RNA sequencing of splenic CD8+ T cells treated with AAV-IL-27/ctrl in vivo
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE195736 | GEO | 2022/02/01
REPOSITORIES: GEO
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Project description:Interleukin-27 (IL-27) is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonstrated that systemic delivery of IL-27 using adeno-associated virus (AAV-IL-27) exhibits potent inhibition of tumor growth in mouse models. In this work, we demonstrate that AAV-IL-27 treatment leads to significant expansion of CD11b+Gr1+ myeloid cells (MCs). AAV-IL-27-induced expansion of CD11b+Gr1+ cells is IL-27R-dependent, requires Stat3 signaling but is inhibited by Stat1 signaling. AAV-IL-27 treatment does not increase the self-renewal capacity of CD11b+Gr1+ cells but induces significant expansion of hematopoietic stem cells (HSCs) and granulocyte-monocyte progenitor (GMP) cells. IL-27-induced Ly6G+ MCs upregulate MHC class I/II molecules but are less immune suppressive in vitro, and their expansion does not promote, but rather inhibit tumor growth in vivo. In the tumor microenvironment, IL-27 gene therapy appears to promote Ly6G+ MCs to differentiate into MHC class I/IIhigh and F4/80high macrophages. Thus, IL-27 gene therapy induces expansion of CD11b+Gr1+ myeloid cells and promotes their differentiation into anti-tumor M1 macrophages in tumor microenvironment.Bone marrow myeloid cells of tumor-bearing C57BL/6 mice treated with AAV-IL-27/ctrl for 2 weeks were sepreated by MACS. Transcriptome profiling (RNA-seq) of these purified Ly6G+ cells (>95%) was completed by BGI. Changing in gene express profiling resulted by IL-27 was analyzed in this study.
2024-03-09 | GSE227476 | GEO
Project description:RNA sequencing of splenic CD8+ T cells treated with AAV-IL-27/ctrl in vivo
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Project description:Single cell changes in AAV-Ctrl or AAV-RSPO1-Fc treated intestinal adenoma cells from ApcMin/+ mice
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Project description:Age-related decline in brain endothelial cell (BEC) function critically contributes to cerebrovascular and neurodegenerative disease. Comprehensive atlases of the BEC transcriptome have become available but results from proteomic profiling are lacking. To gain insights into endothelial pathways affected by aging, we developed a magnetic-activated cell sorting (MACS)-based mouse BEC enrichment protocol compatible with high-resolution mass-spectrometry and analysed the profiles of protein abundance changes across multiple time points between 3 and 18 months of age and identified Arf6 as one of the most prominently downregulated vesicle-mediated transport protein during BEC aging. To better understand the role of Arf6 in BECs, in this experiment we have compared MACS sorted BECs from Arf6-GFP-AAV vs GFP-AAV treated 3-months-old WT mice and found 86 and 110 proteins to be significantly down- and upregulated, respectively. Enrichment analyses of significantly upregulated proteins revealed vesicle-mediated transport, activation of GTPase activity, and ER to Golgi vesicle-mediated transport to be among the most significantly affected biological processes.
2024-02-15 | PXD045006 | Pride
Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines. Splenic CD45.2+ OT-II TCR-Tg CD4 T cells from CD45.1+ B6 mice immunized with Ad5-OVA or Ad26-OVA were purified by FACS on day 10 post-immunization
2016-06-01 | E-GEOD-73118 | biostudies-arrayexpress
Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines.
2016-06-01 | GSE73118 | GEO
Project description:Chronic infection and cancer are associated with suppressed T cell responses in the presence of activating antigen. Recent work identified memory-like CD8+ T cells termed follicular cytotoxic T cells (TFC) which sustain T cell responses during persistent infection and are essential for the T-cell proliferative burst following PD1 blockade. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to TFC expansion in an IL-27-and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8+ T cells. We found that CD8+ T cell-intrinsic IL-27 signaling safeguards the ability of TCF1-high cells to sustain proliferation and prevents premature cell cycle exit and programmed cell death. Transcriptome analysis revealed an IL-27-regulated gene module controlling survival of activated CD8+ T cells which is enhanced in IFNAR-attenuated conditions. We further demonstrated a cell-intrinsic requirement for the IL-27 target IRF1 in TFC expansion through promoting sustained division. These findings reveal that IL-27 opposes IFN-I to uncouple cell division from effector differentiation, and suggest IL-27 signaling could be exploited to augment self-renewing T cell populations in patients with chronic infections.
2019-04-01 | GSE97139 | GEO
Project description:To examine the broad impact of IL-27 on human T lymphocytes, we performed a microarray analysis assessing >20,000 well annotated genes on purified naïve (CD45RA+CD45RO-CCR7+) and central memory (CD45RA-CD45RO+CCR7+) CD4+ and CD8+ T cells from three healthy donors that were activated in vitro (plate bound anti-CD3 and soluble anti-CD28) in the presence or absence of human recombinant IL-27 (100 ng/mL). Our goal was to investigate the impact of interleukin-27 on the gene expression profil of human CD4 and CD8 T lymphocytes.
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Project description:HIV-specific T cells have diminished effector function and fail to control/eliminate the virus. IL-27, a member of the IL-6/IL-12 cytokine superfamily has been shown to inhibit HIV replication however whether IL-27 can enhance function on HIV-specific T cell is largely unknown. Because of the important implication in cure strategies, in the present manuscript, we investigated the role of IL-27 signaling in human T cells by evaluating the global transcriptional changes and its impact in the function of HIV-specific T cells. We found that T cells from people living with HIV (PLWH), expressed higher levels of STAT1 that leads to enhanced STAT1 activation upon IL-27 stimulation. IL-27 induced transcriptional changes associated with IFN/STAT1-dependent pathways in CD4 and CD8 T cells. More importantly, IL-27 promoted cytokine secretion of TIGIT+HIVGag-specific T cell function by modulating the expression levels of T-bet. This new immunomodulatory property of IL-27 on HIV-specific T cell function suggests its potential therapeutic use in cure strategies.
2021-12-09 | GSE189997 | GEO
Project description:We constructed AAV-vectors for systemic expression of a soluble RSPO1 protein in ApcMin/+ mice. We found that the RSPO1-Fc fusion protein suppresses the Wnt/ß-catenin signaling activity in intestinal adenomas and in adenoma-derived intestinal organoids ex vivo, but not in normal intestinal epithelial cells. In the Apc mutant cells, the RSPO1-Fc fusion protein activated the TGFß/SMAD signaling pathway to suppress several Wnt target genes and adenoma growth, which effect was rescued suppressed by the TGFß receptor kinase inhibitor SB-431542. Simultaneously, RSPO1-Fc induced proliferation of the normal intestinal stem cells, giving them a growth advantage over the mutant cells, which enabled the intestinal epithelium to eventually outgrow the adenoma cells. Prolonged systemic expression of AAV-RSPO1-Fc decreased significantly the number of the intestinal adenomas and improved the overall survival of ApcMin/+ mice. Thus RSPO1-Fc provides the normal intestinal epithelial cells a growth advantage when compared to the adenoma cells, which eventually leads to the extrusion of the adenomatous tissue. An attractive idea now is to exploit such differential response of normal vs. cancer cells in cancer therapy.
2020-03-01 | GSE146138 | GEO