Mettl14-mediated m6A modification enhances the function of Foxp3+ regulatory T cells and promotes allograft acceptance
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE215371 | GEO | 2022/11/09
REPOSITORIES: GEO
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Project description:Regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis and self‑tolerance, and can be therapeutically used for prevention of unwanted immune responses such as allotransplant rejection. Tregs are characterized by the expression of the transcription factor Foxp3, and recent work suggested that epigenetic imprinting of Foxp3 and other Treg‑specific epigenetic signatures genes is crucial for the stabilization of both Foxp3 expression and immunosuppressive properties within Tregs. Lately, Vitamin C was reported to enhance the activity of enzymes of the ten‑eleven‑translocation family, thereby fostering the demethylation of Foxp3 and other Treg‑specific epigenetic signatures genes in developing Tregs. Here, we in vitro generated alloantigen‑specific Foxp3+ Tregs (allo‑iTregs) in presence of vitamin C, and those Tregs showed a pronounced demethylation of Foxp3 and other Treg‑specific epigenetic signatures genes, accompanied with an enhanced stability of Foxp3 expression. However, RNA‑seq analysis revealed an only minor impact of Vitamin C on the transcriptome of allo‑iTregs. Importantly, when being tested in vivo in a highly immunogenic skin transplantation model vitamin C‑treated allo‑iTregs showed a superior suppressive capacity as compared to allo‑iTregs generated in absence of vitamin C. Together, our results might pave the way for the establishment of novel protocols for the in vitro generation of allo‑antigen specific Foxp3+ Tregs for therapeutic usage in transplantation medicine.
2017-06-22 | GSE96960 | GEO
Project description:To elucidate the role of METTL14-mediated m6A modification in epidermal development, we conditionally knocked out the m6A methyltransferase METTL14 in mouse epidermal keratinocytes. We then performed MeRIP-seq analysis of epidermal keratinosis from P0 control mice (K14Cre,Mettl14F/+).
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Project description:To elucidate the role of METTL14-mediated m6A modification in epidermal development, we conditionally knocked out the m6A methyltransferase METTL14 in mouse epidermal keratinocytes. We then performed RNA-seq analysis of epidermal keratinosis from P0 control mice (K14Cre,Mettl14F/+) and cKO mice (K14CreMettl14F/F).
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Project description:To elucidate the role of METTL14-mediated m6A modification in epidermal development, we conditionally knocked out the m6A methyltransferase METTL14 in mouse epidermal keratinocytes. We then performed ribosome-profiling analysis of epidermal keratinosis from P0 control mice (K14Cre,Mettl14F/+) and cKO mice (K14CreMettl14F/F).
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Project description:Natural CD4+FOXP3+ regulatory T (Treg) cells constitute a unique T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. Recent studies provide evidence for the heterogeneity and plasticity of the Treg cell lineage. However, the fate of human Treg cells after loss of FOXP3 expression and the underlying epigenetic mechanisms remain to be fully elucidated. Here, we compared gene expression profiles and histone methylation status on two histone H3 lysine residues (H3K4me3 and H3K27me3) of expanded FOXP3+ and corresponding FOXP3-losing Treg cells. DGE assay showed that human Treg cells down-regulated Treg signature genes, whereas up-regulated a set of Th lineages-associated genes, especially for Th2, such as GATA3, GFI1 and IL13, after in vitro expansion. Furthermore, we found that reprogramming of Treg cells was associated with histone modifications, as shown by decreased abundance of permissive H3K4me3 within down-regulated Treg signature genes, such as FOXP3, CTLA4 and LRRC32 loci, although with no significant changes in H3K27me3 modification. Thus, our results indicate that human Treg cells could convert into a Th-like cells upon in vitro expansion, displaying a gene expression signature dominated by Th2 lineage associated genes, and the histone methylation might contribute to such conversion. mRNA profiles of in-vitro-expanded FOXP3+ Treg and FOXP3-losing Treg cells generated by deep sequencing.
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Project description:Heart transplantation is the optimal therapy for patients with end-stage heart disease, but its long-term outcome remains inadequate. Recent studies have highlighted the importance of the melanocortin receptors (MCRs) in inflammation, but how MCRs regulate the balance between alloreactive T cells and Tregs, and whether they impact chronic heart transplant rejection, is unknown. Here, we found that Tregs express MC2R, and MC2R expression was highest among all MCRs by Tregs. Our data indicate that adrenocorticotropic hormone (ACTH), the sole ligand for MC2R, promoted the formation of Tregs by increasing the expression of IL-2Rα (CD25) in CD4+ T cells and activation of STAT5 in CD4+CD25+ T cells. ACTH treatment also improved the survival of heart allografts and increased the formation of Tregs in CD28KO mice. ACTH treatment synergized with the tolerogenic effect of CTLA-4-Ig, resulting in long-term survival of heart allografts and an increase in intragraft Tregs. ACTH administration also demonstrated higher prolongation of heart allograft survival in transgenic mouse recipients with both complete KO and conditional KO of PI3Kγ in T cells. Finally, ACTH treatment reduced chronic rejection markedly. These data demonstrate that ACTH treatment improved heart transplant outcomes, and this effect correlated with an increase in Tregs.
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Project description:We hypothesize that nuclear factors co-occupying the genetic elements with regulatory T (Treg) cell lineage–specifying factor Foxp3 play critical roles in transcriptional regulation of Treg immune suppression function, thus, offering a unique approach to investigate the factors and their mechanisms controlling Treg-mediated immune tolerance involved in self-tolerance and antitumor immunity. We seek to identify the proteins occupying Foxp3 targets in the resting state or after cells receiving stimulation. To this end, we projected the spatial information (PSI) of Foxp3, Histone H3, or Stat5 onto their adjacent proteins with peroxidase–catalyzed biotin-phenoxyl radicals and identify these biotinylated proteins with tandem mass tag (TMT)–based quantitative mass spectrometry (MS).
2024-06-08 | PXD019050 | Pride
Project description:Regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis and self-tolerance and can be therapeutically used for prevention of unwanted immune responses such as allotransplant rejection. Tregs are characterized by expression of the transcription factor Foxp3, and recent work suggests that epigenetic imprinting of Foxp3 and other Treg-specific epigenetic signatures genes is crucial for the stabilization of both Foxp3 expression and immunosuppressive properties within Tregs. Lately, vitamin C was reported to enhance the activity of enzymes of the ten-eleven translocation family, thereby fostering the demethylation of Foxp3 and other Treg-specific epigenetic signatures genes in developing Tregs. Here, we in vitro generated alloantigen-induced Foxp3+ Tregs (allo-iTregs) in presence of vitamin C. Although vitamin C hardly influenced the transcriptome of allo-iTregs as revealed by RNA-seq, those vitamin C-treated allo-iTregs showed a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signatures genes accompanied with an enhanced stability of Foxp3 expression. Accordingly, when being tested in vivo in an allogeneic skin transplantation model, vitamin C-treated allo-iTregs showed a superior suppressive capacity. Together, our results pave the way for the establishment of novel protocols for the in vitro generation of alloantigen-induced Foxp3+ Tregs for therapeutic use in transplantation medicine.
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Project description:The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function. Pharmacological manipulation of this phosphorylation-ubiquitination axis may provide therapeutic opportunities for regulating TREG cell function, for example during cancer immunotherapy.
2019-09-02 | PXD011164 | Pride
Project description:Lungs allografts have worse long-term survival compared with other organ transplants. This is most likely due to their unique immunoregulation that may not respond to traditional immunosuppression. For example, local NO generation by inducible NOS (iNOS) is critical for lung allograft acceptance but associates with rejection of other solid organs. The source of NO in accepting lung allografts remains unknown. Here, we report that, unlike the case for other pulmonary processes in which myeloid cells control NO generation, recipient-derived eosinophils play a critical and nonredundant role in iNOS-mediated lung allograft acceptance. Depletion of eosinophils reduces NO levels to that of recipients with global deletion of iNOS and leads to a costimulatory blockade-resistant form of rejection. Furthermore, NO production by eosinophils depends on Th1 polarization by inflammatory mediators, such as IFN-? and TNF-?. Neutralization of such mediators abrogates eosinophil suppressive capacity. Our data point to what we believe to be a unique and previously unrecognized role of eosinophil polarization in mediating allograft tolerance and put into perspective the use of high-dose eosinophil-ablating corticosteroids after lung transplantation.
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