Single cell RNA-seq reveals expansion of IGRP-reactive CD4+ T cells in recent onset type I diabetes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA379009 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5340240.fastq.gz | Fastqsanger.gz | |||
| SRR5340250.fastq.gz | Fastqsanger.gz | |||
| SRR5340260.fastq.gz | Fastqsanger.gz | |||
| SRR5340270.fastq.gz | Fastqsanger.gz | |||
| SRR5340280.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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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.
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Project description:OBJECTIVE: Novel biomarkers of disease progression after type 1 diabetes onset are needed. RESEARCH DESIGN AND METHODS: We profiled peripheral blood (PB) monocyte gene expression in 6 healthy subjects and 16 children with type 1 diabetes diagnosed ~3 months previously, and analyzed clinical features from diagnosis to 1 year. RESULTS: Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy controls, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose-adjusted HbA1c levels during the first year, compared to patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g. induction of HIF1A, DDIT3, DDIT4 and GRP78). qPCR quantitation of a 9-gene panel correlated with glycaemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. CONCLUSIONS: A PB gene expression signature correlates with glycaemic control in the first year after diabetes diagnosis, and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and post-onset, and systemic stresses as contributors to innate immune function in type 1 diabetes. CD14+ monocytes from a total of 16 children with recent-onset type 1 diabetes and 6 adult healthy controls were profiled in 2 independent microarrays.
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2020-09-02 | GSE157252 | GEO
Project description:OBJECTIVE: Novel biomarkers of disease progression after type 1 diabetes onset are needed. RESEARCH DESIGN AND METHODS: We profiled peripheral blood (PB) monocyte gene expression in 6 healthy subjects and 16 children with type 1 diabetes diagnosed ~3 months previously, and analyzed clinical features from diagnosis to 1 year. RESULTS: Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy controls, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose-adjusted HbA1c levels during the first year, compared to patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g. induction of HIF1A, DDIT3, DDIT4 and GRP78). qPCR quantitation of a 9-gene panel correlated with glycaemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. CONCLUSIONS: A PB gene expression signature correlates with glycaemic control in the first year after diabetes diagnosis, and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and post-onset, and systemic stresses as contributors to innate immune function in type 1 diabetes.
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