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Impact of Acute methionine restriction on proteome of Th1 cells - Part 2

ABSTRACT: CD4 T cells were activated using CD3/CD28 antibodies in the presence of IL2 and IL12, to generate Th1 cells. Th1 cells were maintained and expanded in IL2 and IL12, on D5 Th1 cells were sorted for CD4+ expression and DAP1 exclusion. After flow sorting, live TH1 cells were resuspended (1e6 per ml) in methionine free RPMI, supplemented with 10% dialysed FBS, IL2 and IL12, and with L-methionine (100μM, or 1μM). Cells were cultured for 5 hrs before collection for proteomics processing.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): T Cell, Lymph Node

SUBMITTER: Andrew Howden

LAB HEAD: Professor Doreen Cantrell

PROVIDER: PXD012053 | Pride | 2019-03-29

REPOSITORIES: Pride

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	PT9102-11.raw	Raw
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	PT9102-3-2.raw	Raw
	PT9102-4.raw	Raw
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Publications

Antigen receptor control of methionine metabolism in T cells.

Sinclair Linda V LV Howden Andrew Jm AJ Brenes Alejandro A Spinelli Laura L Hukelmann Jens L JL Macintyre Andrew N AN Liu Xiaojing X Thomson Sarah S Taylor Peter M PM Rathmell Jeffrey C JC Locasale Jason W JW Lamond Angus I AI Cantrell Doreen A DA

eLife 20190327

Immune activated T lymphocytes modulate the activity of key metabolic pathways to support the transcriptional reprograming and reshaping of cell proteomes that permits effector T cell differentiation. The present study uses high resolution mass spectrometry and metabolic labelling to explore how murine T cells control the methionine cycle to produce methyl donors for protein and nucleotide methylations. We show that antigen receptor engagement controls flux through the methionine cycle and RNA a ...[more]

PMID: 30916644

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P2X7 signaling drives Th1 cell differentiation through metabolic reprogramming for aerobic glycolysis

Project description:This study provides evidence on the molecular mechanisms by which P2RX7 signaling promotes Th1 cell differentiation. P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-polarized CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, ATP synthase blockade in vitro and the consequent inhibition of oxidative phosphorylation, which forces cells to use aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 cell differentiation and suggest that ATP synthase inhibition is a fundamental mechanism by which P2X7 signaling induces the Th1 response.

2023-03-08 | PXD037754 | Pride

miR-182 and miR-10a are Key Regulators of Treg specialisation and stability during Th2 and Th1-associated Inflammation

Project description:A variety of CD4+Foxp3+ Treg cell types have been described previously, indicating molecular heterogeneity within the Foxp3+ pool of CD4+ T cells. However, the factors that shape the transcriptomic identities of different Foxp3+ Treg cells are poorly understood. To identify the molecular pathways involved, we isolated CD4+Foxp3gfp+ cells from Th1-rich or Th2-rich environments following chronic Leishmania major or Schistosoma mansoni infection, respectively. Whole genome expression profiling and next generation small RNA sequencing revealed significantly different mRNA and miRNA profiles. In-silico analyses identified miR-10a and miR-182 as âregulatory miRNA hubsâ in CD4+Foxp3+ cells in Th1 and Th2-environments, respectively. Using in vitro and in vivo systems we identified that IL-12/IFNg down-regulated miR-10a and its putative transcription factor, Creb. Importantly, we demonstrated that miR-10a controls a suite of genes that regulate IFNg production in Th1-Treg cells. Also, Treg cells treated with IL-4 increased miR-182 and its putative transcription factor, cMaf. Up-regulation of miR-182 mitigated IL-2 secretion, in part through repression of IL2-promoting genes, including Bach2 and Cd2ap. This study indicates that CD4+Foxp3+ cells are influenced by their environment, and that Th1 or Th2 environments promote distinct miRNA pathways, preserving Treg stability and suppressor function. mouse infection vs. naÃ¯ve

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Project Title: Proteome analysis of CD4+ T cell subsets

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TGFb dependent Treg conversion and the inhibition of conversion by IL6

Project description:Analysis of CD4+ cells activated with anti-CD3 and cultured in the presence of IL2. The effects of TGFb and IL6 on Treg conversion were analyzed to discover methods of inhibiting Treg conversion and/or Treg functional inhibition. CD4+ T-cells were enriched from lymph nodes of Foxp3-GFP mice and cultured under the under the following conditions: 1) anti-CD3+IL2; 2) anti-CD3+IL2+TGFÎ²; 3) anti-CD3+IL2+TGFÎ²+IL6; and 4) anti-CD3+IL2+IL6. On day 4 cells were collected, stained with anti-CD4-PE, and sorted into CD4+FOXP3- and CD4+FOXP3+ populations (>95% purity). For each treatment condition T-effector cells and Tregs were labeled independently (either cy3 or cy5) and hybridized together for a two-color array experiment. Each treatment condition had dye swapped replicates, and a minimum of 3 replicate in total. Two color experiment. Four conditions : 1) anti-CD3+IL2, 3 samples 2) anti-CD3+IL2+TGFÎ², 3 samples 3) anti-CD3+IL2+TGFÎ²+IL6, 4 samples 4) anti-CD3+IL2+IL6, 3 samples

2010-04-07 | E-GEOD-21027 | biostudies-arrayexpress

RNA-seq of Th1 and Th2 differentiated T helper cells re-stimulated with pma/ionomycin after 7 days of differentiation.

Project description:Naive CD4 T helper cells were isolated using magnetic negative selection kit from 4 weeks old Balb\c mice. The cells were activated with anti CD3/CD28 antibodies in the presence of Th1 th2 skewing cytokines and antibodies. The cells were disconnected for resting conditions after 48hours and further proliferated for 7 days in the presence of IL2 and skewing cytokines. In the 7th day the cells were collected and re-stimulated for 1hr using PMA/ionomycin and RNA was extracted for transcriptomics.

2022-03-31 | E-MTAB-9908 | biostudies-arrayexpress

miR-182 and miR-10a are Key Regulators of Treg specialisation and stability during Th2 and Th1-associated Inflammation

Project description:A variety of CD4+Foxp3+ Treg cell types have been described previously, indicating molecular heterogeneity within the Foxp3+ pool of CD4+ T cells. However, the factors that shape the transcriptomic identities of different Foxp3+ Treg cells are poorly understood. To identify the molecular pathways involved, we isolated CD4+Foxp3gfp+ cells from Th1-rich or Th2-rich environments following chronic Leishmania major or Schistosoma mansoni infection, respectively. Whole genome expression profiling and next generation small RNA sequencing revealed significantly different mRNA and miRNA profiles. In-silico analyses identified miR-10a and miR-182 as ‘regulatory miRNA hubs’ in CD4+Foxp3+ cells in Th1 and Th2-environments, respectively. Using in vitro and in vivo systems we identified that IL-12/IFNg down-regulated miR-10a and its putative transcription factor, Creb. Importantly, we demonstrated that miR-10a controls a suite of genes that regulate IFNg production in Th1-Treg cells. Also, Treg cells treated with IL-4 increased miR-182 and its putative transcription factor, cMaf. Up-regulation of miR-182 mitigated IL-2 secretion, in part through repression of IL2-promoting genes, including Bach2 and Cd2ap. This study indicates that CD4+Foxp3+ cells are influenced by their environment, and that Th1 or Th2 environments promote distinct miRNA pathways, preserving Treg stability and suppressor function.

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Cytokine receptor modulation by interleukin-2 broadly regulates T helper cell lineage differentiation

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