PanCancer Immune panel on infiltrating memory CD8 T cells purified from the allografts subjected to prolonged cold ischemic storage in mice cardiac heart transpalnatation model.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE233620 | GEO | 2024/03/20
REPOSITORIES: GEO
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Project description:We tested the impact of prolonged graft cold storage on graft injury.Transcroptome analysis using total RNA isolated from the allografts showed differential expression of transcripts in this model.
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Project description:T cells receive numerous positive and negative signals during primary antigen encounter that control their proliferation and function, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mTOR inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mTOR inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation and an optimal metabolic program for CD8+ T cell memory. Total RNA was isolated from FACS-sorted, antigen-specific CD8+T cells from different treatment conditions at 5 or 35 days after primary T cell activation
2015-01-31 | E-GEOD-63022 | biostudies-arrayexpress
Project description:Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection. However, despite heightened readiness to respond, memory cells exist in a functionally quiescent state. The paradigm is that memory cells remain inactive due to lack of TCR stimuli. Here we report a unique role of Tregs in orchestrating memory quiescence by inhibiting effector and proliferation programs through CTLA-4. Loss of Tregs resulted in activation of genome-wide transcriptional programs characteristic of potent effectors, and both developing and established memory quickly reverted to a terminally differentiated (KLRG-1hi/IL-7R±lo/GzmBhi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality and protective efficacy. CTLA-4, an inhibitory receptor overexpressed on Tregs, functionally replaced Tregs in trans to rescue Treg-less memory defects and restore homeostasis of secondary mediators as well. These studies present CD28-CTLA-4-CD80/CD86 axis as a novel target to potentially accelerate vaccine-induced immunity and improve T-cell memory quality in current cancer immunotherapies proposing transient Treg-depletion. We used microarray analysis to detail the global programming of gene expression in LCMV GP33-specific CD8 T cells differentiated in the presence or absence of regulatory T cells Differentiation of memory CD8 T cells entails a progressive transition of highly activated effector program to a quiescent memory program. A key question in the field is to understand the factors that aid in the differentiation of memory cells from effector cells. It is a generally accepted paradigm that effector cells transition to a memory state by default after antigen clearance, since TCR stimuli is the key driver of effector programs in CD8 T cells. We hypothesized that the effector to memory transition of CD8 T cells involves active immunological brakes through regulatory T cells (Tregs) that allow the highly activated effector cells to convert into quiescent memory cells. To address this hypothesis, we used FoxP3-DTR mice to deplete Tregs during the window following antigen clearance, during which the effector CD8 T cells convert to long-lived memory cells. To get a deeper understanding of the global transcriptome of CD8 T cells as they transition from an effector to a memory state, we isolated and arrayed the antigen-specific CD8 T cells at day 16 post-infection that have experienced the transitional environment with and without the presence of Tregs.
2015-06-16 | E-GEOD-67593 | biostudies-arrayexpress
Project description:Ischemia/reperfusion injury (IRI) has a major impact on the long-term outcome of renal allografts. However, the mechanisms of IRI related to chronic allograft nephropathy (CAN) are still poorly understood. To address this issue, in a F344 to Lewis transplantation model of the rat, kidneys were either subjected to 20 min. or 24 hours of cold ischemia. A customized cDNA microarray representing 737 immune related genes was used for gene expression analysis after 12 hours and 6 months of engraftment. Thereby showing the 6-month graft function and histology were only moderately deteriorated following short cold ischemic time (20 min.), while prolonged ischemia (24 hrs) accelerated CAN development. Following prolonged cold ischemia already 12 hrs after engraftment about 30 genes were differentially expressed up to >20-fold. This included adhesion molecules, heat shock proteins, transcription factors and chemokines (CXCL10) associated with a strong CD68+ macrophage infiltration. Furthermore we observed a remarkable up-regulation of immunoproteasomes implying a re-organisation of the proteasome complex. This data might explain the higher incidence of alloreactivity following enhanced IRI. After 6 months, the prolonged cold ischemia of 24 hours revealed the significant induction of 4 genes: clusterin, C4, and the CCR7 ligands CCL19/21. This supported the observation of enhanced vasculopathy, humoral alloreactivity and increased tracking of MHC-II+ antigen presenting cells during CAN suggesting them as suitable novel targets for combating IRI. Keywords: transplantation, cold ischemia, inflammation, gene expression profiling Renal allografts from F344 donors were transplanted into unmodified LEW recipients. Before harvesting, grafts were perfused with University of Wisconsin solution at 4°C undergoing 20 min. (group A) or 24 hrs (group B) cold ischemia. Engrafted organs were either removed after 12 hrs (group I-A (n=3) and I-B (n=2)) or after 6 months (group II-A (n=3) and II-B (n=2)). Recipient animals of the group II received CyA treatment for 10 days at a dosage of 1.5 mg/kg. Untreated normal kidneys from F344 rats served as control. RNA from transplanted and untreated (control) rat kidneys were labeled by reverse transcription with Cy5 and Cy3 fluorescence, respectively.
2010-06-25 | E-GEOD-4441 | biostudies-arrayexpress
Project description:T cells receive numerous positive and negative signals during primary antigen encounter that control their proliferation and function, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mTOR inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mTOR inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation and an optimal metabolic program for CD8+ T cell memory.
2015-01-31 | GSE63022 | GEO
Project description:BackgroundThe mechanisms underlying the effects of prolonged cold-ischemia storage on kidney allografts are poorly understood.MethodsTo investigate effects of cold ischemia on donor-reactive immune responses and graft pathology, we used a mouse kidney transplantation model that subjected MHC-mismatched BALB/c kidney allografts to cold-ischemia storage for 0.5 or 6 hours before transplant into C57BL/6 mice.ResultsAt day 14 post-transplant, recipients of allografts subjected to 6 versus 0.5 hours of cold-ischemia storage had increased levels of anti-MHC class II (but not class I) donor-specific antibodies, increased donor-reactive T cells, and a significantly higher proportion of transplant glomeruli infiltrated with macrophages. By day 60 post-transplant, allografts with a 6 hour cold-ischemia time developed extensive glomerular injury compared with moderate pathology in allografts with 0.5 hour of cold-ischemia time. Pathology was associated with increased serum levels of anti-class 2 but not anti-class 1 donor-specific antibodies. Recipient B cell depletion abrogated early macrophage recruitment, suggesting augmented donor-specific antibodies, rather than T cells, increase glomerular pathology after prolonged cold ischemia. Lymphocyte sequestration with sphingosine-1-phosphate receptor 1 antagonist FTY720 specifically inhibited anti-MHC class II antibody production and abrogated macrophage infiltration into glomeruli. Adoptive transfer of sera containing anti-donor MHC class II antibodies or mAbs against donor MHC class II restored early glomerular macrophage infiltration in FTY720-treated recipients.ConclusionsPost-transplant inflammation augments generation of donor-specific antibodies against MHC class II antigens. Resulting MHC class II-reactive donor-specific antibodies are essential mediators of kidney allograft glomerular injury caused by prolonged cold ischemia.
| S-EPMC6900787 | biostudies-literature
Project description:Ischemia/reperfusion injury (IRI) has a major impact on the long-term outcome of renal allografts. However, the mechanisms of IRI related to chronic allograft nephropathy (CAN) are still poorly understood. To address this issue, in a F344 to Lewis transplantation model of the rat, kidneys were either subjected to 20 min. or 24 hours of cold ischemia. A customized cDNA microarray representing 737 immune related genes was used for gene expression analysis after 12 hours and 6 months of engraftment. Thereby showing the 6-month graft function and histology were only moderately deteriorated following short cold ischemic time (20 min.), while prolonged ischemia (24 hrs) accelerated CAN development. Following prolonged cold ischemia already 12 hrs after engraftment about 30 genes were differentially expressed up to >20-fold. This included adhesion molecules, heat shock proteins, transcription factors and chemokines (CXCL10) associated with a strong CD68+ macrophage infiltration. Furthermore we observed a remarkable up-regulation of immunoproteasomes implying a re-organisation of the proteasome complex. This data might explain the higher incidence of alloreactivity following enhanced IRI. After 6 months, the prolonged cold ischemia of 24 hours revealed the significant induction of 4 genes: clusterin, C4, and the CCR7 ligands CCL19/21. This supported the observation of enhanced vasculopathy, humoral alloreactivity and increased tracking of MHC-II+ antigen presenting cells during CAN suggesting them as suitable novel targets for combating IRI. Keywords: transplantation, cold ischemia, inflammation, gene expression profiling
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