Abstract
MicroRNAs (miRNAs) are small endogenous noncoding RNAs that regulate genome expression posttranscriptionally and are involved in autoimmune diseases. Previous studies have indicated that follicular helper T (Tfh) cells play a critical role in the pathogenesis of Graves’ disease (GD). However, the molecular mechanisms that contribute to circulating Tfh memory cell response in GD patients remain incompletely understood. This study aimed to investigate the role of miRNAs on circulating Tfh memory cells in GD patients. Herein, our data showed that the proportion of circulating Tfh memory cells, the transcript levels of IL-21, and the plasma concentrations of IL-21 were increased in the peripheral blood from GD patients. We also found that inducible co-stimulator (ICOS) expression, an important molecule expressed on Tfh cells, were significantly augmented in the peripheral blood mononuclear cells (PBMCs) from GD patients and positively correlated with the percentage of circulating Tfh memory cells and the transcript levels of IL-21 in GD. Intriguingly, miRNA sequencing screened miR-29a-3p expression was downregulated and inversely correlated with ICOS expression and the frequency of circulating Tfh memory cells in patients with GD. Luciferase assay demonstrated that ICOS was the direct target gene of miR-29a-3p, and miR-29a-3p could inhibit ICOS at both transcriptional and translational levels. Overexpression of miR-29a-3p reduced the proportion of circulating Tfh memory cells. Moreover, miR-29a-3p expression negatively correlated with serum concentrations of TSH receptor antibody (TRAb) in GD patients. Collectively, our results demonstrate that miR-29a-3p emerges as a post-transcriptional brake to limit circulating Tfh memory cell response in GD patients and may be involved in the pathogenesis of GD.
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Data availability
The sequencing datasets of miRNAs can be found in the GEO/GSE183576, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE183576. The data that support the findings of this study are available from the corresponding author on reasonable request.
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Funding
This work was supported by National Natural Science Foundation of China (Grant No. 81800698), Zhenjiang Sixth Phase 169 Project Training Fund Support Project (No. 28 of academic hard-core personnel research project), and Zhenjiang Science and Technology Planning Project (Grant Nos. SH2021026, SH2021059).
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Y.L., X.W., and W.L. designed the methodology, performed the experiments, and analyzed or synthesized study data. Y.L. wrote the original draft. J.Z. provided study materials, reagents, and materials and maintained research data. J.X. participated in the collection of specimens. S.W. and H.P. were responsible for the conceptualization, funding acquisition, project administration, and supervision for the research activity. All authors participated in the discussion and finalization of this manuscript.
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The study was reviewed and approved by the Ethics Committee of the Affiliated People’s Hospital of Jiangsu University and the ethics approval number is K-20200012-Y. The participants provided their written informed consent to participate in the study. All operations in this study adhered to standard biosecurity and institutional safety procedures.
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Fig. S1
The relative expression of intersected miRNAs in the PBMCs from 10 GD patients and 10 healthy controls was verified in the preliminary study. The transcript levels of miR-29a-3p (a), miR-29b-3p (b), and miR-98-5p (c) are shown. Each data point represents an individual subject, and the horizontal lines show the mean. ***p< 0.001, NS: no significance (PNG 82 kb)
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Liu, Y., Wang, X., Luan, W. et al. MiR-29a-3p negatively regulates circulating Tfh memory cells in patients with Graves’ disease by targeting ICOS. Immunol Res 71, 173–184 (2023). https://doi.org/10.1007/s12026-022-09333-5
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DOI: https://doi.org/10.1007/s12026-022-09333-5