Age-related gene changes of naïve and memory T cells in a mouse age-tracking model
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA687750 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13316000_1.fastq.gz | Fastqsanger.gz | |||
| SRR13316000_2.fastq.gz | Fastqsanger.gz | |||
| SRR13316001_1.fastq.gz | Fastqsanger.gz | |||
| SRR13316001_2.fastq.gz | Fastqsanger.gz | |||
| SRR13316002_1.fastq.gz | Fastqsanger.gz |
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Project description:The transcriptomic changes of young and aged T cells are still unknown. Our previous study successfully tracked aged T cells generated from one wave of developing thymocytes of young age by a lineage-specific and inducible Cre-controlled reporter (TCRδCreERR26ZsGreen mouse strain). We used this transgenic mice and RNA-Seq to study the immunosenescence of naïve and memory T cell populations. A large number of genes involved in cellular and molecular functions, protein activity, cell cycle, cell adhesion, and immune functions were identified as having altered expression during aging. Our work revealed aged CD8 memory T cells with increased T cell activation and immunity genes, yet high expression of immunosuppressive checkpoints and resistance to cell death, implying aberrant T cell immunity in old mice. These feature genes identified in the current study serve as new therapeutic targets for correcting age-related defects.
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Project description:An early-differentiated CD8+ memory T cell subset with stem cell-like properties (TSCM) can be identified within the naïve-like T cell population by the expression of CD95/Fas. Based on experiments including exon- and gene-level expression analysis, we provide evidence that this subset of antigen-specific cells represents an early precursor of conventional central (TCM) and effector (TEM) memory CD8+ T cells with enhanced self-renewal capacity and proliferative potential. We identified 900 genes differentially expressed between major T cell subsets defined along with memory T cell commitment. Based on the analysis of these genes, CD95+ naïve T cells (TSCM) cluster closer to the CD8+ T memory compartment than to classical (CD95-) naïve T (TN) cells, and display an intermittent phenotype between classical TN and TCM cells in terms of all major T cell differentiation markers analyzed. Three healthy human blood donors provided lymphocyte-enriched apheresis blood for this study after informed consent. From all samples, total RNA was isolated using an RNEasy Micro kit (Qiagen), processed by Ambion’s WT expression kit, fragmented and labeled with a WT Terminal Labeling Kit (Affymetrix), hybridized to WT Human Gene 1.0 ST arrays (Affymetrix) and stained on a Genechip Fluidics Station 450 (Affymetrix), all according to the respective manufacturer's instructions. Samples represent "exon-level" and "gene-level" analyses.
2011-07-12 | E-GEOD-23321 | biostudies-arrayexpress
Project description:Atherosclerosis is a major pathological condition that underlies many cardiovascular diseases (CVDs). Its etiology involves breach of tolerance to self, leading to clonal expansion of autoreactive apolipoprotein B (APOB)–reactive CD4+T cells that correlates with clinical CVD. The T-cell receptor (TCR) sequences that mediate activation of APOB-specific CD4+T cells are unknown. Methods: In a previous study, we had profiled the hypervariable complementarity determining region 3 (CDR3) of CD4+T cells that respond to six immunodominant APOB epitopes in most donors. Here, we comprehensively analyze this dataset of 149,065 APOB-reactive and 199,211 non-reactive control CDR3s from six human leukocyte antigen–typed donors. Results: We identified 672 highly expanded (frequency threshold > 1.39E-03) clones that were significantly enriched in the APOB-reactive group as compared to the controls (log10 odds ratio ≥1, Fisher’s test p < 0.01). Analysis of 114,755 naïve, 91,001 central memory (TCM) and 29,839 effector memory (TEM) CDR3 sequences from the same donors revealed that APOB+ clones can be traced to the complex repertoire of unenriched blood T cells. The fraction of APOB+ clones that overlapped with memory CDR3s ranged from 2.2% to 46% (average 16.4%). This was significantly higher than their overlap with the naïve pool, which ranged from 0.7% to 2% (average 1.36%). CDR3 motif analysis with the machine learning–based in-silico tool, GLIPHs (grouping of lymphocyte interactions by paratope hotspots), identified 532 APOB+ motifs. Analysis of naïve and memory CDR3 sequences with GLIPH revealed that ~40% (209 of 532) of these APOB+motifs were enriched in the memory pool. Network analysis with Cytoscape revealed extensive sharing of the memory-affiliated APOB+ motifs across multiple donors. We identified six motifs that were present in TCM and TEM CDR3 sequences from >80% of the donors and were highly enriched in the APOB-reactive TCR repertoire. Discussion: The identified APOB-reactive expanded CD4+T cell clones and conserved motifs can be used to annotate and track human atherosclerosis-related autoreactive CD4+T cells and measure their clonal expansion.
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Project description:Neonates are intrinsically defective at creating memory CD8+ T cells in response to infection with intracellular pathogens. Here we investigated differential of small RNAs, transcription factors, and chemokine receptors regulation in neonates as compared to adults before and during infection. We found that prior to infection, naïve cells have a different expression profile for many microRNAs, and gene targets of these microRNAs show widespread expression differences. These targets and other changes in gene expression in naïve cells result in neonatal cells that get activated more easily, express chemokine receptors that home to sites of infection, and are less protected from apoptosis during contraction. As a result, changes in neonatal naïve cells drive effector cell terminal differentiation at the expense of creating long-lived memory cells. total RNAs were sequenced from adult and neonatal CD8+ T cells before and during infection
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Project description:Histone methylations play a major role in regulating the chromatin state and gene expression, yet little is known about their involvement in differential gene expression and function of memory CD8 T cells. Here, we report a genome-wide analysis of two histone H3 methylations (H3K4me3 and H3K27me3) and gene expression in naïve, central (TCM) and effector (TEM) memory CD8 T cells. Analysis of 16,314 annotated genes in CD8 T cell subsets revealed that gene expression were positively correlated with the levels of H3K4me3 and negatively correlated with the levels of H3K27me3 in these gene loci. The correlation between differential H3K4me3 orH3K27me3 levels with gene expressions in memory CD8 T cells displayed four distinct modes: repressive, active, poised, and bivalent, reflecting their complex regulation and different function of these genes. Furthermore, accessible chromatin states of different gene loci were preferentially influenced by different histone modifications as demonstrated here high levels of H3K9ac found in active gene loci without high levels of H3K4me3. These findings reveal a histone methylation based complex regulation of differential gene expression in memory CD8 T cells. Thus, change of chromatin structure mediated by histone methylation may serve a fundamental basis for the rapid transcriptional response of memory CD8 T cells. Keywords: Histone methylations, chromatin state, CD8 memory T cells Enriched naïve and memory CD8 T cells were purified into CD8+CD45RA+CD62L+ naïve T cells, CD8+CD45RA-CD62L+ central memory T cells (TCM), and CD8+CD45RA-CD62L- effector memory T cells (TEM) by a cell sorter (MoFlo; Dako Cytomation, Carpentaria, CA). Triplicates of each cell type were either used right away or incubated with anti-CD3 and anti-CD28 Ab (anti-CD3/CD28) coupled magnetic beads (Invitrogen) at the cell:bead ratio of 1:1 for 16 hours in RPMI-1640 with 10% Fetal bovine serum and penicillin (10 U/ml)/streptomycin (10 ug/ml) (Invitrogen). The freshly isolated and 16 hr stimulated cells from several donors as a pool were used for gene expression microarray analysis. All sample data was normalized to a standard control RNA labeled and hybed along with each sample and all data from the 3 replicates was averaged.
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Project description:Neonates are intrinsically defective at creating memory CD8+ T cells in response to infection with intracellular pathogens. Here we investigated differential of small RNAs, transcription factors, and chemokine receptors regulation in neonates as compared to adults before and during infection. We found that prior to infection, naïve cells have a different expression profile for many microRNAs, and gene targets of these microRNAs show widespread expression differences. These targets and other changes in gene expression in naïve cells result in neonatal cells that get activated more easily, express chemokine receptors that home to sites of infection, and are less protected from apoptosis during contraction. As a result, changes in neonatal naïve cells drive effector cell terminal differentiation at the expense of creating long-lived memory cells. Small RNAs were sequenced from adult and neonatal CD8+ T cells before and during infection
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Project description:Neonates are intrinsically defective at creating memory CD8+ T cells in response to infection with intracellular pathogens. Here we investigated differential of small RNAs, transcription factors, and chemokine receptors regulation in neonates as compared to adults before and during infection. We found that prior to infection, naïve cells have a different expression profile for many microRNAs, and gene targets of these microRNAs show widespread expression differences. These targets and other changes in gene expression in naïve cells result in neonatal cells that get activated more easily, express chemokine receptors that home to sites of infection, and are less protected from apoptosis during contraction. As a result, changes in neonatal naïve cells drive effector cell terminal differentiation at the expense of creating long-lived memory cells. Small RNAs were sequenced from adult and neonatal CD8+ T cells before infection.
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Project description:Neonates are intrinsically defective at creating memory CD8+ T cells in response to infection with intracellular pathogens. Here we investigated differential of small RNAs, transcription factors, and chemokine receptors regulation in neonates as compared to adults before and during infection. We found that prior to infection, naïve cells have a different expression profile for many microRNAs, and gene targets of these microRNAs show widespread expression differences. These targets and other changes in gene expression in naïve cells result in neonatal cells that get activated more easily, express chemokine receptors that home to sites of infection, and are less protected from apoptosis during contraction. As a result, changes in neonatal naïve cells drive effector cell terminal differentiation at the expense of creating long-lived memory cells. PolyA RNA was selected and sequenced from adult and neonatal CD8+ T cells before and during infection
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