Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with nave CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy.
Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy.
Sex, Specimen part, Time
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Analysis of microRNA transcriptome by deep sequencing of small RNA libraries of peripheral blood.
Specimen part, Cell line
View SamplesMicroRNAs are a class of small non-coding RNAs that regulate mRNA expression at the post-transcriptional level and thereby many fundamental biological processes. A number of methods, such as multiplex polymerase chain reaction, microarrays have been developed for profiling levels of known miRNAs. These methods lack ability to identify novel miRNAs and accurately determine expression at a range of concentration. Deep or massively parallel sequencing methods are providing suitable platforms for genome wide transcriptome analysis and have the ability to identify novel transcripts. The results of analysis of small RNA sequences obtained by Solexa technology of normal peripheral blood mononuclear cells, tumor cell lines K562 (chronic myelogenous leukemia) and HL60 (acute promyelogenous leukemia) are presented. Custom computation pipelines were used to generate expression profiles of known and for identification of novel miRNAs. Some of the highly expressed miRNAs in the leukocytes include several members of the let 7 family, mir-21, 103, 185, 191 and 320a. Comparison of the miRNA profiles of normal versus K562 cells or HL60 revealed a specific set of differentially expressed molecules. Correlation of the miRNA with that of mRNA expression profiles, obtained by microarray, revealed a set of target genes showing inverse correlation with miRNA levels. Our computational pipeline also predicted a number of novel miRNAs. Some of the predictions were validated by realtime RT-PCR and or RNAase protection assay. Overall design: The small RNA population from four samples - Two Normal Peripheral blood mononuclear cells (PBMC) samples, K562 cell line (This cell line is used as a model to study Chronic Myelogenous Leukemia), HL60 (This cell line is used to study acute promyelogenous leukemia) was sequenced using Solexa technology.
Analysis of microRNA transcriptome by deep sequencing of small RNA libraries of peripheral blood.
No sample metadata fields
View SamplesWe did microarray to compare the gene expression profile of peripheral blood mononuclear cells (PBMC from normal volunteer) and two leukemic cell lines that is K562 (Chronic myelogenous leukemia cell line), HL60 (Promyelocytic leukemia cell line) in order to find differentially expressed genes in these samples.
Analysis of microRNA transcriptome by deep sequencing of small RNA libraries of peripheral blood.
Specimen part, Cell line
View SamplesWe reprogrammed fibroblasts from 5 HLHS patients and 2 controls into iPSCs and differentiated into cardiomyocytes. By comparison of HLHS and control groups we uncovered the developmental, structural and functional defects of HLHS cells. Through high through-put screening, the underlying molecular mechnisms of HLHS ontology was explored. Overall design: Cardiomyocyte mRNA profiles of normal control and HLHS samples were generated by deep sequencing, in duplicate, using Illumina HiSeq4000.
Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis.
Specimen part, Subject
View SamplesComparison of gene and protein expression in the large airway epithelium of never and current smokers.
Comparison of proteomic and transcriptomic profiles in the bronchial airway epithelium of current and never smokers.
Sex, Age, Specimen part, Race, Subject
View SamplesAstrocyte elevated gene-1 (AEG-1) as a positive inducer of hepatocellular carcinoma (HCC). Transgenic mice with hepatocyte-specific expression of AEG-1 were challenged with N-nitrosodiethylamine (DEN) and developed multinodular HCC with steatotic features. Thus, we have identified the follwoing AEG-1 functions: induction of steatosis, inhibition of senescence and activation of coagulation pathway to augment an aggressive hepatocarcinogenic phenotype.
Astrocyte elevated gene-1 promotes hepatocarcinogenesis: novel insights from a mouse model.
No sample metadata fields
View SamplesWe report the phenotype of human lung ILC2 and ILC3 populations from individuals with tuberculosis (TB) and non-TB cancer controls. We find that ILC2s demonstrate moderate transcriptional differences in TB infection, whereas ILC3s demonstrate large differences. Overall design: ILC2s and ILC3s were purified by FACS from lung biopsies from TB infected lung tissue and peripheral healthy lung tissue from individuals with cancer. Low-input RNA-seq was performed on 1-3 replicates (dependent on cell number) on 5 individuals with TB infection and 2 controls.
Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis.
Specimen part, Disease, Subject
View SamplesTranscriptomic analysis of primary human umbilical vein endothelial cells (HUVEC). HUVEC were treated in vitro with CoCl2 to induce hypoxia, high glucose and high glucose plus hypoxia in different intervals (1, 3, 12 hours). Subsequently, the effect of metformin (anti-diabetic drug) on all conditions was studied to take advantage of transcriptomics to prospectively explore the mechanism of this drug to reduce the risk of cardiovascular diseases in type II diabetic patients.
Reference genes for expression studies in hypoxia and hyperglycemia models in human umbilical vein endothelial cells.
Specimen part
View SamplesTranscriptomic analysis of primary CD34+ cells. CD34+ cell were induced in vitro with hypoxia (3 hours), high glucose and high glucose plus hypoxia. Subsequently, the effect of metformin (anti-diabetic drug) on all conditions was studied to take advantage of transcriptomics to prospectively explore the mechanism of this drug to reduce the risk of cardiovascular diseases in type II diabetic patients.
Metformin improves the angiogenic potential of human CD34⁺ cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction.
Specimen part
View Samples