positive gamma delta T lymphocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE27291 | GEO | 2011/02/15
SECONDARY ACCESSION(S): PRJNA137339
REPOSITORIES: GEO
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Project description:We used microarrays to detail the global programme of gene expression by circulating TCRVgamma9+ gamma delta T cells isolated from healthy individuals,tested either as resting cells or cells activated by phosphoantigen BrHPP and IL-2at an early(+6hrs) and a late (+7days) timepoint. We find that with more M-bM-^@M-^\NK cellM-bM-^@M-^] genes than alphabeta T cells and more M-bM-^@M-^\T cellM-bM-^@M-^] genes than NK cells, the circulating TCRVgamma9+ gamma delta T cells cells have a hybrid transcriptome. The gene signature of the activated cells recapitulates their physiological functions: Th1 cytokine, chemokine and cytotoxic activities at first and mitotic activity at later time points. The gene expression pattern of activated normal gamma delta T cells is nevertheless clearly distinctive from that of NK/T and peripheral T cell lymphomas of the gamma delta subtype. Human TCRVg9positive gamma delta T cells were isolated from PBMC by cell sorting (>98% purity) and activated for RNA extraction and hybridization on Affymetrix microarrays. Samples comprise cells before activation (control time 0), early after activation with BrHPP/IL2 (+6 hours) and at a later timepoint of the activated in vitro culture with BrHPP/IL2 (day 7).
2011-02-15 | E-GEOD-27291 | biostudies-arrayexpress
Project description:Comparative gene expression analysis (PIQOR Immunology) Human Vg9Vd2 T cells amplified (soluble phosphoantigen) from ex vivo fresh PBMC of healthy human donors 3 weeks of culture in the presence of either IL-2 or IL-2+IL-21 Total RNA extracted from resting purified gamma delta T cells PIQOR microarrays
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Project description:Gamma-delta T cells are potent anti-cancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or HLA background. Gamma-delta T cells can sense conserved cell stress signals prevalent in transformed cells, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vg9Vd2 T cells – the most abundant subset of human gamma-delta T cells – recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1, a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here, we layered genome-wide CRISPR screens in target cancer cells to identify pathways that regulate: (1) killing by gamma-delta T cells during co-culture, and (2) BTN3A cell surface expression. In addition to confirming the importance of the phosphoantigen-producing mevalonate pathway, the screens revealed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of gamma-delta T cells through transcription, post-translational modifications, membrane trafficking. Notably, IRF1 and ZNF217 were discovered to be positive and negative transcriptional regulators that directly occupy the promoters of BTN3A1/2/3 genes. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of BTN3A, as well as BTN2A1, during metabolic crises was dependent on AMP-activated protein kinase (AMPK). Finally, small molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1-BTN3A complex and increased Vg9Vd2 TCR-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of gamma-delta T cell stress surveillance and suggests new avenues to enhance gamma-delta T cell anti-cancer activity.
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Project description:Comparative gene expression analysis (PIQOR Immunology) Human Vg9Vd2 T cells amplified (soluble phosphoantigen) from ex vivo fresh PBMC of healthy human donors 3 weeks of culture in the presence of either IL-2 or IL-2+IL-21 Total RNA extracted from resting purified gamma delta T cells PIQOR microarrays PIQOR Human Immunology Service Topic-defined microarrays (Miletnyi Biotec) Comparison IL-2+IL-21 (Cy5) versus IL-2(Cy3) T7-amplified RNA
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Project description:target tumours broadly, independent of patient-specific neoantigens or HLA background. Gamma-delta T cells can sense conserved cell stress signals prevalent in transformed cells, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vg9Vd2 T cells – the most abundant subset of human gamma-delta T cells – recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1, a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here, we layered genome-wide CRISPR screens in target cancer cells to identify pathways that regulate: (1) killing by gamma-delta T cells during co-culture, and (2) BTN3A cell surface expression. In addition to confirming the importance of the phosphoantigen-producing mevalonate pathway, the screens revealed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of gamma-delta T cells through transcription, post-translational modifications, membrane trafficking. Notably, IRF1 and ZNF217 were discovered to be positive and negative transcriptional regulators that directly occupy the promoters of BTN3A1/2/3 genes. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of BTN3A, as well as BTN2A1, during metabolic crises was dependent on AMP-activated protein kinase (AMPK). Finally, small molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1-BTN3A complex and increased Vg9Vd2 TCR-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of gamma-delta T cell stress surveillance and suggests new avenues to enhance gamma-delta T cell anti-cancer activity.
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