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Expression data from human memory CD4 T-cells stimulated with autologous monocytes pulsed with HCMV

ABSTRACT: The present study reports an unbiased analysis of the genetic profile and regulation of NKG2D expressing CD4 T-cells.An Affymetrix microarray analysis was used to explore the genetic profile of NKG2D+ versus NKG2D- CD4 T-cells. The genetic profile was studied by single gene analysis and gene set enrichment analysis. I found that several immune regulatory receptors was regulated differently in NKG2D+ versus NKG2D- CD4 T-cells. Futhermore, I found that NKG2D+ CD4 T-cells display a genetic profile of cytotoxic T-cells. The gene set enrichment analysis revealed a change in 19 processes, including ARF GTPase activator activity; RNA splicing; Signal transduction; Interspecies interaction between organisms; Regulation of ARF GTPase activity; Cell motility; Mitosis; Cell cycle; Anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process; Induction of apoptosis by extracellular signals; Negative regulation of apoptosis; mRNA export from nucleus; Positive regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; Cell division; Protein polymerization; Spliceosome assembly; Microtubule-based movement; Immune response; mRNA processing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE33670 | GEO | 2012/08/15

SECONDARY ACCESSION(S): PRJNA148731

REPOSITORIES: GEO

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Expression data from human memory CD4 T-cells stimulated with autologous monocytes pulsed with HCMV

Project description:The present study reports an unbiased analysis of the genetic profile and regulation of NKG2D expressing CD4 T-cells.An Affymetrix microarray analysis was used to explore the genetic profile of NKG2D+ versus NKG2D- CD4 T-cells. The genetic profile was studied by single gene analysis and gene set enrichment analysis. I found that several immune regulatory receptors was regulated differently in NKG2D+ versus NKG2D- CD4 T-cells. Futhermore, I found that NKG2D+ CD4 T-cells display a genetic profile of cytotoxic T-cells. The gene set enrichment analysis revealed a change in 19 processes, including ARF GTPase activator activity; RNA splicing; Signal transduction; Interspecies interaction between organisms; Regulation of ARF GTPase activity; Cell motility; Mitosis; Cell cycle; Anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process; Induction of apoptosis by extracellular signals; Negative regulation of apoptosis; mRNA export from nucleus; Positive regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; Cell division; Protein polymerization; Spliceosome assembly; Microtubule-based movement; Immune response; mRNA processing. Human CD4 T-cells were isolated from buffy coat by anti-CD4 conjugated magnetic beads. Memory CD4 T-cells were sorted, labeled with CFSE and stimulated with autologous monocytes pulsed with HCMV. HCMV stimulated CD4 T-cells were sorted as CFSE-NKG2D+ or CFSE-NKG2D- and processed for microarray analysis.

2012-08-14 | E-GEOD-33670 | biostudies-arrayexpress

Proximal interaction network of ARF GTPases

Project description:The Arf GTPase family is involved in a wide range of cellular regulation including membrane trafficking and organelle structure assembly. Here, we have generated a proximity interaction network for the Arf family using the miniTurboID approach combined with TMT-based quantitative mass spectrometry. Our interactome confirmed known interactions and identifies many novel interactors that provide leads for defining Arf pathway cell biological functions.

2022-07-20 | PXD033382 | Pride

The ARFGEF IQSEC1 is a targetable scaffold controlling collective cell invasion.

Project description:The signalling pathways underpinning cell growth and migration share overlapping components but what determines whether cells grow or move, when exposed to the same extrinsic signal, is unclear. We identify that in epithelial cancer cells cultured in extracellular matrix (ECM) these molecular functions can be uncoupled when signals are transduced through alternate transcript variants of IQSEC1, an ARF GTPase Exchange Factor. IQSEC1 associates with the receptor tyrosine kinase (RTK) Met and acts as an organising centre for phosphoinositide signalling, activating ARF5- and ARF6-dependent PIP5-kinase activity, and scaffolding multiple components of the mTORC2 signalling complex to control Akt activation and cell growth. Expression of IQSEC1 variants containing extended N-terminal regions switch this output from growth to collective invasion by conferring association with the endocytic co-receptor LRP1, thereby enhancing Met internalisation and trafficking. These pro-invasive IQSEC1 variants localise the Met/LRP1/IQSEC1 signalling module to the tips of invasive protrusions to induce PI(3,4,5)P3-dependent collective invasion. Chemical or genetic inhibition of these alternate signalling modules targets growth or invasion, independently. Alternate IQSEC1-ARF GTPase signalling complexes thus control RTK signal output by influencing RTK trafficking and the balance between growth or invasion in epithelial cells. Elevated expression of this IQSEC1-ARF module occurs in prostate cancer patient metastases and predicts poor outcome. IQSEC1 may therefore represent a therapeutic vulnerability in prostate cancer cells.

2021-02-04 | PXD013810 | Pride

RNA-seq analysis of CAR-NKAE cells and CD45RA- CAR-T cells

Project description:CAR-T cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the anti-tumor activity of activated and expanded NK cells (NKAE) and CD45RA- T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and two of the treated mice remained disease-free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced anti-myeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR NK cell therapy for MM.

2021-08-16 | GSE179408 | GEO

Comparison of gene expression by activated T-cells that express NKG2D-based CARs

Project description:NKG2D ligands are broadly expressed in cancer. To exploit this, we engineered an adaptor chimeric antigen receptor (CAR) termed NKG2D / Dap10-12 in which NKG2D is co-expressed with a fusion of Dap10 and the Dap12 endodomain. Dap10 was deployed to provide co-stimulation while Dap12 delivers an activation signal via a single immunoreceptor tyrosine-based activation motif (ITAM). NKG2D / Dap10-12 T-cells elicited compelling anti-tumor activity in several solid tumor xenograft models. Disease eradication was accompanied by sustained functional persistence, indicated by reproducible protection from secondary tumor re-challenge. Anti-cancer activity was consistently superior to an analog of a clinical stage linear CAR comprising an NKG2D-CD3 fusion. Mechanistically, functionality of NKG2D / Dap10-12 CAR T-cells was underpinned by transcriptomic re-programming to increase oxidative phosphorylation and ribosome biosynthesis..

2024-10-01 | GSE249511 | GEO

The E3 Ubiquitin Ligase AFF1 targets ARF19 to the proteasome

Project description:Auxin critically regulates nearly every aspect of plant growth and development. Auxin-driven transcriptional responses are mediated through the AUXIN RESPONSE FACTOR (ARF) family of transcription factors. Although ARF protein stability is regulated via the 26S proteasome, molecular mechanisms underlying ARF stability and turnover are unknown. Here, we report the identification and functional characterization of an F-Box E3 ubiquitin ligase, which we have named AUXIN RESPONSE FACTOR F-BOX1 (AFF1). AFF1 directly interacts with ARF19 and regulates its accumulation. Mutants defective in AFF1 display ARF19 protein hyperaccumulation, mild auxin resistance, and developmental defects. Together, our data suggest a new mechanism, namely control of ARF protein stability, in regulating auxin responsiveness.

2022-06-09 | GSE172353 | GEO

Activated TNFa/NFkB Signaling Via Down Regulation of Faf1 in Asbestos-Induced Mesotheliomas from Arf Knock-out Mice

Project description:The human CDKN2A locus encodes two distinct proteins, p16(INK4A) and p14(ARF) [mouse p19(Arf)], designated INK4A and ARF herein, that are translated from alternatively spliced mRNAs. Human ARF is implicated as a tumor suppressor gene, mainly in association with the simultaneous deletion of INK4A. However, questions remain as to whether loss of ARF alone is sufficient to drive tumorigenesis. Here we report that mice deficient for Arf are susceptible to accelerated asbestos-induced malignant mesothelioma (MM). MMs arising in Arf (+/-) mice consistently exhibit biallelic inactivation of Arf, but unexpectedly, do not acquire additional recurrent genetic alterations that we previously identified in asbestos-induced MMs arising in Nf2 (+/-) mice. Array CGH analysis was used to detect a recurrent deletion at chromosome 4C6. A candidate in this region, Faf1 (FAS-associated factor 1), was further explored because it encodes a protein implicated in tumor cell survival and in the pathogenesis of some human tumor types. We confirmed hemizygous loss of Faf1 and down regulation of Faf1 protein in a series of MMs from Arf (+/-) mice, and then showed that Faf1 regulates TNFalpha-mediated NFkappaB signaling, a mechanism previously implicated in asbestos-induced oncogenesis of human mesothelial cells. Collectively, these investigations divulge important information regarding the significance of Arf inactivation in MM pathogenesis, and implicate Faf1 as a key component in the TNFalpha/NFkappaB signaling node that has now been independently implicated in the asbestos-induced oncogenesis.

2008-12-31 | GSE12419 | GEO

Combining targeting of the cancer-metabolome with cancer-associated stress antigens impacts transcriptomic heterogeneity, dynamics, and efficacy of engineered T-cells

Project description:The majority of cancers cannot be efficiently targeted with engineered T cell strategies. In this line, we explored how and whether γδTCR-mediated cancer metabolome targeting can be combined with the attack of cancer-associated stress antigens, like NKG2D-ligands, in order to overcome limited targeting of many tumors, and at the same time skew heterogeneous transcriptomic signatures of engineered immune cells towards more active, and less exhausted phenotypes.Single cell transcriptomic analysis revealed that only NKG2D-4-1BBCD28TM chimera reprogrammed TEGs significantly, by skewing CD4+ TEG heterogeneity towards more adhesive, proliferative, cytotoxic, and less exhausted transcriptional signatures.

2023-09-27 | GSE244053 | GEO

Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Project description:The development of approaches for inflaming cold tumors is critical for increasing response to immunotherapy. Here we report that low-dose radiotherapy (LDRT) in mice promotes tumor T-cell inflammation and enables responsiveness to combinatorial immunotherapyin an interferon-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity, and depended on both cytotoxic CD4+and CD8+T cells. LDRTinduced predominantly CD4+cells which exhibited features of exhausted effector and cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, and a novel subset of dendritic cells with activated phenotype that expressed the NKG2D ligand Rae1. Finally, tumor immune rejection was critically dependent on the NKG2D pathway. We translated these findings toa phase I clinical trial. Like in mice, combinatorial treatmenttriggered peripheral T-cell mobilization and resulted in important tumor T-cell infiltration, predominantly of CD4+cells and with Th1 signatures, observed only in patients with immune desert tumors who responded to a novel combination of LDRT, low dose cyclophosphamide and immune checkpoint blockade therapy.These results suggest the novel possibility of rationally combining LDRT with immune checkpoint therapy for the treatment of cold tumors, based on the simultaneous activation of antitumoral innate and adaptive immunity

2021-08-13 | GSE165612 | GEO

Transcriptional profiling of 2D colonies derived from WT, Bmi1-/-, and Bmi1-/-;Ink4a/Arf Labial cervical loops

Project description:This experiment is aimed at determining the genetic signature of dental stem cell colonies grown in vitro and how that signature changes when Bmi1 activity is removed. Another question to be answered by the experiment is whether Bmi1 has alternate targets besides Ink4a/Arf.

2013-04-12 | GSE46000 | GEO

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