Publisher: Rockefeller University Press   (Total: 3 journals)   [Sort alphabetically]

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J. of Cell Biology     Full-text available via subscription   (Followers: 54, SJR: 6.479, CiteScore: 7)
J. of Experimental Medicine     Full-text available via subscription   (Followers: 48, SJR: 8.615, CiteScore: 9)
J. of General Physiology     Full-text available via subscription   (Followers: 4, SJR: 2.623, CiteScore: 3)
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Journal of Experimental Medicine
Journal Prestige (SJR): 8.615
Citation Impact (citeScore): 9
Number of Followers: 48  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0022-1007 - ISSN (Online) 1540-9538
Published by Rockefeller University Press Homepage  [3 journals]
  • Correction: Broader Epstein–Barr virus–specific T cell receptor
           repertoire in patients with multiple sclerosis

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      Abstract: Vol. 219, No. 11 https://doi.org/10.1084/jem.20220650 September 1, 2022
      PubDate: Fri, 28 Oct 2022 00:00:00 GMT
      DOI: 10.1084/jem.2022065010252022c
      Issue No: Vol. 219, No. 11 (2022)
       
  • Metabolic features of innate lymphoid cells

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      Abstract: Innate and adaptive immune cells are found in distinct tissue niches where they orchestrate immune responses. This requires intrinsic and temporal metabolic adaptability to coordinately activate the immune response cascade. Dysregulation of this program is a key feature of immunosuppression. Direct or indirect metabolic immune cell reprogramming may offer new approaches to modulate immune cells behavior for therapy to overcome dysregulation. In this review, we explored how metabolism regulates lymphocytes beyond the classical T cell subsets. We focus on the innate lymphoid cell (ILC) family, highlighting the distinct metabolic characteristics of these cells, the impact of environmental factors, and the receptors that could alter immune cell functions through manipulation of metabolic pathways to potentially prevent or treat various diseases.
      PubDate: Thu, 27 Oct 2022 00:00:00 GMT
      DOI: 10.1084/jem.20221140
      Issue No: Vol. 219, No. 11 (2022)
       
  • Correction: Profiling HPV-16–specific T cell responses reveals broad
           antigen reactivities in oropharyngeal cancer patients

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      Abstract: Vol. 217, No. 10 https://doi.org/10.1084/jem.20200389 July 27, 2020
      PubDate: Tue, 25 Oct 2022 00:00:00 GMT
      DOI: 10.1084/jem.2020038910192022c
      Issue No: Vol. 219, No. 11 (2022)
       
  • Expression of Concern: In vivo NCL targeting affects breast cancer
           aggressiveness through miRNA regulation

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      Abstract: Based on an investigation by the College of Medicine Investigation Committee (the COMIC) at The Ohio State University, and JEM’s review, JEM is issuing this Expression of Concern regarding Figures 1 E and 1 F from Pichiorri et al. (2013) J. Exp. Med. 210(5):951–68 and Correction Pichiorri et al. (2017) J. Exp. Med. 214(5):1557.
      PubDate: Mon, 03 Oct 2022 00:00:00 GMT
      DOI: 10.1084/jem.2012095009272022e
      Issue No: Vol. 219, No. 11 (2022)
       
  • Sleep exerts lasting effects on hematopoietic stem cell function and
           diversity

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      Abstract: A sleepless night may feel awful in its aftermath, but sleep’s revitalizing powers are substantial, perpetuating the idea that convalescent sleep is a consequence-free physiological reset. Although recent studies have shown that catch-up sleep insufficiently neutralizes the negative effects of sleep debt, the mechanisms that control prolonged effects of sleep disruption are not understood. Here, we show that sleep interruption restructures the epigenome of hematopoietic stem and progenitor cells (HSPCs) and increases their proliferation, thus reducing hematopoietic clonal diversity through accelerated genetic drift. Sleep fragmentation exerts a lasting influence on the HSPC epigenome, skewing commitment toward a myeloid fate and priming cells for exaggerated inflammatory bursts. Combining hematopoietic clonal tracking with mathematical modeling, we infer that sleep preserves clonal diversity by limiting neutral drift. In humans, sleep restriction alters the HSPC epigenome and activates hematopoiesis. These findings show that sleep slows decay of the hematopoietic system by calibrating the hematopoietic epigenome, constraining inflammatory output, and maintaining clonal diversity.
      PubDate: Wed, 21 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20220081
      Issue No: Vol. 219, No. 11 (2022)
       
  • Autoantibodies against type I IFNs in patients with critical influenza
           pneumonia

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      Abstract: Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6–73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients’ autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10−5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10−5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10−10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.
      PubDate: Fri, 16 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20220514
      Issue No: Vol. 219, No. 11 (2022)
       
  • Transit-amplifying cells control R-spondins in the mouse crypt to modulate
           intestinal stem cell proliferation

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      Abstract: Intestinal epithelium regenerates rapidly through proliferation of intestinal stem cells (ISCs), orchestrated by potent mitogens secreted within the crypt niche. However, mechanisms regulating these mitogenic factors remain largely unknown. Here, we demonstrate that transit-amplifying (TA) cells, marked by unconventional prefoldin RPB5 interactor (URI), control R-spondin production to guide ISC proliferation. Genetic intestinal URI ablation in mice injures TA cells, reducing their survival capacity, leading to an inflamed tissue and subsequently decreasing R-spondin levels, thereby causing ISC quiescence and disruption of intestinal structure. R-spondin supplementation or restoration of R-spondin levels via cell death inhibition by c-MYC elimination or the suppression of inflammation reinstates ISC proliferation in URI-depleted mice. However, selective c-MYC and p53 suppression are required to fully restore TA cell survival and differentiation capacity and preserve complete intestinal architecture. Our data reveal an unexpected role of TA cells, which represent a signaling platform instrumental for controlling inflammatory cues and R-spondin production, essential for maintaining ISC proliferation and tissue regeneration.
      PubDate: Tue, 13 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20212405
      Issue No: Vol. 219, No. 11 (2022)
       
  • GPX4 regulates cellular necrosis and host resistance in Mycobacterium
           tuberculosis infection

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      Abstract: Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.
      PubDate: Wed, 07 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20220504
      Issue No: Vol. 219, No. 11 (2022)
       
  • Innatus immunis: Evolving paradigm of adaptive NK cells

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      Abstract: The mechanisms that govern the development of adaptive-like NK cells are elusive. Shemesh et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220551) report that the development of FcRγ−/low adaptive-like NK cells requires reduced mTOR activity and depends on TGF-β or IFN-α. These findings provide exciting new molecular blueprints explaining the development and functions of adaptive-like NK cells.
      PubDate: Tue, 06 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20221254
      Issue No: Vol. 219, No. 11 (2022)
       
  • A glycan-based approach to cell characterization and isolation:
           Hematopoiesis as a paradigm

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      Abstract: Cell surfaces display a wide array of molecules that confer identity. While flow cytometry and cluster of differentiation (CD) markers have revolutionized cell characterization and purification, functionally heterogeneous cellular subtypes remain unresolvable by the CD marker system alone. Using hematopoietic lineages as a paradigm, we leverage the extraordinary molecular diversity of heparan sulfate (HS) glycans to establish cellular “glycotypes” by utilizing a panel of anti-HS single-chain variable fragment antibodies (scFvs). Prospective sorting with anti-HS scFvs identifies functionally distinct glycotypes within heterogeneous pools of mouse and human hematopoietic progenitor cells and enables further stratification of immunophenotypically pure megakaryocyte–erythrocyte progenitors. This stratification correlates with expression of a heptad of HS-related genes that is reflective of the HS epitope recognized by specific anti-HS scFvs. While we show that HS glycotyping provides an orthogonal set of tools for resolution of hematopoietic lineages, we anticipate broad utility of this approach in defining and isolating novel, viable cell types across diverse tissues and species.
      PubDate: Tue, 06 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20212552
      Issue No: Vol. 219, No. 11 (2022)
       
  • Diminished cell proliferation promotes natural killer cell adaptive-like
           phenotype by limiting FcεRIγ expression

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      Abstract: Human adaptive-like natural killer (NK) cells express low levels of FcεRIγ (FcRγ−/low) and are reported to accumulate during COVID-19 infection; however, the mechanism underlying and regulating FcRγ expression in NK cells has yet to be fully defined. We observed lower FcRγ protein expression in NK cell subsets from lung transplant patients during rapamycin treatment, suggesting a link with reduced mTOR activity. Further, FcRγ−/low NK cell subsets from healthy donors displayed reduced mTOR activity. We discovered that FcRγ upregulation is dependent on cell proliferation progression mediated by IL-2, IL-15, or IL-12, is sensitive to mTOR suppression, and is inhibited by TGFβ or IFNα. Accordingly, the accumulation of adaptive-like FcRγ−/low NK cells in COVID-19 patients corresponded to increased TGFβ and IFNα levels and disease severity. Our results show that an adaptive-like NK cell phenotype is induced by diminished cell proliferation and has an early prognostic value for increased TGFβ and IFNα levels in COVID-19 infection associated with disease severity.
      PubDate: Tue, 06 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20220551
      Issue No: Vol. 219, No. 11 (2022)
       
  • Megakaryopoiesis impairment through acute innate immune signaling
           activation by azacitidine

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      Abstract: Thrombocytopenia, prevalent in the majority of patients with myeloid malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), is an independent adverse prognostic factor. Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant–ineligible patients with MDS/AML, often transiently induces or further aggravates disease-associated thrombocytopenia by an unknown mechanism. Here, we uncover the critical role of an acute type-I interferon (IFN-I) signaling activation in suppressing megakaryopoiesis in AZA-mediated thrombocytopenia. We demonstrate that megakaryocytic lineage-primed progenitors present IFN-I receptors and, upon AZA exposure, engage STAT1/SOCS1-dependent downstream signaling prematurely attenuating thrombopoietin receptor (TPO-R) signaling and constraining megakaryocytic progenitor cell growth and differentiation following TPO-R stimulation. Our findings directly implicate RNA demethylation and IFN-I signal activation as a root cause for AZA-mediated thrombocytopenia and suggest mitigation of TPO-R inhibitory innate immune signaling as a suitable therapeutic strategy to support platelet production, particularly during the early phases of AZA therapy.
      PubDate: Fri, 02 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20212228
      Issue No: Vol. 219, No. 11 (2022)
       
  • Chronic activation of pDCs in autoimmunity is linked to dysregulated ER
           stress and metabolic responses

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      Abstract: Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I–stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1–controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1–PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.
      PubDate: Fri, 02 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20221085
      Issue No: Vol. 219, No. 11 (2022)
       
  • Group 3 innate lymphoid cells require BATF to regulate gut homeostasis in
           mice

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      Abstract: Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host–microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain lineage identity of intestinal ILC3s and ILC3-mediated orchestration of microbiota and mucosal T cell immunity are elusive. Here, we identified BATF as a gatekeeper of ILC3 homeostasis in the gut. Depletion of BATF in ILC3s resulted in excessive interferon-γ production, dysbiosis, aberrant T cell immune responses, and spontaneous inflammatory bowel disease (IBD), which was considerably ameliorated by the removal of adaptive immunity, interferon-γ blockade, or antibiotic treatment. Mechanistically, BATF directly binds to the cis-regulatory elements of type 1 effector genes, restrains their chromatin accessibility, and inhibits their expression. Conversely, BATF promotes chromatin accessibility of genes involved in MHCII antigen processing and presentation pathways, which in turn directly promotes the transition of precursor ILC3s to MHCII+ ILC3s. Collectively, our findings reveal that BATF is a key transcription factor for maintaining ILC3 stability and coordinating ILC3-mediated control of intestinal homeostasis.
      PubDate: Thu, 01 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20211861
      Issue No: Vol. 219, No. 11 (2022)
       
  • EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine
           multipotent progenitors

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      Abstract: Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) generate all cells of the blood system. Despite their multipotency, MPPs display poorly understood lineage bias. Here, we examine whether lineage-specifying transcription factors, such as the B-lineage determinant EBF1, regulate lineage preference in early progenitors. We detect low-level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, coinciding with expression of the myeloid determinant C/EBPα. Hematopoietic deletion of Ebf1 results in enhanced myelopoiesis and reduced HSC repopulation capacity. Ebf1-deficient MPP3 and MPP4 cells exhibit an augmented myeloid differentiation potential and a transcriptome with an enriched C/EBPα signature. Correspondingly, EBF1 binds the Cebpa enhancer, and the deficiency and overexpression of Ebf1 in MPP3 and MPP4 cells lead to an up- and downregulation of Cebpa expression, respectively. In addition, EBF1 primes the chromatin of B-lymphoid enhancers specifically in MPP3 cells. Thus, our study implicates EBF1 in regulating myeloid/lymphoid fate bias in MPPs by constraining C/EBPα-driven myelopoiesis and priming the B-lymphoid fate.
      PubDate: Thu, 01 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20212437
      Issue No: Vol. 219, No. 11 (2022)
       
  • Broader Epstein–Barr virus–specific T cell receptor repertoire in
           patients with multiple sclerosis

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      Abstract: Epstein–Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor β chain (TCRβ) repertoires of 1,395 MS patients, 887 controls, and 35 monozygotic, MS-discordant twin pairs for multimer-confirmed, viral antigen–specific TCRβ sequences. We detected more MHC-I–restricted EBV-specific TCRβ sequences in MS patients. Differences in genetics or upbringing could be excluded by validation in monozygotic twin pairs discordant for MS. Anti–VLA-4 treatment amplified this observation, while interferon β– or anti-CD20 treatment did not modulate EBV-specific T cell occurrence. In healthy individuals, EBV-specific CD8+ T cells were of an effector-memory phenotype in peripheral blood and cerebrospinal fluid. In MS patients, cerebrospinal fluid also contained EBV-specific central-memory CD8+ T cells, suggesting recent priming. Therefore, MS is not only preceded by EBV infection, but also associated with broader EBV-specific TCR repertoires, consistent with an ongoing anti-EBV immune reaction in MS.
      PubDate: Thu, 01 Sep 2022 00:00:00 GMT
      DOI: 10.1084/jem.20220650
      Issue No: Vol. 219, No. 11 (2022)
       
  • A “multi-omics” analysis of blood–brain barrier and synaptic
           dysfunction in APOE4 mice

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      Abstract: Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease, leads to blood–brain barrier (BBB) breakdown in humans and mice. Remarkably, BBB dysfunction predicts cognitive decline and precedes synaptic deficits in APOE4 human carriers. How APOE4 affects BBB and synaptic function at a molecular level, however, remains elusive. Using single-nucleus RNA-sequencing and phosphoproteome and proteome analysis, we show that APOE4 compared with APOE3 leads to an early disruption of the BBB transcriptome in 2–3-mo-old APOE4 knock-in mice, followed by dysregulation in protein signaling networks controlling cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, as well as transcription and RNA splicing suggestive of DNA damage in pericytes. Changes in BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes, which preceded postsynaptic interactome disruption and behavioral deficits that developed 2–5 mo later. Thus, dysregulated signaling mechanisms in endothelium and pericytes in APOE4 mice reflect a molecular signature of a progressive BBB failure preceding changes in synaptic function and behavior.
      PubDate: Tue, 30 Aug 2022 00:00:00 GMT
      DOI: 10.1084/jem.20221137
      Issue No: Vol. 219, No. 11 (2022)
       
 
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