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Transcriptional regulatory networks of circulating immune cells in type 1 diabetes: A community knowledgebase.

ABSTRACT: Investigator-generated transcriptomic datasets interrogating circulating immune cell (CIC) gene expression in clinical type 1 diabetes (T1D) have underappreciated re-use value. Here, we repurposed these datasets to create an open science environment for the generation of hypotheses around CIC signaling pathways whose gain or loss of function contributes to T1D pathogenesis. We firstly computed sets of genes that were preferentially induced or repressed in T1D CICs and validated these against community benchmarks. We then inferred and validated signaling node networks regulating expression of these gene sets, as well as differentially expressed genes in the original underlying T1D case:control datasets. In a set of three use cases, we demonstrated how informed integration of these networks with complementary digital resources supports substantive, actionable hypotheses around signaling pathway dysfunction in T1D CICs. Finally, we developed a federated, cloud-based web resource that exposes the entire data matrix for unrestricted access and re-use by the research community.

SUBMITTER: Ochsner SA

PROVIDER: S-EPMC9272393 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Transcriptional regulatory networks of circulating immune cells in type 1 diabetes: A community knowledgebase.

Ochsner Scott A SA Pillich Rudolf T RT Rawool Deepali D Grethe Jeffrey S JS McKenna Neil J NJ

iScience 20220611 7

Investigator-generated transcriptomic datasets interrogating circulating immune cell (CIC) gene expression in clinical type 1 diabetes (T1D) have underappreciated re-use value. Here, we repurposed these datasets to create an open science environment for the generation of hypotheses around CIC signaling pathways whose gain or loss of function contributes to T1D pathogenesis. We firstly computed sets of genes that were preferentially induced or repressed in T1D CICs and validated these against com ...[more]

PMID: 35832893

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Project description:IntroductionType 1 diabetes (T1D) is defined by immune cell infiltration of the pancreas, in particular the islets of Langerhans, referred to as insulitis, which is especially prominent during the early disease stages in association with decreased beta cell mass. An in-depth understanding of the dynamics and phenotype of the immune cells infiltrating the pancreas and the accompanying changes in their profiles in peripheral blood during T1D development is critical to generate novel preventive and therapeutic approaches, as well as to find biomarkers for the disease process.MethodsUsing multi-parameter flow cytometry, we explored the dynamic changes of immune cells infiltrating the pancreas and the pancreatic draining lymph nodes (PLN), compared to those in peripheral blood in female and male non-obese diabetic (NOD) mice during T1D progression.ResultsThe early stages of T1D development were characterized by an influx of innate dendritic cells and neutrophils in the pancreas. While dendritic cells seemed to move in and out (to the PLN), neutrophils accumulated during the pre-symptomatic phase and reached a maximum at 8 weeks of age, after which their numbers declined. During disease progression, CD4+ and CD8+ T cells appeared to continuously migrate from the PLN to the pancreas, which coincided with an increase in beta cell autoimmunity and insulitis severity, and a decline in insulin content. At 12 weeks of age, CD4+ and especially CD8+ T cells in the pancreas showed a dramatic shift from naïve to effector memory phenotype, in contrast to the PLN, where most of these cells remained naïve. A large proportion of pancreas infiltrating CD4+ T cells were naïve, indicating that antigenic stimulation was not necessary to traffic and invade the pancreas. Interestingly, a pre-effector-like T cell dominated the peripheral blood. These cells were intermediates between naïve and effector memory cells as identified by single cell RNA sequencing and might be a potential novel therapeutic target.ConclusionThese time- and tissue-dependent changes in the dynamics and functional states of CD4+ and CD8+ T cells are essential steps in our understanding of the disease process in NOD mice and need to be considered for the interpretation and design of disease-modifying therapies.

Dataset Information

Transcriptional regulatory networks of circulating immune cells in type 1 diabetes: A community knowledgebase.

Publications

Transcriptional regulatory networks of circulating immune cells in type 1 diabetes: A community knowledgebase.

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