A1 Refereed original research article in a scientific journal
Single-cell RNA-seq analysis of longitudinal CD4+ T cell samples reveals cell-type-specific changes during early stages of type 1 diabetes
Authors: Biradar, Rahul; Kalim, Ubaid Ullah; Lönnberg, Tapio; Junttila, Sini; Suomi, Tomi; Norman, Sebastián Zúñiga; Starskaia, Inna; Paulin, Niklas; Mikkola, Lea; Vaarala, Outi; Rasool, Omid; Knip, Mikael; Elo, Laura L.; Lahesmaa, Riitta
Publisher: Springer Science and Business Media LLC
Publication year: 2025
Journal: Genome Medicine
Article number: 154
Volume: 17
eISSN: 1756-994X
DOI: https://doi.org/10.1186/s13073-025-01574-x
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.1186/s13073-025-01574-x
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/506507270
Background
T cells play a pivotal role in the autoimmune destruction of beta cells in type 1 diabetes. However, our understanding of the disease has been limited by lack of a comprehensive single-cell transcriptome analysis of T cells during its early stages.
Methods
We performed single cell RNA sequencing analysis of 73 longitudinal CD4+ T cell samples collected at an early age of 3–24 months from children who subsequently developed type 1 diabetes (N = 11) and their matched controls (N = 11). The samples analysed here were at or before the age of seroconversion, i.e., appearance of beta cell specific autoantibodies. These samples were obtained from the Trial to Reduce Insulin Dependent Diabetes Mellitus (IDDM) in Genetically at Risk (TRIGR) study (ClincalTrials.gov ID: NCT00179777).
Results
By phenotypically characterizing over 99,000 cells, we identified cell-type-specific gene expression patterns associated with disease progression. While the cell-type compositions were similar, several genes were differentially regulated in cases in different cell types. Besides pathways altered in cases in specific cell types, interferon related pathways and pathways related to viral response were altered in multiple cell types in cases. We also identified gene regulatory networks (regulon) that drives the transcriptional state of the cell types. Notably, we observed increased PRDM1 regulon activity in Th17 cells and diminished GATA3 regulon activity in naïve T cells, among other changes in the activity of different regulons in children progressing to disease.
Conclusions
Our findings reveal early, cell-type-specific changes in transcription and gene regulatory networks in CD4⁺ T cells associated with type 1 diabetes progression, highlighting key pathways and transcriptional regulators. These insights provide a foundation for understanding early immune dysregulation in type 1 diabetes and basis for strategies to develop early diagnosis and intervention.
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Funding information in the publication:
The TRIGR study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (grants HD040364, HD042444 and HD051997), Canadian Institutes of Health Research, JDRF and the Commission of the European Communities (specific RTD pro-gramme “Quality of Life and management of Living Resources”, contract number QLK1-2002–00372 “Diabetes Prevention”) and the EFSD/JDRF/Novo Nordisk Focused Research Grant. RL is supported by Academy of Finland grants 250114, 292335, 294337, 292482, 319280, 329277, 331793, 335435 and 31444, Breakthrough T1D Foundation grant, the Novo Nordisk Foundation grant NNF19OC0057218, Jane and Aatos Erkko Foundation grant, and the Finnish Cancer Foundation grant. LLE is supported by European Research Council ERC 677943, European Union’s Horizon 2020 research and innovation programme 955321 Academy of Finland grants 310561, 314443, 329278, 335434, 335611 and 341342. RL and LLE were supported by the Sigrid Juselius Foundation, Turku Graduate School University of Turku, Åbo Akademi University. InFLAMES Flagship Programme of the Academy of Finland 337530, Biocenter Finland and ELIXIR Finland. R.B. was funded by Turku Doctoral Programme of Molecular Medicine, University of Turku and InFLAMES Flagship doctoral module.
