tRNA-derived fragments in T lymphocyte-beta cell crosstalk and in type 1 diabetes pathogenesis in NOD mice.

IF 8.4 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-07-05 DOI:10.1007/s00125-024-06207-3

Flora Brozzi, Cécile Jacovetti, Cristina Cosentino, Véronique Menoud, Kejing Wu, Mustafa Bilal Bayazit, Baroj Abdulkarim, Christian Iseli, Nicolas Guex, Claudiane Guay, Romano Regazzi

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Abstract

Aims/hypothesis: 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.

Methods: 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⁺ 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.

Results: 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⁺ T lymphocytes infiltrating the islets. Indeed, we identified several tRFs that were enriched in extracellular vesicles from CD4⁺/CD25^- 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.

Conclusions/interpretation: 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.

Data availability: Sequences are available from the Gene Expression Omnibus (GEO) with accession numbers GSE242568 and GSE256343.

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tRNA 衍生片段在 T 淋巴细胞-β 细胞串联和 NOD 小鼠 1 型糖尿病发病机制中的作用。

目的/假说：tRNA 在蛋白质合成中发挥着核心作用。除了这一典型功能外，最近还发现它们能产生非编码 RNA 片段（tRFs），调节不同的细胞活动。本研究的目的是评估 tRFs 在免疫细胞和 beta 细胞之间的串扰中的参与情况，并研究它们对 1 型糖尿病发病的贡献：通过小RNA-seq对4周龄和8周龄NOD小鼠的胰岛以及活化的CD4+ T淋巴细胞释放的细胞外囊泡中存在的tRFs进行了全面分析。特定片段水平的变化通过定量 PCR 得到了证实。采用 RNA 标记方法评估了胰岛炎期间免疫细胞向β细胞转移 tRFs 的情况。通过在离体胰岛细胞中过表达 tRFs，并确定其对基因表达和β细胞凋亡的影响，确定了在 1 型糖尿病初期阶段β细胞中增加的 tRFs 的功能作用：结果：我们发现，在 1 型糖尿病的初期阶段，NOD 小鼠胰岛中的 tRF 池发生了变化。这些变化部分是由于β细胞长期暴露于促炎细胞因子（IL-1β、TNF-α和IFN-γ）引起的，另一部分则是由于浸润胰岛的CD4+ T淋巴细胞产生的tRFs传递所致。事实上，我们发现了几种富含在 CD4+/CD25- T 细胞胞外囊泡中的 tRFs，这些 tRFs 在 NOD.SCID 小鼠的免疫细胞收养性转移过程中被转移到了β细胞中。在自身免疫反应中传递给β细胞的tRFs引发了基因表达变化，影响了胰岛素分泌细胞的免疫调节能力，并使细胞更容易凋亡：我们的数据表明，tRFs是免疫系统与胰岛素分泌细胞之间相互影响的新角色，并表明这类新型非编码RNA可能参与了1型糖尿病的发病机制：序列可从基因表达总库（GEO）获得，登录号为 GSE242568 和 GSE256343。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetologia 医学-内分泌学与代谢

CiteScore

18.10

自引率

2.40%

发文量

193

审稿时长

1 months

期刊介绍： Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.