Cell reports最新文献

Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis. The effect of TEPP-46 is abolished in PKM2-deficient macrophages. Extracellular ATP is converted into adenosine by ectonucleotidases that activate adenosine receptor A2a (A2aR) to enhance IL-10 production. Interestingly, IL-10 production induced by PKM2 activation is associated with improved mitochondrial health. Our results identify adenosine derived from glycolytic ATP as a driver of IL-10 production, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production.

Cortical neurons in brain slices display intrinsic spike frequency adaptation (I-SFA) to constant current inputs, while extracellular recordings show extrinsic SFA (E-SFA) during sustained visual stimulation. Inferring how I-SFA contributes to E-SFA during behavior is challenging due to the isolated nature of slice recordings. To address this, we recorded macaque lateral prefrontal cortex (LPFC) neurons in vivo during a visually guided saccade task and in vitro in brain slices. Broad-spiking (BS) putative pyramidal cells and narrow-spiking (NS) putative inhibitory interneurons exhibit both E-SFA and I-SFA. Developing a data-driven hybrid circuit model comprising NS model neurons receiving BS input reveals that NS model neurons exhibit longer SFA than observed in vivo; however, adding feedforward inhibition corrects this in a manner dependent on I-SFA. Identification of this circuit motif shaping E-SFA in LPFC highlights the roles of both intrinsic and network mechanisms in neural activity underlying behavior.

Neurogenic microRNAs 9/9^∗ and 124 (miR-9/9^∗-124) drive the direct reprogramming of human fibroblasts into neurons with the initiation of the fate erasure of fibroblasts. However, whether the miR-9/9^∗-124 fate erasure logic extends to the neuronal conversion of other somatic cell types remains unknown. Here, we uncover that miR-9/9^∗-124 induces neuronal conversion of multiple cell types: dura fibroblasts, astrocytes, smooth muscle cells, and pericytes. We reveal the cell-type-specific and pan-somatic gene network erasure induced by miR-9/9^∗-124, including cell cycle, morphology, and proteostasis gene networks. Leveraging these pan-somatic gene networks, we predict upstream regulators that may antagonize somatic fate erasure. Among the predicted regulators, we identify TP53 (p53), whose inhibition is sufficient to enhance neuronal conversion even in post-mitotic cells. This study extends miR-9/9^∗-124 reprogramming to alternate somatic cells, reveals the pan-somatic gene network fate erasure logic of miR-9/9^∗-124, and shows a neurogenic role for p53 inhibition in the miR-9/9^∗-124 signaling cascade.

CD8⁺ T cell exhaustion (Tex) has been widely acknowledged in human cancer, while the underlying mechanisms remain unclear. Here, we demonstrate that reduced amino acid (aa) metabolism and mTOR inactivation are accountable for Tex in human non-small cell lung cancer (NSCLC). NSCLC cells impede the T cell-intrinsic transcription of SLC7A5 and SLC38A1, disrupting aa transport and consequently leading to mTOR inactivation. Further, the ubiquitination of YAP1 protein is the basis for NSCLC-mediated transcriptional inhibition of aa transporters. Mechanistically, NSCLC cells transfer β-TrCP-containing exosomes into T cells, inducing YAP1 ubiquitination and Tex. Consequently, inhibiting cancer-associated β-TrCP effectively restores the anti-tumor immune response of CD8⁺ T cells and curtails tumor growth in NSCLC patient-derived organoids. Together, our findings highlight a β-TrCP-dependent mechanism in steering intrinsic metabolic adaptation and CD8⁺ Tex, emphasizing microenvironmental β-TrCP as an immune checkpoint for therapeutic exploration against human NSCLC.

Virus neutralization profiles against primary infection sera and corresponding antigenic cartography are integral part of the COVID-19 and influenza vaccine strain selection processes. Human single variant exposure sera have previously defined the antigenic relationships among SARS-CoV-2 variants but are now largely unavailable due to widespread population immunity. Therefore, antigenic characterization of future SARS-CoV-2 variants will require an animal model, analogous to using ferrets for influenza virus. We evaluated neutralization profiles against 23 SARS-CoV-2 variants in nonhuman primates (NHPs) after single variant exposure and generated an NHP-derived antigenic map. We identified a distant antigenic region occupied by BA.2.86, JN.1, and the descendants KP.2, KP.3, and KZ.1.1.1. We also found that the monovalent XBB.1.5 mRNA vaccine induced broad immunity against the mapped antigenic space. In addition, substantial concordance was observed between our NHP-derived and two human antigenic maps, demonstrating the utility of NHPs as a surrogate for antigenic cartography in humans.

Tumor cells must optimize metabolite acquisition between synthesis and uptake from a microenvironment characterized by hypoxia, lactate accumulation, and depletion of many amino acids, including arginine. We performed a metabolism-focused functional screen using CRISPR-Cas9 to identify pathways and factors that enable tumor growth in an arginine-depleted environment. Our screen identified the SLC-family transporter SLC7A5 as required for growth, and we hypothesized that this protein functions as a high-affinity citrulline transporter. Using isotope tracing experiments, we show that citrulline uptake and metabolism into arginine are dependent upon expression of SLC7A5. Pharmacological inhibition of SLC7A5 blocks growth under low-arginine conditions across a diverse group of cancer cell lines. Loss of SLC7A5 reduces tumor growth and citrulline import in a mouse tumor model. We identify a conditionally essential role for SLC7A5 in arginine metabolism, and we propose that SLC7A5-targeting therapeutic strategies in cancer may be effective in the context of arginine limitation.

CD226 plays a vital role in natural killer (NK) cell cytotoxicity, interacting with its ligands CD112 and CD155 to initiate immune synapse formation, primarily through leukocyte function-associated-1 (LFA-1). Our study examined the role of CD226 in NK cell surveillance of acute myeloid leukemia (AML). NK cells in patients with AML had lower expression of CD226. CRISPR-Cas9 deletion of CD226 led to reduced LFA-1 recruitment, poor synapse formation, and decreased NK cell anti-leukemic activity. Engineering NK cells to express a chimeric antigen receptor targeting the AML antigen CD38 (CAR38) could overcome the need for CD226 to establish strong immune synapses. LFA-1 blockade reduced CAR38 NK cell activity, and this depended on the CD38 expression levels of AML cells. This suggests parallel but potentially cooperative roles for LFA-1 and CAR38 in synapse formation. Our findings suggest that CAR38 NK cells could be an effective therapeutic strategy to overcome CD226-mediated immune evasion in AML.

Control of cell proliferation is critical for the lymphocyte life cycle. However, little is known about how stage-specific alterations in cell cycle behavior drive proliferation dynamics during T cell development. Here, we employed in vivo dual-nucleoside pulse labeling combined with the determination of DNA replication over time as well as fluorescent ubiquitination-based cell cycle indicator mice to establish a quantitative high-resolution map of cell cycle kinetics of thymocytes. We developed an agent-based mathematical model of T cell developmental dynamics. To generate the capacity for proliferative bursts, cell cycle acceleration followed a "stretch model" characterized by the simultaneous and proportional contraction of both G1 and S phases. Analysis of cell cycle phase dynamics during regeneration showed tailored adjustments of cell cycle phase dynamics. Taken together, our results highlight intrathymic cell cycle regulation as an adjustable system to maintain physiologic tissue homeostasis and foster our understanding of dysregulation of the T cell developmental program.

The most severe form of α-thalassemia results from loss of all four copies of α-globin. Postnatally, patients face challenges similar to β-thalassemia, including severe anemia and erythrotoxicity due to the imbalance of β-globin and α-globin chains. Despite progress in genome editing treatments for β-thalassemia, there is no analogous curative option for α-thalassemia. To address this, we designed a Cas9/AAV6-mediated genome editing strategy that integrates a functional α-globin gene into the β-globin locus in α-thalassemia patient-derived hematopoietic stem and progenitor cells (HSPCs). Incorporation of a truncated erythropoietin receptor transgene into the α-globin integration cassette significantly increased erythropoietic output from edited HSPCs and led to the most robust production of α-globin, and consequently hemoglobin tetramers. By directing edited HSPCs toward increased production of clinically relevant erythroid cells, this approach has the potential to mitigate the limitations of current treatments for the hemoglobinopathies, including low genome editing and low engraftment rates.

Humans are widely exposed to phthalates, a common chemical plasticizer. Previous cohort studies have revealed that maternal exposure to monobutyl phthalate (MBP), a key metabolite of phthalates, is associated with neurodevelopmental defects. However, the molecular mechanism remains unclear. Here, we demonstrate that maternal exposure to MBP enhances neural stem cell (NSC) differentiation into astrocytes with highly expressed C3 and LCN2 in mouse offspring, resulting in increased synapse phagocytosis and cognitive dysfunction. Mechanistically, we find that MBP exposure activates the IRE1α/XBP1s (spliced XBP1) stress response pathway, which regulates key genes involved in astrocyte differentiation (SOX9 and ATF3) and reactivity (C3 and LCN2). Conditional knockout or pharmacological inhibition of IRE1α markedly inhibits NSC differentiation into astrocytes and astrocyte reactivity, attenuates synapse phagocytosis, and improves cognitive function. This phenotype is further recapitulated in a human brain organoid model. Together, these findings unveil the molecular mechanism underlying the neurodevelopmental deficits caused by a widespread environmental pollutant.