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Expression data from recent-onset T1D patients and controls

ABSTRACT: Naturally occurring FoxP3+CD4+CD25+high regulatory T cells (Tregs) play an important role in dominant tolerance, suppressing auto-reactive CD4+CD25- T cell activity. Although Tregs from T1D subjects are functionally deficient, there is little knowledge of the molecular mechanisms that orchestrate this loss of Treg function. We observed increased apoptosis (by a novel YOPRO-1/7AAD dual staining protocol) and decreased suppression in polyclonal Tregs in the periphery from high at-risk and T1D subjects. We hypothesize that prior to and during the onset of disease, Tregs lack pro-survival signals and are caught up in a relatively deficient cytokine milieu whose effects may be detectable in the periphery. Microarray analysis was performed on un-stimulated Tregs from 12 subjects with newly diagnosed T1D and 15 healthy controls. Keywords: disease-state analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE10586 | GEO | 2008/02/22

SECONDARY ACCESSION(S): PRJNA107855

REPOSITORIES: GEO

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Transcription profiling of human FoxP3+CD4+CD25+high regulatory T cells (Tregs) isolated from recent-onset type 1 diabetes mellitus (T1D) patients and controls

Project description:Naturally occurring FoxP3+CD4+CD25+high regulatory T cells (Tregs) play an important role in dominant tolerance, suppressing auto-reactive CD4+CD25- T cell activity. Although Tregs from T1D subjects are functionally deficient, there is little knowledge of the molecular mechanisms that orchestrate this loss of Treg function. We observed increased apoptosis (by a novel YOPRO-1/7AAD dual staining protocol) and decreased suppression in polyclonal Tregs in the periphery from high at-risk and T1D subjects. We hypothesize that prior to and during the onset of disease, Tregs lack pro-survival signals and are caught up in a relatively deficient cytokine milieu whose effects may be detectable in the periphery. Microarray analysis was performed on un-stimulated Tregs from 12 subjects with newly diagnosed T1D and 15 healthy controls. Experiment Overall Design: Recent-onset T1D subjects were T1D patients diagnosed within 1 year. At the time of each visit, the following clinical measurements were taken: HbA1c, glucose level, height, weight and BMI. The presence of auto-antibodies was measured from peripheral blood. Peripheral blood mononuclear cells (PBMCs) were collected and Tregs were isolated using FACS isolation. RNA was isolated, amplified and cRNA was fragmented and hybridized to Affymetrix whole genome U133Plus2.0 arrays having 54675 probe-sets. Bayesian Hierarchical analysis (BGX) was used to analyze the data.

2008-04-07 | E-GEOD-10586 | biostudies-arrayexpress

Shifts in isoform usage underlie transcriptional differences in regulatory T cells in type 1 diabetes

Project description:Genome-wide association studies have identified numerous loci with allelic associations to Type 1 Diabetes (T1D) risk. Most disease-associated variants are enriched in regulatory sequences active in lymphoid cell types, suggesting that lymphocyte gene expression is altered in T1D. We assayed gene expression between T1D cases and healthy controls in two autoimmunity-relevant lymphocyte cell types, memory CD4+/CD25+ T-regulatory cells (Treg) and memory CD4+/CD25- T-cells, using a splicing event-based approach to characterize tissue-specific transcriptomes. Limited differences in isoform usage between T1D cases and controls were observed in memory CD4+/CD25- T-cells. In Tregs, 402 genes demonstrated differences in isoform usage between cases and controls, particularly RNA recognition and splicing factor genes. Many of these genes are regulated by the variable inclusion of exons that can trigger nonsense mediated decay. Our results suggest that dysregulation of gene expression, through shifts in alternative splicing in Tregs, contributes to T1D pathophysiology.

2024-01-03 | GSE237218 | GEO

Distinct exhausted CD8 T cell populations are linked to C-peptide preservation in alefacept-treated, recent onset T1D subjects

Project description:Bulk RNA-sequencing of sorted CD8 T cells from recent-onset T1D subjects treated with alefacept.

2020-12-10 | GSE158292 | GEO

Single cell RNA-seq reveals expansion of IGRP-reactive CD4+ T cells in recent onset type I diabetes (bulk RNA-seq of T-cell clone)

Project description:Islet-reactive T cells found in peripheral blood of type 1 diabetes (T1D) subjects are thought to be involved in disease pathogenesis, but full understanding of their role is complicated by their presence also in blood of in healthy subjects. To elucidate their role in T1D, we have combined flow cytometry and single cell RNA sequencing (RNA-seq) techniques to link prior antigen exposure, inferred from expanded TCR clonotypes, and functional capacities of islet antigen-reactive CD4+ memory T cells. We find that cells activated by pooled peptides from immunodominant islet antigens showed significantly higher clonotype sharing within recent onset T1D subjects than in healthy individuals, consistent with in vivo T cell expansion during disease progression. There was no clonotype sharing between donors, indicating a predominance of TCRs with distinct or “private” specificities. Expanded clonotypes could be stable, as one was detected at repeat visits by spanning more than a year by one subject. We identified distinct IGRP peptides as the targets of expanded TCR clonotypes from two T1D subjects, thereby implicating this molecule as a trigger for CD4+ T cell expansion during T1D. Transcriptome profiles of cells from T1D and healthy subjects differed, particularly in cells having the most highly expanded TCR clonotypes. As a group, cells with the most highly expanded TCR clonotypes showed Th2-like phenotypes, but at the single cell level there was phenotypic heterogeneity within and between donors. Our findings demonstrate unique specificities and phenotypes of individual islet-reactive CD4+ memory T cells that have expanded during disease progression.

2017-06-08 | GSE96563 | GEO

Single cell RNA-seq reveals expansion of IGRP-reactive CD4+ T cells in recent onset type I diabetes (single-cell RNA-seq of T-cell clone)

2017-06-08 | GSE96562 | GEO

Gene expression profiling of CD4+CD25+Foxp3+ regulatory T cells and CD4+CD25-Foxp3- T cells in the course of Plasmodium yoelii infection of BALB/c mice

Project description:The objective of the present study was to characterize the phenotype of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in the course of parasitic Plasmodium yoelii (P .yoelii) infection of BALB/c mice. Therefore we performed microarray expression analysis of CD4+CD25+Foxp3+ Tregs isolated by FACS from spleens of non-infected mice and from spleens of mice infected with P. yoelii 3 days and 5 days post infection. By comparing the gene expression profiles, we were able to identify molecules which were differentially expressed by Tregs during parasitic infection and thereby might be involved in their immune-suppressive function. Moreover, we included CD4+CD25-Foxp3- T cells from spleens of non-infected and P. yoelii-infected mice in our analysis. It was proposed that immune-suppressive CD4+CD25-Foxp3- T cells might be induced during Plasmodium infection of mice. Thus, detailed gene expression data of these cells in comparison to CD4+CD25+Foxp3+ Tregs would contribute a better understanding in the phenotype. FACS sorted CD4+CD25+Foxp3+ Tregs and CD4+CD25-Foxp3- T cells from pooled spleens of non-infected Foxp3/ eGFP mice (served as reference) and from pooled spleens of P. yoelii infected Foxp3/ eGFP mice 3 days and 5 days post infection were analyzed as single probes.

2012-04-15 | E-GEOD-34621 | biostudies-arrayexpress

Single cell RNA-seq reveals expansion of IGRP-reactive CD4+ T cells in recent onset type I diabetes (single-cell RNA-seq of CD8+ influenza-reactive T cells)

2017-06-08 | GSE96564 | GEO

Profiling of naÃ¯ve and memory Tregs

Project description:Changes in Treg function are difficult to quantify due to the lack of Treg-exclusive markers in humans and the complexity of functional experiments. We sorted naive and memory human Tregs and conventional T cells, and identified genes that identify human Tregs regardless of their state of activation. We developed this Treg signature using Affymetrix human genome U133A 2.0 microarrays. To generate Tregs and Tconvs in multiple states of activation, naÃ¯ve (CD4+CD25hiCD45RA+) and memory (CD4+CD25hiCD45RA-) Tregs, and naÃ¯ve (CD4+CD25-CD45RA+) and memory (CD4+CD25-CD45RA-) Tconvs were sorted from blood of 7 healthy adults and RNA was isolated ex vivo or after stimulation for 40h, promoting activation-induced FOXP3 in Tconvs. The gene-expression profile of the eight cell subsets was analyzed. 7 adult healthy control samples were sorted into 4 subsets: naÃ¯ve (CD4+CD25hiCD45RA+) and memory (CD4+CD25hiCD45RA-) Tregs, and naÃ¯ve (CD4+CD25-CD45RA+) and memory (CD4+CD25-CD45RA-) Tconvs. These were used for RNA ex vivo and after 40h stimulation with anti-CD3/CD28 beads to induce an activation phenotype.

2016-01-19 | E-GEOD-76598 | biostudies-arrayexpress

Single cell RNA-seq reveals expansion of IGRP-reactive CD4+ T cells in recent onset type I diabetes (single-cell RNA-seq of CD4+ pooled islet antigen-reactive T cells)

2017-06-08 | GSE96568 | GEO

Comprehensive analysis of miRNA expression in T-cell subsets of Rheumatoid arthritis patients and healthy controls reveals defined miRNA signatures of naive and memory Tregs

Project description:Disturbed expression of microRNAs (miRNAs) in regulatory T-cells (Tregs) leads to development of autoimmunity in experimental mouse models. However, the miRNA expression signature characterizing Tregs of autoimmune diseases, such as rheumatoid arthritis (RA) has not been determined yet. Moreover, the technical limitations prevented the analysis of such minute T-cell population as naive and memory Tregs. In this study we have used a microarray approach to comprehensively analyze miRNA expression signatures of naive Tregs (CD4+CD45RO-CD25++), memory Tregs (CD4+CD45RO+CD25+++), as well as conventional naive (CD4+CD45RO-CD25-) and memory (CD4+CD45RO+CD25-) T-cells (Tconvs) derived from peripheral blood of RA patients, and matched healthy controls. Differential expression of selected miRNAs was validated by TaqMan-based qRT-PCR. We found a positive correlation between increased expression of miR-451 in T-cells of RA patients and disease activity score (DAS28), ESR levels, and serum levels of IL-6. Moreover, we found characteristic, disease and treatment independent, global miRNA expression signatures defining naive Tregs, memory Tregs, naive Tconvs and memory Tconvs. The analysis allowed us to define miRNAs characteristic for a general naive phenotype (e.g. miR-92a), a general memory phenotype (e.g. miR-21, miR-155), and most importantly miRNAs specifically expressed in both naive and memory Tregs, defining as such the Treg phenotype (i.e. miR-146a, miR-3162, miR-1202, miR-1246a, and miR-4281). MicroRNA profiling was performed in four CD4+ T-cell subsets: naive Tconventional (CD3+CD8-CD45RO-CD25-), naive Tregulatory (CD3+CD8-CD45RO-CD25+), memory Tconventional (CD3+CD8-CD45RO+CD25-), and memory Tregulatory (CD3+CD8-CD45RO+CD25+) derived from 2 healthy controls, and 6 rheumatoid arthritis patients (total n=8).

2014-01-22 | E-GEOD-50646 | biostudies-arrayexpress

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