IL-7-dependent STAT1 activation limits homeostatic CD4+ T cell expansion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA417271 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6260890_1.fastq.gz | Fastqsanger.gz | |||
| SRR6260890_2.fastq.gz | Fastqsanger.gz | |||
| SRR6260900_1.fastq.gz | Fastqsanger.gz | |||
| SRR6260900_2.fastq.gz | Fastqsanger.gz | |||
| SRR6260910_1.fastq.gz | Fastqsanger.gz |
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Project description:IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that, under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in an IL-7-dependent STAT1 and STAT5 activation. Consequently, the IL-7-induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs). Moreover, STAT1 overexpression was associated with reduced survival in CD4+ T cells undergoing lymphopenia-induced proliferation (LIP). We propose a model in which T cells undergoing LIP upregulate STAT1 protein, "switching on" an alternate IL-7-dependent program. This mechanism could be a physiological process to regulate the expansion and size of the CD4+ T cell pool. During HIV infection, the virus could exploit this pathway, leading to the homeostatic dysregulation of the T cell pools observed in these patients.
2018-01-01 | GSE106575 | GEO
Project description:IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that, under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in an IL-7-dependent STAT1 and STAT5 activation. Consequently, the IL-7-induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs). Moreover, STAT1 overexpression was associated with reduced survival in CD4+ T cells undergoing lymphopenia-induced proliferation (LIP). We propose a model in which T cells undergoing LIP upregulate STAT1 protein, "switching on" an alternate IL-7-dependent program. This mechanism could be a physiological process to regulate the expansion and size of the CD4+ T cell pool. During HIV infection, the virus could exploit this pathway, leading to the homeostatic dysregulation of the T cell pools observed in these patients.
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Project description:SerpinB1 is an endogenous inhibitor of serine proteases recognized for its anti-inflammatory and host-protective properties. Although loss of serpinB1 in mice does not result in gross immune deregulation, serpinb1a(-/-) mice display increased mortality and inflammation-associated morbidity upon challenge with influenza virus. Here, we show that IL-17A(+) ?? and CD4(+) Th17 cells are already expanded in the lungs of serpinb1a(-/-) mice at steady-state. Both ?? and ??(+) CD4(+) CCR6(+) T cells isolated from the lungs of naive serpinb1a(-/-) mice displayed a skewed transcriptional profile relative to WT cells, including increased Th17 signature transcripts [Il17a, l17f, and Rorc (ROR?t)] and decreased Th1 signature transcripts [Ifng, Cxcr3, and Tbx21 (T-bet)] in ?? T cells. In addition to the lung, IL-17A(+) ?? and CD4(+) Th17 cells were increased in the spleen of naive serpinb1a(-/-) mice, despite normal ?? and ?? T cell development in the thymus. Within the ?? T cell compartment, loss of serpinb1a prompted selective expansion of V?4(+) and V?6/V?1(+) cells, which also displayed elevated expression of the proliferating cell nuclear antigen, Ki-67, and IL-17A. Given that serpinb1a is preferentially expressed in WT IL-17A(+) ?? and CD4(+) Th17 cell subsets vis-à-vis other T cell lineages, our findings reveal a novel function of serpinB1 in limiting untoward expansion of lymphocytes with a Th17 phenotype.
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Project description:Homeostatic proliferation, driven by cytokines including IL-7, maintains stable T cell populations over time and expands these during lymphopenia, for example following stem cell transplantation. Yet, impaired T cell expansion in this context is associated with diminished immune protection, whilst excessive proliferation contributes to graft versus host disease. This highlights the need to understand molecular mechanisms regulating this process. Here, we studied the metabolic basis for IL-7-driven CD4+ T cell proliferation. We observed that IL-7 promotes glucose uptake and metabolism, including usage for nucleotide synthesis and oxidation in the tricarboxylic acid (TCA) cycle. Of note, contrary to other TCA metabolites, glucose-derived citrate does not accumulate in IL-7 treated cells, indicating diversion into other processes. In agreement, IL-7 promotes glucose-dependent histone acetylation and chromatin accessibility during proliferation. This is particularly notable at gene loci of the amino acid-sensing Ragulator complex. Consistently, expression of its subunit LAMTOR5 is promoted by IL-7 in a glucose-dependent manner. Functionally, glucose availability determined amino acid-dependent mTOR activation in CD4+ T cells, confirming integrated sensing of these nutrients. LAMTOR5 deletion impaired IL-7-mediated CD4+ T cell expansion, establishing that glycolysis in absence of Ragulator activation was insufficient to initiate this process. Clinically, CD4+ T cells isolated from patients following myeloablative autologous stem cell transplantation demonstrate coordinated upregulation of genes encoding glycolytic and TCA cycle enzymes, as well as amino acid sensing machinery and mTOR targets. Our findings uncover integrated sensing of glucose and amino acid metabolism and demonstrate its relevance during homeostatic T cell proliferation.
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Project description:Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but the downstream mechanisms remain unclear and in particular little is known about the role of STAT1 in regulating hematopoietic stem/progenitor cells during homeostasis. Here we show that loss of STAT1 alters the steady state hematopoietic stem and progenitor (HSPC) landscape, impairs HSC function in transplantation assays and delays blood cell regeneration following myeloablation. Under steady state conditions STAT1 was essential for several HSC transcriptional programs including expression of genes involved in virus life cycle, a subset of interferon-stimulated genes, MHC class I genes and genes involved in cell cycle arrest. In addition Stat-1 deficient mice lacked a previously unrecognized quiescent subset of homeostatic HSCs with high levels of MHC II expression (MHC IIhi HSCs). This subset was refractory to 5’-FU induced myeloablation and displayed reduced megakaryocytic potential. Mutant calreticulin, which causes increased megakaryopoiesis in human myeloproliferative neoplasms, gave rise to preferential expansion of MHC IIlo HSCs. These data reveal a STAT1 dependent MHC IIhi quiescent HSC subset and show that STAT1 protects HSCs from proliferative exhaustion.
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Project description:Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but the downstream mechanisms remain unclear and in particular little is known about the role of STAT1 in regulating hematopoietic stem/progenitor cells during homeostasis. Here we show that loss of STAT1 alters the steady state hematopoietic stem and progenitor (HSPC) landscape, impairs HSC function in transplantation assays and delays blood cell regeneration following myeloablation. Under steady state conditions STAT1 was essential for several HSC transcriptional programs including expression of genes involved in virus life cycle, a subset of interferon-stimulated genes, MHC class I genes and genes involved in cell cycle arrest. In addition Stat-1 deficient mice lacked a previously unrecognized quiescent subset of homeostatic HSCs with high levels of MHC II expression (MHC IIhi HSCs). This subset was refractory to 5’-FU induced myeloablation and displayed reduced megakaryocytic potential. Mutant calreticulin, which causes increased megakaryopoiesis in human myeloproliferative neoplasms, gave rise to preferential expansion of MHC IIlo HSCs. These data reveal a STAT1 dependent MHC IIhi quiescent HSC subset and show that STAT1 protects HSCs from proliferative exhaustion.
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