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Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8- double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus.

ABSTRACT: The mechanistic target of rapamycin (mTOR) is activated in CD4(-)CD8(-) double-negative (DN) T cells and its blockade is therapeutic in systemic lupus erythematosus (SLE) patients. Murine studies showed the involvement of mTOR complex 1 (mTORC1) and 2 (mTORC2) in the differentiation of Th1/Th17 cells and Th2 cells, respectively. In this study, we investigated the roles of mTORC1 and mTORC2 in T cell lineage development in SLE and matched healthy control (HC) subjects. mTORC1 activity was increased, whereas mTORC2 was reduced, as assessed by phosphorylation of their substrates phosphorylated S6 kinase 1 or phosphorylated S6 ribosomal protein and phosphorylated Akt, respectively. Rapamycin inhibited mTORC1 and enhanced mTORC2. IL-4 expression was increased in freshly isolated CD8(+) lupus T cells (SLE: 8.09 ± 1.93%, HC: 3.61 ± 0.49%; p = 0.01). DN T cells had greater IL-4 expression than CD4(+) or CD8(+) T cells of SLE patients after 3-d in vitro stimulation, which was suppressed by rapamycin (control: 9.26 ± 1.48%, rapamycin: 5.03 ± 0.66%; p < 0.001). GATA-3 expression was increased in CD8(+) lupus T cells (p < 0.01) and was insensitive to rapamycin treatment. IFN-? expression was reduced in all lupus T cell subsets (p = 1.0 × 10(-5)) and also resisted rapamycin. IL-17 expression was increased in CD4(+) lupus T cells (SLE: 3.62 ± 0.66%, HC: 2.29 ± 0.27%; p = 0.019), which was suppressed by rapamycin (control: 3.91 ± 0.79%, rapamycin: 2.22 ± 0.60%; p < 0.001). Frequency of regulatory T cells (Tregs) was reduced in SLE (SLE: 1.83 ± 0.25%, HC: 2.97 ± 0.27%; p = 0.0012). Rapamycin inhibited mTORC1 in Tregs and promoted their expansion. Neutralization of IL-17, but not IL-4, also expanded Tregs in SLE and HC subjects. These results indicate that mTORC1 expands IL-4(+) DN T and Th17 cells, and contracts Tregs in SLE.

SUBMITTER: Kato H

PROVIDER: S-EPMC3995867 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8- double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus.

Kato Hiroshi H Perl Andras A

Journal of immunology (Baltimore, Md. : 1950) 20140328 9

The mechanistic target of rapamycin (mTOR) is activated in CD4(-)CD8(-) double-negative (DN) T cells and its blockade is therapeutic in systemic lupus erythematosus (SLE) patients. Murine studies showed the involvement of mTOR complex 1 (mTORC1) and 2 (mTORC2) in the differentiation of Th1/Th17 cells and Th2 cells, respectively. In this study, we investigated the roles of mTORC1 and mTORC2 in T cell lineage development in SLE and matched healthy control (HC) subjects. mTORC1 activity was increas ...[more]

PMID: 24683191

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Project description:The emerging epitranscriptome plays an essential role in autoimmune disease. As a novel mRNA modification, N4-acetylcytidine (ac4C) could promote mRNA stability and translational efficiency. However, whether epigenetic mechanisms of RNA ac4C modification are involved in systemic lupus erythematosus (SLE) remains unclear. Herein, we detected eleven modifications in CD4+ T cells of SLE patients using mass spectrometry (LC-MS/MS). Furthermore, using samples from four CD4+ T cell pools, we identified lower modification of ac4C mRNA in SLE patients as compared to that in healthy controls (HCs). Meanwhile, significantly lower mRNA acetyltransferase NAT10 expression was detected in lupus CD4+ T cells by RT-qPCR. We then illustrated the transcriptome-wide ac4C profile in CD4+ T cells of SLE patients by ac4C-RIP-Seq and found ac4C distribution in mRNA transcripts to be highly conserved and enriched in mRNA coding sequence regions. Using bioinformatics analysis, the 3879 and 4073 ac4C hyper-acetylated and hypoacetylated peaks found in SLE samples, respectively, were found to be significantly involved in SLE-related function enrichments, including multiple metabolic and transcription-related processes, ROS-induced cellular signaling, apoptosis signaling, and NF-κB signaling. Moreover, we demonstrated the ac4C-modified regulatory network of gene biological functions in lupus CD4+ T cells. Notably, we determined that the 26 upregulated genes with hyperacetylation played essential roles in autoimmune diseases and disease-related processes. Additionally, the unique ac4C-related transcripts, including USP18, GPX1, and RGL1, regulate mRNA catabolic processes and translational initiation. Our study identified novel dysregulated ac4C mRNAs associated with critical immune and inflammatory responses, that have translational potential in lupus CD4+ T cells. Hence, our findings reveal transcriptional significance and potential therapeutic targets of mRNA ac4C modifications in SLE pathogenesis.

Project description:Background and objectiveUmbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown immunoregulation of various immune cells. The aim of this study was to investigate the mechanism of UC MSCs in the regulation of peripheral regulatory T cells (Treg) and T helper 17 (Th17) cells in patients with systemic lupus erythematosus (SLE).MethodsThirty patients with active SLE, refractory to conventional therapies, were given UC MSCs infusions. The percentages of peripheral blood CD4+CD25+Foxp3+ regulatory T cells (Treg) and CD3+CD8-IL17A+ Th17 cells and the mean fluorescence intensities (MFI) of Foxp3 and IL-17 were measured at 1 week, 1 month, 3 months, 6 months, and 12 months after MSCs transplantation (MSCT). Serum cytokines, including transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-17A were detected using ELISA. Peripheral blood mononuclear cells from patients were collected and co-cultured with UC MSCs at ratios of 1:1, 10:1, and 50:1, respectively, for 72 h to detect the proportions of Treg and Th17 cells and the MFIs of Foxp3 and IL-17 were determined by flow cytometry. The cytokines in the supernatant solution were detected using ELISA. Inhibitors targeting TGF-β, IL-6, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 were added to the co-culture system, and the percentages of Treg and Th17 cells were observed.ResultsThe percentage of peripheral Treg and Foxp3 MFI increased 1 week, 1 month, and 3 months after UC MSCs transplantation, while the Th17 proportion and MFI of IL-17 decreased 3 months, 6 months, and 12 months after the treatment, along with an increase in serum TGF-β at 1 week, 3 months, and 12 months and a decrease in serum TNF-α beginning at 1 week. There were no alterations in serums IL-6 and IL-17A before or after MSCT. In vitro studies showed that the UC MSCs dose-dependently up-regulated peripheral Treg proportion in SLE patients, which was not depended on cell-cell contact. However, the down-regulation of Th17 cells was not dose-dependently and also not depended on cell-cell contact. Supernatant TGF-β and IL-6 levels significantly increased, TNF-α significantly decreased, but IL-17A had no change after the co-culture. The addition of anti-TGF-β antibody significantly abrogated the up-regulation of Treg, and the addition of PGE2 inhibitor significantly abrogated the down-regulation of Th17 cells. Both anti-IL-6 antibody and IDO inhibitor had no effects on Treg and Th17 cells.ConclusionsUC MSCs up-regulate Treg and down-regulate Th17 cells through the regulation of TGF-β and PGE2 in lupus patients.

Dataset Information

Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8- double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus.

Publications

Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8- double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus.

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