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Cited by 149Diabetes and associated disordersPancreatic function and diabetesT-cell and B-cell Immunology

Single-cell RNA sequencing of murine islets shows high cellular complexity at all stages of autoimmune diabetes

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Zakharov, Pavel N., Hu, Hao, Wan, Xiaoxiao, Unanue, Emil R.·2020·Journal of Experimental Medicine
DOI 10.1084/jem.20192362PMC PMC7971127
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Abstract

Tissue-specific autoimmune diseases are driven by activation of diverse immune cells in the target organs. However, the molecular signatures of immune cell populations over time in an autoimmune process remain poorly defined. Using single-cell RNA sequencing, we performed an unbiased examination of diverse islet-infiltrating cells during autoimmune diabetes in the nonobese diabetic mouse. The data revealed a landscape of transcriptional heterogeneity across the lymphoid and myeloid compartments. Memory CD4 and cytotoxic CD8 T cells appeared early in islets, accompanied by regulatory cells with distinct phenotypes. Surprisingly, we observed a dramatic remodeling in the islet microenvironment, in which the resident macrophages underwent a stepwise activation program. This process resulted in polarization of the macrophage subpopulations into a terminal proinflammatory state. This study provides a single-cell atlas defining the staging of autoimmune diabetes and reveals that diabetic autoimmunity is driven by transcriptionally distinct cell populations specialized in divergent biological functions.

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  • The non-obese diabetic (NOD) mouse model is a clinically relevant model of T1D and shares many features with the human disease, including spontaneous CD4 and CD8 T cell responses to many of the same β-cell antigens.

    “The non-obese diabetic (NOD) mouse model is a clinically relevant model of T1D6,7 and shares many features with the human disease, including spontaneous CD4 and CD8 T cell responses to many of the same β-cell antigens6–9.”

    From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [9]

    The Introduction describes NOD diabetes as chronic and similar to human T1D, and the Discussion says both have CD4 and CD8 T cells in their islets. The Discussion reports responses to insulin and other β-cell antigens in NOD mice, but says this study did not determine T-cell specificity; it does not establish that mouse and human T cells respond to many of the same antigens. No page numbers are available in our copy. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Zakharov, P. N., Hu, H., Wan, X., & Unanue, E. R.
Affiliations
Washington University in St. Louis (US)
Corresponding author
  • Zakharov, Pavel N.
  • Unanue, Emil R.
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2020-04-06
Volume
217
Issue
6
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20192362
PMC
PMC7971127
OpenAlex
W3014673551
Cited by
149
References
12
Citations by year
2026: 20 · 2025: 33 · 2024: 24 · 2023: 26 · 2022: 21 · 2021: 21 · 2020: 3 · 2019: 1
FWCI
10.39
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-sa)
Funders
  • National Institutes of Health (AI114551, NK508177)
  • Kilo Diabetes & Vascular Research Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
autoimmune diabetes, nonobese diabetic mouse, pancreatic islets, macrophage polarization, inflammatory macrophages, memory CD4+ T cells, CD8+ cytotoxic T lymphocytes, regulatory T cells, disease staging, transcriptional heterogeneity
MeSH terms
Animals, Dendritic Cells, Diabetes Mellitus, Type 1, Inflammation, Islets of Langerhans, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Phenotype, CD4-Positive T-Lymphocytes, Autoimmunity, Mice, Inbred NOD, Sequence Analysis, RNA, CD8-Positive T-Lymphocytes, Single-Cell Analysis

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