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RNA-seq analysis of human T CD4+ cells after their interaction with autologous antigen-specific vitamin D3-generated tolerogenic dendritic cells

ABSTRACT: The use of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases. Among the different alternatives available, the use of vitamin D3 for the generation of tolDC (vitD3‑tolDC) constitutes one of the most robust approaches due to their immune regulatory properties, which are currently being tested in clinical trials. However, the mechanisms that vitD3‑tolDC are triggering for the induction of tolerance remain elusive. For this reason, we have performed a full transcriptomic characterization of T cells upon their interaction with autologous, antigen-specific vitD3-tolDC. Our results evidenced a strong down-modulation of genes involved in cell cycle and cell response to immune-related stimuli in T CD4+ cells after their interaction with vitD3-tolDC. Consequently, our results show the induction of a strong antigen-specific hyporresponsiveness, which manifests the regulatory properties of these cells and therefore their therapeutic potential in the clinic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128816 | GEO | 2020/12/21

REPOSITORIES: GEO

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RNA-seq analysis of human T CD4+ cells after their interaction with autologous antigen-specific vitamin D3-generated tolerogenic dendritic cells

Project description:RNA-seq analysis of human T CD4+ cells after their interaction with autologous antigen-specific vitamin D3-generated tolerogenic dendritic cells

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Tolerogenic dendritic cells protect against acute kidney injury

Project description:We use tolDCs from syngeneic (C57BL6) and allogeneic (BALB/c) mice to show potent renoprotective abilities in a ischemia reperfusion AKI model. Dendritic cells were derived from mice bone marrow and cultured for 7 days with GM-CSF and IL-4. Tolerogenic DCs were cultured in the same DC media but with the addition of VitD3 and IL10. LPS was added on day 6 and cells harvested for use or analysis on day 7.

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Stimulation of tolerogenic dendritic cells using dexamethasone and 1,25-dihydroxyvitamin D3 represses autologous T cell activation and chondrocyte inflammation.

Project description:Human osteoarthritis (OA) has been reclassified as a systemic musculoskeletal disorder involving activation of the innate and adaptive immune systems. Elevated pro-inflammatory cytokines may serve a key function in the development of the disease. 1,25-Dihydroxyvitamin D3 and dexamethasone (vitD3/Dex) may inhibit inflammation by acting on tolerogenic dendritic cells (tolDCs) in chronic inflammatory conditions. In the present study, DCs were isolated from peripheral blood mononuclear cells of patients with OA. DCs expressing high levels of co-stimulatory molecules maintain a tolerogenic phenotype under stimulation with LPS, which promotes DC maturation to generate tolDCs. When vitD3/Dex were added in the current study, the tolDCs produced pro-inflammatory cytokines, including low levels of tumor necrosis factor-?, interleukin (IL)-1?, IL-6 and IL-10, and high levels of transforming growth factor-?. However, when vitD3/Dex were added to DCs without LPS stimulation, the levels of IL-10 were high. DCs with LPS stimulation increased the percentage of T-cells that produced IFN-? and IL-17 and DCs with vitD3/Dex treatment alone increased the percentage of T-cells that produced IL-10 and FoxP3. However, those cytokines decrease in DCs co-processed with LPS and vitD3/Dex. The IL-10 release by the stimulated T cells was indicated to repress autologous T cell proliferation via soluble IL-10 and cell-cell contact. Furthermore, tolDCs and regulatory T cells suppressed matrix metalloproteinase (MMP)-1 and MMP-13 secretion by chondrocytes. Additionally, Akt and p38 mitogen-activated protein kinase signaling were demonstrated to be involved in the regulatory effects of Dec and vitD3 in DCs. The present findings suggest a novel mechanism underlying the beneficial effects of tolDCs, particularly in association with the pathogenesis of OA.

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Effect of Cryopreservation on Autologous Chimeric Antigen Receptor T Cell Characteristics

Project description:Effect of Cryopreservation on Autologous Chimeric Antigen Receptor T Cell Characteristics

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In vitro effects of equine autologous conditioned serum and autologous equine serum on inflamed chondrocyte pellets

Project description:The aim of the study was to investigate the effects of autologous equine serum (AES) incubated for 24 h and autologous conditioned serum (ACS) on inflamed equine chondrocyte pellets in vitro.

2023-04-19 | GSE152253 | GEO

Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis.

Project description:OBJECTIVES:To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities. METHODS:An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×106, 3×106 or 10×106 tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5?days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood. RESULTS:There were no target knee flares within 5?days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×106 tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91?days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high. CONCLUSION:IA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×106 tolDC but no systemic clinical or immunomodulatory effects were detectable. TRIAL REGISTRATION NUMBER:NCT01352858.

| S-EPMC5264217 | biostudies-literature

Tolerogenic transcriptome landscape in CD8+ T lymphocytes after exposure to erythrocyte-targeted antigen

Project description:Our group has recently shown induction of antigen-specific T cell tolerance through targeting antigen to erythrocytes in situ, based on the premise that as the erythrocytes age and are cleared eryptotically, their carried antigen payload is processed tolerogenically. The tolerogenic state is characterized by initial proliferation of antigen-specific CD4+ and CD8+ T cells, and subsequent acquisition of deletional, anergic and CD25+FOXP3+ regulatory T cell phenotypes. In this study, we wished to further understand the molecular mechanisms behind induction of tolerance by erythrocyte-targeted antigens. RNA sequencing was performed to determine how genes are regulated in tolerized ovalbumin-specific CD8+ T cells and which pathways are activated after treatment with this technology. High similarity between the gene response reported during self-tolerance, deletional tolerance and tolerance induced by erythrocyte-targeted antigens was observed. Treatment with erythrocyte-targeted antigens led to the upregulation of genes encoding several TCR co-inhibitory receptors such as CTLA4, PD1, LAG3, TIGIT and CD200R1, and lack of upregulation of cytotoxic and pro-inflammatory signaling molecule genes. Modulation in expression of the master transcription factors Egr2/NFatc1, Nur77 family and E2f1 was also observed, all known to be associated with the process of peripheral tolerance. Expression of these genes differed in response to treatment with soluble ovalbumin or free SIINFEKL MHCI peptide, suggesting a specific mechanism of T cell modulation and tolerance induction in response to the erythrocyte-associated forms. Together these results provide novel insights to further understand the mechanisms and potential of erythrocyte-targeted antigens for induction of antigen-specific immune tolerance.

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Generation of Autologous Pluripotent Stem Cells from Adult Testis Biopsy

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2011-01-23 | GSE20031 | GEO

Induction of senescence renders cancer cells highly immunogenic

Project description:Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy.

2022-11-09 | PXD034059 | Pride

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

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