Heterochromatin-dependent gene silencing controls CD4 T cell response to Treg-mediated suppression [ATAC-seq]
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ABSTRACT:
PROVIDER: PRJNA1034955 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26638841_1.fastq.gz | Fastqsanger.gz | |||
| SRR26638841_2.fastq.gz | Fastqsanger.gz |
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Project description:Heterochromatin-dependent gene silencing controls CD4 T cell response to Treg-mediated suppression.
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Project description:The integrity of the organism depends on close and dynamic interactions between conventional and regulatory (Treg) T cells. The extracellular signals and signaling events that regulate this crosstalk have been extensively characterized. However, how conventional T cells translate Treg-dependent immunosuppressive signals at the chromatin level remains largely unknown. In differentiating CD4+ T helper (Th) cells, we and others previously reported that transcriptional specificity is largely controlled by heterochromatin-dependent gene silencing. We therefore hypothesized that Treg-mediated T cell suppression could also involve the repressive mark H3K9me3 and the histone-binding factor heterochromatin protein 1 (HP1). Using a bone marrow allograft model, in which graft rejection is coordinated by adoptively-transferred naive CD4+ T cells and can be inhibited by Treg, we show that Treg-dependent suppressive signals indeed mobilize HP1a to repress Th-cell effector genes. Unexpectedly, our screen also revealed that T cells deficient for HP1g or the lysine methyltransferase SUV39H1 are better tolerized than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identified HP1g as a negative regulator of a network of genes functionally associated with T-cell anergy and exhaustion, including those encoding the transcription factor TOX and the inhibitory receptors PD-1, TIM-3 and LAG-3. In response to T cell receptor engagement, the expression of these immune checkpoints is deregulated in HP1g-deficient cells, thus promoting their better inhibition by Treg. Therefore, we demonstrate that H3K9me3-dependent epigenetic pathways critically regulate Th cell susceptibility to Treg-mediated suppression, and we identify HP1a and HP1g as new epigenetic players whose expression may be manipulated to restore protective immune responses or correct immunopathology, respectively.
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Project description:Heterochromatin-dependent gene silencing controls CD4 T cell response to Treg-mediated suppression [Tmem]
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Project description:The integrity of the organism depends on close and dynamic interactions between conventional and regulatory (Treg) T cells. The extracellular signals and signaling events that regulate this crosstalk have been extensively characterized. However, how conventional T cells translate Treg-dependent immunosuppressive signals at the chromatin level remains largely unknown. In differentiating CD4+ T helper (Th) cells, we and others previously reported that transcriptional specificity is largely controlled by heterochromatin-dependent gene silencing. We therefore hypothesized that Treg-mediated T cell suppression could also involve the repressive mark H3K9me3 and the histone-binding factor heterochromatin protein 1 (HP1). Using a bone marrow allograft model, in which graft rejection is coordinated by adoptively-transferred naive CD4+ T cells and can be inhibited by Treg, we show that Treg-dependent suppressive signals indeed mobilize HP1a to repress Th-cell effector genes. Unexpectedly, our screen also revealed that T cells deficient for HP1g or the lysine methyltransferase SUV39H1 are better tolerized than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identified HP1g as a negative regulator of a network of genes functionally associated with T-cell anergy and exhaustion, including those encoding the transcription factor TOX and the inhibitory receptors PD-1, TIM-3 and LAG-3. In response to T cell receptor engagement, the expression of these immune checkpoints is deregulated in HP1g-deficient cells, thus promoting their better inhibition by Treg. Therefore, we demonstrate that H3K9me3-dependent epigenetic pathways critically regulate Th cell susceptibility to Treg-mediated suppression, and we identify HP1a and HP1g as new epigenetic players whose expression may be manipulated to restore protective immune responses or correct immunopathology, respectively.
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Project description:The integrity of the organism depends on close and dynamic interactions between conventional and regulatory (Treg) T cells. The extracellular signals and signaling events that regulate this crosstalk have been extensively characterized. However, how conventional T cells translate Treg-dependent immunosuppressive signals at the chromatin level remains largely unknown. In differentiating CD4+ T helper (Th) cells, we and others previously reported that transcriptional specificity is largely controlled by heterochromatin-dependent gene silencing. We therefore hypothesized that Treg-mediated T cell suppression could also involve the repressive mark H3K9me3 and the histone-binding factor heterochromatin protein 1 (HP1). Using a bone marrow allograft model, in which graft rejection is coordinated by adoptively-transferred naive CD4+ T cells and can be inhibited by Treg, we show that Treg-dependent suppressive signals indeed mobilize HP1a to repress Th-cell effector genes. Unexpectedly, our screen also revealed that T cells deficient for HP1g or the lysine methyltransferase SUV39H1 are better tolerized than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identified HP1g as a negative regulator of a network of genes functionally associated with T-cell anergy and exhaustion, including those encoding the transcription factor TOX and the inhibitory receptors PD-1, TIM-3 and LAG-3. In response to T cell receptor engagement, the expression of these immune checkpoints is deregulated in HP1g-deficient cells, thus promoting their better inhibition by Treg. Therefore, we demonstrate that H3K9me3-dependent epigenetic pathways critically regulate Th cell susceptibility to Treg-mediated suppression, and we identify HP1a and HP1g as new epigenetic players whose expression may be manipulated to restore protective immune responses or correct immunopathology, respectively.
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Project description:The integrity of the organism depends on close and dynamic interactions between conventional and regulatory (Treg) T cells. The extracellular signals and signaling events that regulate this crosstalk have been extensively characterized. However, how conventional T cells translate Treg-dependent immunosuppressive signals at the chromatin level remains largely unknown. In differentiating CD4+ T helper (Th) cells, we and others previously reported that transcriptional specificity is largely controlled by heterochromatin-dependent gene silencing. We therefore hypothesized that Treg-mediated T cell suppression could also involve the repressive mark H3K9me3 and the histone-binding factor heterochromatin protein 1 (HP1). Using a bone marrow allograft model, in which graft rejection is coordinated by adoptively-transferred naive CD4+ T cells and can be inhibited by Treg, we show that Treg-dependent suppressive signals indeed mobilize HP1a to repress Th-cell effector genes. Unexpectedly, our screen also revealed that T cells deficient for HP1g or the lysine methyltransferase SUV39H1 are better tolerized than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identified HP1g as a negative regulator of a network of genes functionally associated with T-cell anergy and exhaustion, including those encoding the transcription factor TOX and the inhibitory receptors PD-1, TIM-3 and LAG-3. In response to T cell receptor engagement, the expression of these immune checkpoints is deregulated in HP1g-deficient cells, thus promoting their better inhibition by Treg. Therefore, we demonstrate that H3K9me3-dependent epigenetic pathways critically regulate Th cell susceptibility to Treg-mediated suppression, and we identify HP1a and HP1g as new epigenetic players whose expression may be manipulated to restore protective immune responses or correct immunopathology, respectively.
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Project description:Heterochromatin-dependent gene silencing pathways control CD4 T cell susceptibility to regulatory T cell-mediated suppression [RNAnaivetconv]
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Project description:Heterochromatin-dependent gene silencing pathways control CD4 T cell susceptibility to regulatory T cell-mediated suppression [RNAtreg]
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Project description:Foxp3+ regulatory T (Treg) cells prevent inflammatory disease but the mechanistic basis of suppression is not understood completely . Gene silencing by RNA interference can act in a cell-autonomous and non-cell-autonomous manner, providing mechanisms of inter-cellular regulation. Here, we demonstrate that non-cell-autonomous gene silencing, mediated by miRNA-containing exosomes, is a mechanism employed by Treg cells to suppress T cell-mediated disease. Treg cells transferred microRNAs (miRNA) to various immune cells, including T helper 1 (Th1) cells, suppressing Th1 cell proliferation and cytokine secretion. Use of Dicer-deficient or Rab27a and Rab27b double-deficient Treg cells to disrupt miRNA-biogenesis or the exosomal pathway, respectively, established a requirement for miRNAs and exosomes for Treg cell-mediated suppression. Transcriptional analysis and miRNA inhibitor studies showed that exosome-mediated transfer of Let-7d from Treg cell to Th1 cells contributed to suppression and prevention of systemic disease. These studies reveal a mechanism of Treg cell-mediated suppression mediated by miRNA-containing exosomes. Regulatory T cells (CD4+CD25hiFoxp3rfp+, Treg) were isolated from naive mice. RNA as extracted form some Treg cells, while others were cultured in complete IMDM media for 3 days, stimulated with anti-CD3 anti-CD3 (1ug/ml) and anti-CD28 (10ug/ml). Exosomes were recovered from Treg cell supernatant, as described, and RNA was extracted form the purified exosomes. To identify which miRNAs were transferred to Dicer-deficient (KO) cells from Treg cells, we cultured Dicer KO cells alone, or co-cultured Dicer KO cells with Treg cells. RNA was extracted form Dicer KO cells cultured alone or from Dicer KO cells cultured in the presence of Treg cells. 3 x biological replicates were used. Each biological replicate was derived from a pool of 3-5 samples.
2014-08-27 | E-GEOD-60615 | biostudies-arrayexpress
Project description:In this screen we compared cDNA from rTreg (AICD resistent TReg cells) against cDNA derived from all CD4+CD25hi Treg for further molecular characterization of rTreg Experiment Overall Design: Single comparison of rTReg vs. TReg. We pooled rTreg-cDNA derived from FACS-sorted CD4+CD25hi Treg of eight healthy blood donors and performed gene chip microarray analysis.
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