Hobit- and Blimp-1-driven CD4+ P2X7+ tissue resident memory T cells critically control chronic intestinal inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA506785 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8240421.fastq.gz | Fastqsanger.gz | |||
| SRR8240422.fastq.gz | Fastqsanger.gz | |||
| SRR8240424.fastq.gz | Fastqsanger.gz | |||
| SRR8240419.fastq.gz | Fastqsanger.gz |
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Project description:Although tissue resident memory T (TRM) cells have been shown to regulate host protection in infectious disorders, their functional role in inflammatory bowel diseases (IBD) remains to be investigated. Here, we characterized TRM cells in human IBD and addressed their role in experimental models of intestinal inflammation with mice deficient for TRM-associated transcription factors and by TRM depletion. We show that pro-inflammatory TRM cells are increased in active IBD. Moreover, the presence of CD4+ but not CD8+ TRM cells in IBD patients predicts subsequent development of flares. In vivo, mice deficient in Hobit and Blimp-1 are protected from several models of colitis due to decreased pro-inflammatory cytokine secretion, impaired cytotoxicity and leukocyte chemotaxis. Finally, P2X7-induced TRM depletion via NAD enema leads to suppression of colitis activity. Taken together, our data argue for a central role of TRM cells in the pathogenesis of IBD and suggest that these cells are an interesting target for future therapeutic approaches.
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Project description:Blimp-1 regulates the overall accumulation of virus-specific CD8+ T cells during acute viral infections. Increased proliferation and survival of Blimp-1-deficient CD8+ T cells is promoted by persistent cytokine responsiveness, resulting from sustained expression of CD25 and CD27. Knockdown of these genes reduced the Blimp-1-deficient CD8+ T cell response. Genome-wide ChIP-sequencing analysis identified CD25 and CD27 genes as direct targets of Blimp-1. At the peak of the anti-viral response, but not earlier, Blimp-1 recruited the histone modifying enzymes G9a and HDAC2 to the Il2ra and Cd27 loci, thereby repressing expression of these genes. In the absence of Blimp-1, the Il2ra and Cd27 genes exhibited enhanced histone H3-acetylation and reduced histone H3K9-trimethylation. These data elucidate a central mechanism by which Blimp-1 acts as an epigenetic regulator, enhancing the numbers of short-lived effector cells while suppressing the development of memory precursor CD8+ T cells. NaM-CM-/ve CD8+ T cells from OT-I TCR transgenic Rag1-/- mice were stimulated with anti-CD3 and anti-CD28 for three days in vitro, in the presence of IL-2 to up-regulate Blimp-1 protein. Genome-wide mapping of Blimp-1 binding in mouse CD8+ T cells was conducted.
2013-10-10 | E-GEOD-48358 | biostudies-arrayexpress
Project description:The P2X7 ion channel, a key sensor of sterile inflammation, has been implicated as a therapeutic target in glomerulonephritis and P2X7-antagonistic nanobodies can attenuate experimental glomerulonephritis. However, little is known about the expression of P2X7 on renal immune cells. We used i.p. injection of nanobodies in mice followed by flow cytometry analysis of parenchymal T cells and RNA-sequencing to elucidate the expression and function of P2X7 on parenchymal and vascular immune cells in the mouse kidney. We show that parenchymal T cells, including a large subset NKT cells and tissue-resident memory T cells, display much higher cell surface levels of P2X7 than vascular T cells. These parenchymal T cells are highly sensitive to NAD+-induced cell death unless injection of P2X7-antagonistic nanobodies was performed before cell preparation. Remarkably, within 30 min after a single intraperitoneal injection of P2X7-blocking nanobodies, P2X7 is fully occupied by the injected nanobodies on parenchymal T cells in the kidney. This results in an effective protection of these cells from NAD+-induced cell death. Conversely, systemic injection of NAD+ that mimics sterile inflammation results in the selective depletion of P2X7hiCD69hi T cells from the kidney parenchyma. In summary, our study uncovers a novel purinergic regulatory mechanism affecting kidney resident T cell populations.
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Project description:Bone marrow (BM) has been put forward as a major reservoir for memory CD8+ T cells. In order to fulfill that function, BM should "store" memory CD8+ T cells, which in biological terms would require these "stored" memory cells to be in disequilibrium with the circulatory pool. This issue is a matter of ongoing debate. Here, we unequivocally demonstrate that murine and human BM harbors a population of tissue-resident memory CD8+ T (TRM ) cells. These cells develop against various pathogens, independently of BM infection or local antigen recognition. BM CD8+ TRM cells share a transcriptional program with resident lymphoid cells in other tissues; they are poly-functional cytokine producers and dependent on IL-15, Blimp-1 and Hobit. CD8+ TRM cells reside in the BM parenchyma, but are in close contact with the circulation. Moreover, this pool of resident T cells is not size-restricted and expands upon peripheral antigenic re-challenge. This works extends the role of the BM in the maintenance of CD8+ T cell memory to include the preservation of an expandable reservoir of functional, non-recirculating memory CD8+ T cells, which develop in response to a large variety of peripheral antigens. This article is protected by copyright. All rights reserved.
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Project description:Blimp-1 regulates the overall accumulation of virus-specific CD8+ T cells during acute viral infections. Increased proliferation and survival of Blimp-1-deficient CD8+ T cells is promoted by persistent cytokine responsiveness, resulting from sustained expression of CD25 and CD27. Knockdown of these genes reduced the Blimp-1-deficient CD8+ T cell response. Genome-wide ChIP-sequencing analysis identified CD25 and CD27 genes as direct targets of Blimp-1. At the peak of the anti-viral response, but not earlier, Blimp-1 recruited the histone modifying enzymes G9a and HDAC2 to the Il2ra and Cd27 loci, thereby repressing expression of these genes. In the absence of Blimp-1, the Il2ra and Cd27 genes exhibited enhanced histone H3-acetylation and reduced histone H3K9-trimethylation. These data elucidate a central mechanism by which Blimp-1 acts as an epigenetic regulator, enhancing the numbers of short-lived effector cells while suppressing the development of memory precursor CD8+ T cells.
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Project description:Inflammasome activation in adipose tissue has been implicated in obesity-associated insulin resistance and type 2 diabetes. However, when and how inflammasome is activated in adipose tissue remains speculative. Here we test the hypothesis that extracellular ATP, a potent stimulus of inflammasome in macrophages via purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7), may play a role in inflammasome activation in adipose tissue in obesity. Our data show that inflammasome is activated in adipose tissue upon 8-week feeding of 60% HFD, coinciding with the onset of hyperglycemia and hyperinsulinemia as well as the induction of P2X7 in adipose tissue. Unexpectedly, P2X7-deficient animals on HFD exhibit no changes in metabolic phenotypes, nor in inflammatory responses or inflammasome activation when compared to the wildtype controls. Similar observations have been obtained in hematopoietic cell-specific P2X7-deficient animals generated by bone marrow transplantation. Thus, we conclude that inflammasome activation in adipose tissue in obesity coincides with the onset of hyperglycemia and hyperinsulinemia, but unexpectedly, is not mediated by the ATP-P2X7 signaling axis. The nature of the inflammasome-activating danger signal(s) in adipose tissue in obesity remains to be characterized. Wild type and P2X7 knockout mice were fed a low fat diet (chow) or high fat diet for 12 weeks. After the diet intervention period, the animals were killed and epididymal white adipose tissue was removed. Total RNA was isolated and subjected to gene expression profiling.
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