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Pannexin-1 channels promotes CD8+ T cell effector and memory responses through distinct metabolic pathways.

ABSTRACT: Sensing of extracellular metabolites controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Here, we report that T cell-specific Panx1 is needed for efficient CD8+ T cell responses to viral infection and cancer. Panx1 favors both the expansion of effector CD8+ T cells and the survival of memory CD8+ T cells. Our data suggests that, while memory CD8+ T cells require Panx1 for mitochondrial function, Panx1 promotes the glycolytic pathway in effector CD8+ T cells. Panx1 promotes memory CD8+ T cell survival together with the eATP sensor P2RX7. However, Panx1 induces effector CD8+ T cells independently of eATP. Rather, we found an unexpected link between Panx1, sodium lactate export and the activation of effector CD8+ T cells. Therefore, Panx1 regulates effector and memory CD8+ T cells through export of distinct metabolites and by engaging different intracellular pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE218643 | GEO | 2023/08/02

REPOSITORIES: GEO

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Pannexin-1 channels promotes CD8+ T cell effector and memory responses through distinct metabolic pathways

Project description:Sensing of extracellular metabolites controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Here, we report that T cell-specific Panx1 is needed for efficient CD8+ T cell responses to viral infection and cancer. Panx1 favors both the expansion of effector CD8+ T cells and the survival of memory CD8+ T cells. Our data suggests that, while memory CD8+ T cells require Panx1 for mitochondrial function, Panx1 promotes the glycolytic pathway in effector CD8+ T cells. Panx1 promotes memory CD8+ T cell survival together with the eATP sensor P2RX7. However, Panx1 induces effector CD8+ T cells independently of eATP. Rather, we found an unexpected link between Panx1, sodium lactate export and the activation of effector CD8+ T cells. Therefore, Panx1 regulates effector and memory CD8+ T cells through export of distinct metabolites and by engaging different intracellular pathways.

2023-08-02 | GSE217292 | GEO

Expression data of ex vivo purified CD4+ cells from WT and P2rx7-/- mice

Project description:Extracellular adenosine triphosphate (eATP) is a signaling molecule that affects T cell function via the ionotropic P2X7 receptor. The study of effector/memory T cells isolated from mice with deletion of P2rx7, the gene encoding for P2X7, allowed understanding the impact of P2X7 activity on T cell function in the eATP-rich tumor microenvironment. To explore the the transcriptional impact of the lack of P2rx7 in CD4+ naïve and TEM cells, we performed genome-wide expression profiling of ex vivo purified CD4+ naïve and TEM cells from WT and P2rx7-/- mice

2020-07-24 | GSE118146 | GEO

RNAseq analysis in TNF treated HUVEC cells compared to controls

Project description:TNF is known to promote opening of the endothelial pannexin 1 (Panx1) membrane channel, allowing for ATP release, associated with inflammatory cell recruitment. However, there is evidence that Panx1 may be involved in the regulation of cellular inflammatory responses independent of direct ATP signalling, although the pathways have not been elucidated. We therefore examined Panx1 for roles in the control of cytokine release in human endothelial cells following treatment with TNF.

2020-03-27 | E-MTAB-8299 | biostudies-arrayexpress

Apoptotic cells actively release metabolite messanger with anti-inflammatory properties

Project description:Apoptosis accounts for ~ 90% of homeostatic cell turnover in the body1. While caspase-dependent apoptosis is known to influence immune tolerance, induction of cell proliferation, and tissue regeneration2-4, how these apoptotic cells contribute to such diverse effects is less understood. Soluble factors released from apoptotic cells could be a means of ‘talking’ to healthy cells in the tissue neighborhood. While a few phagocyte-attracting ‘find-me’ signals released from apoptotic cells are known5, the larger ‘metabolite secretome’ from apoptotic cells is not yet defined. Here, via unbiased profiling of the apoptotic cell secretome, we identified 123 metabolites that are specifically released during apoptosis, while cells still retain membrane integrity. Release of ~25 of these metabolites is dependent on Pannexin 1 (Panx1) channels, which are opened by caspase-dependent cleavage during apoptosis. Interestingly, one of the Panx1-dependent metabolites from apoptotic cells is spermidine, a polyamine whose release could be, in part, due to the continued metabolic activity of dying cells. RNAseq analysis of healthy cells exposed to the apoptotic secretome revealed Panx1-dependent gene programs, including genes linked to suppression of inflammation, cell proliferation, and wound healing. Analysis of the apoptotic secretome across cell types and different apoptotic stimuli, identified a core “set” of 8 Panx1-dependent metabolites. Strikingly, a selected cocktail of these metabolites demonstrated significant immunosuppressive effects by potently reducing disease severity in an inflammatory arthritis model and a lung graft rejection model. Collectively, these data advance the concept that apoptotic cells are not ‘inert’ corpses waiting for removal by phagocytes, but rather they actively communicate with the tissue environment through their metabolite secretome, with implications in tissue inflammation.

2020-03-19 | GSE131906 | GEO

Acetylation level of Pannexin 1 lysine residues following alpha 1 adrenoceptor activation

Project description:Pannexin 1 (Panx1) channels can be activated by alpha 1 adrenoceptor-induced pathways for the sympathetic regulation of blood pressure; however, the molecular mechanisms for this form of Panx1 channel activation remain elusive. To identify potential acetyl-lysine residue(s) of Panx1 channels that might be involved in this receptor-mediated Panx1 channel activation, we performed mass-spectrometry on Strep-tagged Panx1 proteins precipitated from the whole cell lysate of HEK293T cells after stable isotope labeling by amino acids in cell culture (SILAC). Those HEK293T cells were transiently transfected with alpha1D adrenoceptors and human Panx1-Strep, with or without phenylephrine stimulation. Equal amounts of light-labeled (control) and heavy-labeled (phenylephrine stimulated) cell lysates were pooled, and Panx1 proteins were precipitated by Strep-Tactin beads, followed by LC-MS-MS analysis. From three biological replicates, we identified a consistent, albeit modest, reduction of acetylation level at K140, following phenylephrine stimulation. Whereas the acetylation level of other lysine residues (K321, K374, K381, K409) were variable among three replicates or were unaffected by phenylephrine treatment. These results implicate Panx1 K140 as a potential regulatory site for receptor-mediated channel activation via an acetylation-deacetylation mechanism.

2021-07-16 | PXD025912 | Pride

T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections

Project description:CD4+ T cells are key components of the immune response during lung infections and can mediate protection against tuberculosis (TB) or influenza. However, CD4+ T cells can also promote lung pathology during these infections, making it unclear how these cells control such discrepant effects. Using mouse models of hypervirulent TB and influenza, we observed that exaggerated accumulation of parenchymal CD4+ T cells promotes lung damage. Low numbers of lung CD4+ T cells, in contrast, are sufficient to protect against hypervirulent TB. In both situations, lung CD4+ T cell accumulation is mediated by CD4+ T cell-specific expression of the extracellular ATP (eATP) receptor P2RX7. P2RX7 upregulation in lung CD4+ T cells promotes expression of the chemokine receptor CXCR3 and favors in situ proliferation. Our findings suggest that direct sensing of lung eATP by CD4+ T cells is critical to induce tissue CD4+ T cell accumulation and pathology during lung infections.

2024-02-14 | GSE244194 | GEO

Expression of miRNAs in human ex-vivo CD8+ T cell subsets

Project description:The aim was to assess miRNA expression in 3 human ex-vivo CD8+ T cell subsets which span from antigen inexperienced cells (NaM-CM-/ve) to early memory cells (central memory, Tcm) and later stage memory cells (effector memory, Tem) CD8+ T cells were sorted on a FACS Aria II machine. N = naM-CM-/ve = CD8+, CCR7+, CD45RA+, CD45RO-, Tcm = central memory = CD8+, CCR7+, CD45RA-, CD45RO-,Tem= effector memory = CD8+, CCR7-, CD45RA-, CD45RO+ PBMC were isolated from 3 healthy human donors and sorted by FACS into 3 CD8+ T cell subsets. Total RNA was purified using the miRVANA kit (Ambion)

2014-10-24 | E-GEOD-54867 | biostudies-arrayexpress

De novo DNA methylation by DNA Methyltransferase 3a controls early effector CD8+ T cell fate decisions following activation

Project description:DNMT3a is a de novo DNA methyltransferase expressed robustly after T cell activation that regulates plasticity of CD4+ T cell cytokine expression. Here we show that DNMT3a is critical for directing early CD8+ T cell effector and memory fate decisions. While effector function of DNMT3a knockout T cells is normal, they develop more memory precursor and fewer terminal effector cells in a T cell intrinsic manner compared to wild-type animals. Rather than increasing plasticity of differentiated effector CD8+ T cells, loss of DNMT3a biases differentiation of early effector cells into memory precursor cells. This is attributed in part to ineffective repression of Tcf1 expression in knockout T cells, as DNMT3a localizes to the Tcf7 promoter and catalyzes its de novo methylation in early effector WT CD8+ T cells. This data identifies DNMT3a as a crucial regulator of CD8+ early effector cell differentiation and effector versus memory fate decisions. Examination of global genomic DNA methylation by MBD-seq in naÃ¯ve CD8 T cells and CD8 T cells 8 days post Vaccinia-Ova infection, comparing OT1 TCR-Tg CD8 T cells isolated from WT and T cell conditional DNMT3a KO mice.

2016-08-20 | E-GEOD-85823 | biostudies-arrayexpress

Rapid proliferation and differentiation impairs the development of memory CD8+ T cells in early life

Project description:Neonates often generate incomplete immunity against intracellular pathogens, although the mechanism of this defect is poorly understood. An important question is whether the impaired development of memory CD8+ T cells in neonates is due to an immature priming environment or lymphocyte-intrinsic defects. Here we show that neonatal and adult CD8+ T cells adopted different fates when responding to equal amounts of stimulation in the same host. While adult CD8+ T cells differentiated into a heterogeneous pool of effector and memory cells, neonatal CD8+ T cells preferentially gave rise to short-lived effector cells and exhibited a distinct gene expression profile. Surprisingly, impaired neonatal memory formation was not due to a lack of responsiveness, but instead because neonatal CD8+ T cells expanded more rapidly than adult cells and quickly became terminally differentiated. Collectively, these findings demonstrate that neonatal CD8+ T cells exhibit an imbalance in effector and memory CD8+ T cell differentiation, which impairs the formation of memory CD8+ T cells in early life mRNA profiles of effector CD8+ T cells from neonatal and adult mice

2014-05-13 | E-GEOD-56575 | biostudies-arrayexpress

Gene-expression profile of Id2+ versus Id2KO KLRG1lo cells during infection

Project description:CD8+ T cells play a crucial role in the clearance of intracellular pathogens through the generation of cytotoxic effector cells that eliminate infected cells and long-lived memory cells that provide enhanced protection against reinfection. We have previously shown that the inhibitor of E protein transcription factors, Id2, is necessary for accumulation of effector and memory CD8+ T cells during infection. Here we show that CD8+ T cells lacking Id2 did not generate a robust terminally-differentiated KLRG1hi effector population, but displayed a cell-surface phenotype and cytokine profile consistent with memory precursors, raising the question as to whether loss of Id2 impairs the differentiation and/or survival of effector-memory cells. We found that deletion of Bim rescued Id2-deficient CD8+ cell survival during infection. However, the dramatic reduction in KLRG1hi cells caused by loss of Id2 remained in the absence of Bim, such that Id2/Bim double-deficient cells form an exclusively KLRG1loCD127hi memory precursor population. Thus we describe a role for Id2 in both the survival and differentation of normal CD8+ effector and memory populations. Gene-expression analysis of Wild-type, Id2KO, Id2KOBimKO and BimKO effector CD8+ cells on day 6 of Listeria infection. 2 or more replicates per sample were analyzed.

2013-03-07 | E-GEOD-41978 | biostudies-arrayexpress

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