TGF-beta/atRA-induced Tregs express a selected set of microRNAs involved in the repression of transcripts related to Th17 differentiation (original) (raw)
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Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses
2010
Foxp3+ regulatory T (Treg) cells maintain immune homeostasis by limiting different types of inflammatory responses. Here, we report that miR-146a, one of the miRNAs prevalently expressed in Treg cells, is critical for their suppressor function. The deficiency of miR-146a in Treg cells resulted in a breakdown of immunological tolerance manifested in fatal IFNγ-dependent immune-mediated lesions in a variety of organs.
Immunity, 2016
T helper 17 (Th17) cells are key players in autoimmune diseases. However, the roles of non-coding RNAs in Th17 cell development and function are largely unknown. We found that deletion of the endoribonuclease-encoding Dicer1 specifically in Th17 cells protected mice from experimental autoimmune encephalomyelitis. We found that the Dicer1-regulated microRNA (miR)-183-96-182 cluster (miR-183C) was highly expressed in Th17 cells and was induced by cytokine IL-6-STAT3 signaling. miR-183C expression enhanced pathogenic cytokine production from Th17 cells during their development and promoted autoimmunity. Mechanistically, miR-183C in Th17 cells directly repressed expression of the transcription factor Foxo1. Foxo1 negatively regulated the pathogenicity of Th17 cells in part by inhibiting expression of cytokine receptor IL-1R1. These findings indicate that the miR-183C drives Th17 pathogenicity in autoimmune diseases via inhibition of Foxo1 and present promising therapeutic targets.
The Journal of Immunology, 2007
Recent studies have shown that TGF- together with IL-6 induce the differentiation of IL-17-producing T cells (Th17) T cells. We therefore examined whether CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells, i.e., cells previously shown to produce TGF-, serve as Th17 inducers. We found that upon activation purified CD25 ؉ T cells (or sorted GFP ؉ T cells obtained from Foxp3-GFP knockin mice) produce high amounts of soluble TGF- and when cultured with CD4 ؉ CD25 ؊ Foxp3 ؊ T cells in the presence of IL-6 induce the latter to differentiate into Th17 cells. Perhaps more importantly, upon activation, CD4 ؉ CD25 ؉ Foxp3 ؉ (GFP ؉) T cells themselves differentiate into Th17 cells in the presence of IL-6 (and in the absence of exogenous TGF-). These results indicate that CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells can function as inducers of Th17 cells and can differentiate into Th17 cells. They thus have important implications to our understanding of regulatory T cell function and their possible therapeutic use.
2020
Background: Among T helper (Th) lineages differentiated from naïve CD4+ T cells, interleukin (IL)-17-producing Th17 cells are highly correlated with the pathogenesis of autoimmune disorders. Although a series of microRNAs (miRs) that modulate autoimmunity progress have been reported, further studies on microRNAs particularly involved in Th17 lineage commitment are still warranted. Results: In this study, to clarify the involvement of miR-141-3p and miR-200a-3p in Th17 cell differentiation, as well as to explore their potential target gene involved, purified human naïve CD4+ T cells were cultured under Th17 cell polarizing condition. Differentiation process was confirmed applying ELISA method to measure IL-17 secretion and RT-qPCR to assess Th17 cell-defining genes expression during differentiation period. miR-141 and miR-200a expression pattern as well as expression alteration of their predicted downstream genes, which were identified via consensus and integration in-silico approach...
Iranian journal of allergy, asthma, and immunology, 2017
Regulatory T cells (Tregs) are important components of the immune system that modulate responses of other cells. These cells are involved in peripheral tolerance mechanisms, so defect in development and function of these cells can result in autoimmune disease. Increasing evidence supports the role of microRNAs-21 (miR-21) in the regulation of forkhead box P3 (Foxp3) expression in Tregs. We aimed to determine whether miR-21 transfection to naive CD4+ T cells can be useful in generation of iTregs in-vitro. We investigated in-vitro differentiation of miR-21-transfected naive CD4+ T cells to iTregs and compared these iTregs to cytokine-differentiated iTregs and control group. We showed that expression of Foxp3, transforming growth factor beta (TGF-β), and interleukin-10 (IL-10) are increased in iTregs generated after miR-21 transfection in comparison with cytokine-differentiated iTregs and control group. Our findings demonstrate that miR-21 has positive role in in-vitro generation of in...
The Journal of Immunology, 2012
We have investigated the mechanism underlying the immunoregulatory function of membrane Ig-like transcript 3 (ILT3) and soluble ILT3Fc. microRNA (miRNA) expression profile identified genes that were downregulated in ILT3-induced human CD8 + T suppressor cells (Ts) while upregulated in T cells primed in the absence of ILT3. We found that miR-21, miR-30b, and miR-155 target the 39-untranslated region of genes whose expression was strongly increased in ILT3Fc-induced Ts, such as dual specificity phosphatase 10, B cell CLL/lymphoma 6, and suppressor of cytokine signaling 1, respectively. Transfection of miRNA mimics or inhibitors and site-specific mutagenesis of their 39-untranslated region binding sites indicated that B cell CLL/lymphoma 6, dual specificity phosphatase 10, and suppressor of cytokine signaling 1 are direct targets of miR-30b, miR-21, and miR-155. Primed CD8 + T cells transfected with miR-21&30b, miR-21&155, or miR-21&30b&155 inhibitors displayed suppressor activity when added to autologous CD3-triggered CD4 T cells. Luciferase reporter assays of miR-21 and miR-155 indicated that their transcription is highly dependent on AP-1. Analysis of activated T cells showed that ILT3Fc inhibited the translocation to the nucleus of the AP-1 subunits, FOSB and c-FOS, and the phosphorylation of ZAP70 and phospholipase C-g 1. In conclusion, ILT3Fc inhibits T cell activation and induces the generation of Ts targeting multiple inflammatory miRNA pathways.