tRNA-derived fragments in T lymphocyte-beta cell crosstalk and in type 1 diabetes pathogenesis in NOD mice.
Details
Serval ID
serval:BIB_BF3CD8D4736F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
tRNA-derived fragments in T lymphocyte-beta cell crosstalk and in type 1 diabetes pathogenesis in NOD mice.
Journal
Diabetologia
ISSN
1432-0428 (Electronic)
ISSN-L
0012-186X
Publication state
Published
Issued date
10/2024
Peer-reviewed
Oui
Volume
67
Number
10
Pages
2260-2274
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
tRNAs play a central role in protein synthesis. Besides this canonical function, they were recently found to generate non-coding RNA fragments (tRFs) regulating different cellular activities. The aim of this study was to assess the involvement of tRFs in the crosstalk between immune cells and beta cells and to investigate their contribution to the development of type 1 diabetes.
Global profiling of the tRFs present in pancreatic islets of 4- and 8-week-old NOD mice and in extracellular vesicles released by activated CD4 <sup>+</sup> T lymphocytes was performed by small RNA-seq. Changes in the level of specific fragments were confirmed by quantitative PCR. The transfer of tRFs from immune cells to beta cells occurring during insulitis was assessed using an RNA-tagging approach. The functional role of tRFs increasing in beta cells during the initial phases of type 1 diabetes was determined by overexpressing them in dissociated islet cells and by determining the impact on gene expression and beta cell apoptosis.
We found that the tRF pool was altered in the islets of NOD mice during the initial phases of type 1 diabetes. Part of these changes were triggered by prolonged exposure of beta cells to proinflammatory cytokines (IL-1β, TNF-α and IFN-γ) while others resulted from the delivery of tRFs produced by CD4 <sup>+</sup> T lymphocytes infiltrating the islets. Indeed, we identified several tRFs that were enriched in extracellular vesicles from CD4 <sup>+</sup> /CD25 <sup>-</sup> T cells and were transferred to beta cells upon adoptive transfer of these immune cells in NOD.SCID mice. The tRFs delivered to beta cells during the autoimmune reaction triggered gene expression changes that affected the immune regulatory capacity of insulin-secreting cells and rendered the cells more prone to apoptosis.
Our data point to tRFs as novel players in the crosstalk between the immune system and insulin-secreting cells and suggest a potential involvement of this novel class of non-coding RNAs in type 1 diabetes pathogenesis.
Sequences are available from the Gene Expression Omnibus (GEO) with accession numbers GSE242568 and GSE256343.
Global profiling of the tRFs present in pancreatic islets of 4- and 8-week-old NOD mice and in extracellular vesicles released by activated CD4 <sup>+</sup> T lymphocytes was performed by small RNA-seq. Changes in the level of specific fragments were confirmed by quantitative PCR. The transfer of tRFs from immune cells to beta cells occurring during insulitis was assessed using an RNA-tagging approach. The functional role of tRFs increasing in beta cells during the initial phases of type 1 diabetes was determined by overexpressing them in dissociated islet cells and by determining the impact on gene expression and beta cell apoptosis.
We found that the tRF pool was altered in the islets of NOD mice during the initial phases of type 1 diabetes. Part of these changes were triggered by prolonged exposure of beta cells to proinflammatory cytokines (IL-1β, TNF-α and IFN-γ) while others resulted from the delivery of tRFs produced by CD4 <sup>+</sup> T lymphocytes infiltrating the islets. Indeed, we identified several tRFs that were enriched in extracellular vesicles from CD4 <sup>+</sup> /CD25 <sup>-</sup> T cells and were transferred to beta cells upon adoptive transfer of these immune cells in NOD.SCID mice. The tRFs delivered to beta cells during the autoimmune reaction triggered gene expression changes that affected the immune regulatory capacity of insulin-secreting cells and rendered the cells more prone to apoptosis.
Our data point to tRFs as novel players in the crosstalk between the immune system and insulin-secreting cells and suggest a potential involvement of this novel class of non-coding RNAs in type 1 diabetes pathogenesis.
Sequences are available from the Gene Expression Omnibus (GEO) with accession numbers GSE242568 and GSE256343.
Keywords
Animals, Diabetes Mellitus, Type 1/immunology, Diabetes Mellitus, Type 1/metabolism, Diabetes Mellitus, Type 1/genetics, Mice, Inbred NOD, Mice, Insulin-Secreting Cells/metabolism, RNA, Transfer/genetics, RNA, Transfer/metabolism, Female, CD4-Positive T-Lymphocytes/metabolism, CD4-Positive T-Lymphocytes/immunology, Apoptosis, Islets of Langerhans/metabolism, Islets of Langerhans/immunology, Extracellular Vesicles/metabolism, T-Lymphocytes/immunology, T-Lymphocytes/metabolism, RNA, Untranslated/genetics, Autoimmunity, Extracellular vesicles, Insulin, Pancreatic islet
Pubmed
Web of science
Open Access
Yes
Create date
11/07/2024 16:30
Last modification date
05/10/2024 7:02