Showing papers in "Journal of Experimental Medicine in 2022"
TL;DR: In this paper , the authors summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation.
Abstract: Neutrophils are the first responders to infection and inflammation and are thus a critical component of innate immune defense. Understanding the behavior of neutrophils as they act within various inflammatory contexts has provided insights into their role in sterile and infectious diseases; however, the field of neutrophils in cancer is comparatively young. Here, we summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression. We discuss sources of neutrophil heterogeneity in cancer and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation. We address discrepancies in the literature that highlight a need for technical standards that ought to be considered between laboratories. Finally, we review emerging questions in neutrophil biology and innate immunity in cancer. Overall, we emphasize that neutrophils are a more diverse population than previously appreciated and that their role in cancer may present novel unexplored opportunities to treat cancer.
68 citations
TL;DR: Microglia modulate cerebral blood flow through complex purinergic actions, which are mediated by dynamic, P2Y12 receptor-driven interactions with the vasculature, which leads to impaired CBF response during neurovascular coupling, hypercapnia-induced vasodilation and cerebral hypoperfusion.
Abstract: Microglia modulate cerebral blood flow (CBF) through complex purinergic actions, which are mediated by dynamic, P2Y12 receptor-driven interactions with the vasculature. Microglial actions are partially independent of nitric oxide. Microglial dysfunction leads to impaired CBF response during neurovascular coupling, hypercapnia-induced vasodilation and cerebral hypoperfusion.
62 citations
TL;DR: It is described that glymphatic clearance of extracellular tau impacts tau accumulation and neurodegeneration and the study implicates Glymphatic system in the pathophysiology of tauopathies.
Abstract: Tau present in the extracellular fluids has a critical role in the pathogenesis of tauopathies. The authors describe that glymphatic clearance of extracellular tau impacts tau accumulation and neurodegeneration. The study implicates glymphatic system in the pathophysiology of tauopathies.
57 citations
TL;DR: This review summarizes how CD36 dual functions determine immune cell functions and fates, which contribute to common diseases including atherosclerosis and tumor progression.
Abstract: CD36 functions as both a signaling receptor and fatty acid transporter in various immune and non-immune cells. This review summarizes how its dual functions determine immune cell functions and fates, which contribute to common diseases including atherosclerosis and tumor progression.
53 citations
TL;DR: In an international cohort of 112 children hospitalized for moderate to critical COVID-19 pneumonia, 12 children are identified with one of four known recessive inborn errors of type I interferon immunity: X-linked TLR7 and autosomal IFNAR1, STAT2, and TYK2 deficiencies.
Abstract: In an international cohort of 112 children hospitalized for moderate to critical COVID-19 pneumonia, we identified 12 children with one of four known recessive inborn errors of type I interferon immunity: X-linked TLR7 and autosomal IFNAR1, STAT2, and TYK2 deficiencies.
48 citations
TL;DR: It is shown that immunological hot spots in lung tumors are sustained by fibroblasts and these spots prevent CD4 T cells from apoptosis by activating the complement receptor C1qbp.
Abstract: Kerdidani et al. show that immunological hot spots in lung tumors are sustained by fibroblasts. Lung fibroblasts present MHCII cancer antigens locally and at the same time prevent CD4 T cells from apoptosis by activating the complement receptor C1qbp.
45 citations
TL;DR: This study detected SARS-CoV-2–specific nasal-resident T cells in vaccinees only after infection, highlighting the significance of nasal challenge in the formation of antiviral immunity at the site of infection.
Abstract: Virus-specific T cells in the nasal cavity might provide an immediate layer of protection against SARS-CoV-2. This study detected SARS-CoV-2–specific nasal-resident T cells in vaccinees only after infection, highlighting the significance of nasal challenge in the formation of antiviral immunity at the site of infection.
43 citations
TL;DR: In this paper, the authors assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection.
Abstract: As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)-dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients.
34 citations
TL;DR: In this paper, the authors identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.
Abstract: Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-β signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.
33 citations
TL;DR: In this paper , human autoantibodies neutralizing specific cytokines can underlie specific infectious diseases in otherwise healthy patients and mimic inborn errors of the corresponding cytokines or their response pathways.
Abstract: Human autoantibodies neutralizing specific cytokines can underlie specific infectious diseases in otherwise healthy patients. The autoantibodies mimic inborn errors of the corresponding cytokines or their response pathways. Four autoimmune phenocopies of inborn errors of cytokine immunity have already been reported.
33 citations
TL;DR: The present study characterizes the 3D anatomy of meningeal lymphatic vasculature and associated CSF drainage by postmortem light-sheet imaging in mice and by real-time magnetic resonance imaging in humans, demonstrating conserved lymphatic circuitries in contact with dural venous sinuses.
Abstract: The present study characterizes the 3D anatomy of meningeal lymphatic vasculature and associated CSF drainage by postmortem light-sheet imaging in mice and by real-time magnetic resonance imaging in humans, demonstrating conserved lymphatic circuitries in contact with dural venous sinuses.
TL;DR: The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited, and a 3rd antigenic exposure by Delta infection elicits strain- specific memory responses and increases in the overall potency and breadth of the memory B cells.
Abstract: Individuals that receive a 3rd mRNA vaccine dose show enhanced protection against severe COVID19 but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a 3rd or 4th antigenic exposure by Delta or Omicron BA.1 infection, respectively. A 3rd exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a 3rd mRNA vaccine dose. A 4th antigenic exposure with Omicron BA.1 infection increased variant specific plasma antibody and memory B cell responses. However, the 4th exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a 3rd mRNA vaccine dose. In conclusion, a 3rd antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a 4th antigenic exposure with Omicron BA.1 is limited to increased strain specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.
TL;DR: Photoconversion is used to temporally label tumor-infiltrating lymphocytes, revealing the continuous migration of TCF-1+ T cells between the tumor and draining lymphoid tissue.
Abstract: How intratumoral T cell subsets differ in their recruitment or retention is unclear. In this study, photoconversion is used to temporally label tumor-infiltrating lymphocytes, revealing the continuous migration of TCF-1+ T cells between the tumor and draining lymphoid tissue.
TL;DR: In this paper, the authors demonstrate that helminth parasites reshape their intestinal environment in a novel strategy for undermining the host protective response by inducing spheroid growth characteristic of fetal epithelium and homeostatic repair.
Abstract: Helminth parasites are adept manipulators of the immune system, using multiple strategies to evade the host type 2 response. In the intestinal niche, the epithelium is crucial for initiating type 2 immunity via tuft cells, which together with goblet cells expand dramatically in response to the type 2 cytokines IL-4 and IL-13. However, it is not known whether helminths modulate these epithelial cell populations. In vitro, using small intestinal organoids, we found that excretory/secretory products (HpES) from Heligmosomoides polygyrus blocked the effects of IL-4/13, inhibiting tuft and goblet cell gene expression and expansion, and inducing spheroid growth characteristic of fetal epithelium and homeostatic repair. Similar outcomes were seen in organoids exposed to parasite larvae. In vivo, H. polygyrus infection inhibited tuft cell responses to heterologous Nippostrongylus brasiliensis infection or succinate, and HpES also reduced succinate-stimulated tuft cell expansion. Our results demonstrate that helminth parasites reshape their intestinal environment in a novel strategy for undermining the host protective response.
TL;DR: In this article, the authors describe the discovery of an agonist of the nuclear receptor NR2F1 that specifically activates dormancy programs in malignant cells, which led to growth arrest of an HNSCC PDX line, human cell lines, and patient derived organoids in 3D cultures and in vivo.
Abstract: We describe the discovery of an agonist of the nuclear receptor NR2F1 that specifically activates dormancy programs in malignant cells. The agonist led to a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest of an HNSCC PDX line, human cell lines, and patient-derived organoids in 3D cultures and in vivo. This effect was lost when NR2F1 was knocked out by CRISPR-Cas9. RNA sequencing revealed that agonist treatment induces transcriptional changes associated with inhibition of cell cycle progression and mTOR signaling, metastasis suppression, and induction of a neural crest lineage program. In mice, agonist treatment resulted in inhibition of lung HNSCC metastasis, even after cessation of the treatment, where disseminated tumor cells displayed an NR2F1hi/p27hi/Ki-67lo/p-S6lo phenotype and remained in a dormant single-cell state. Our work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis.
TL;DR: In this article, a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes at 9 wk of age in male mice only.
Abstract: We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid β (Aβ) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aβ amyloidosis. Thus, microglia play a critical role in driving gut microbiome-mediated alterations of cerebral Aβ deposition.
TL;DR: A novel form of autosomal recessive IFNAR2 deficiency due to a null and common allele in Arctic populations is reported, broadening its clinical phenotype from diseases caused by live-attenuated viral vaccines to include life-threatening influenza and SARS-CoV-2.
Abstract: The authors report a novel form of autosomal recessive IFNAR2 deficiency due to a null and common allele in Arctic populations, broadening its clinical phenotype from diseases caused by live-attenuated viral vaccines to include life-threatening influenza and SARS-CoV-2.
TL;DR: Immunotherapy using anti–PD-1 is effective in obesity and partially restoresCD8 T cell function and metabolism in mice and suppressive effects of obesity on CD8 T cells in mouse cancer models and human endometrial cancer.
Abstract: Dyck et al. describe suppressive effects of obesity on CD8 T cells in mouse cancer models and human endometrial cancer. Immunotherapy using anti–PD-1 is effective in obesity and partially restores CD8 T cell function and metabolism in mice.
TL;DR: The authors report the first description of two infants with PIK3CA-related overgrowth spectrum treated by alpelisib, associated with clinical, biological, and radiological improvements.
Abstract: Here, the authors report the first description of two infants with PIK3CA-related overgrowth spectrum treated by alpelisib. Patients were monitored with pharmacokinetics. Alpelisib was associated with clinical, biological, and radiological improvements.
TL;DR: The authors report a simple and efficient method for nonviral CRISPR/Cas9-based editing of T lymphocytes using plasmid donor DNA.
Abstract: Effective and precise gene editing of T lymphocytes is critical for advancing our understanding of T cell biology and the development of next-generation cellular therapies. The authors report a simple and efficient method for nonviral CRISPR/Cas9-based editing of T lymphocytes using plasmid donor DNA.
TL;DR: In an international cohort of 279 patients with hypoxemic influenza pneumonia, 13 patients were identified with autoantibodies neutralizing IFN-α and/or -ω, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine.
Abstract: In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-α and/or -ω, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine.
TL;DR: Single-cell transcriptomic analysis shows that macrophages in mucosa and muscularis propria of human colon are very heterogeneous and that their functional properties are closely related to their anatomic position.
Abstract: Single-cell transcriptomic analysis shows that macrophages in mucosa and muscularis propria of human colon are very heterogeneous and that their functional properties are closely related to their anatomic position. The study indicates that distinct differentiation pathways are controlled by extensive interactions with tissue-resident cells.
TL;DR: In this article, the TGF-β superfamily member GDF-15 was identified as a component of the regeneration-promoting program (RPP), which is essential for proper repair.
Abstract: Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte-derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage-derived factors coordinate tissue repair. Gene expression kinetics-based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration-associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor-expressing macrophages [GFEMs]).
TL;DR: A loss-of-function IFNAR1 variant that is surprisingly common in individuals of western Polynesian ancestry is reported, while it is absent or extremely rare elsewhere.
Abstract: Bastard et al. report a loss-of-function IFNAR1 variant that is surprisingly common (allele frequency >1%) in individuals of western Polynesian ancestry, while it is absent or extremely rare elsewhere. Homozygotes for this allele are prone to severe viral diseases.
TL;DR: The EBV-specific T cell receptor repertoire is broader in multiple sclerosis patients, even in diseased siblings of discordant monozygotic twin pairs, indicating an ongoing immune response to Epstein–Barr virus inmultiple sclerosis patients.
Abstract: The EBV-specific T cell receptor repertoire is broader in multiple sclerosis patients, even in diseased siblings of discordant monozygotic twin pairs, indicating an ongoing immune response to Epstein–Barr virus in multiple sclerosis patients, which might hold clues for multiple sclerosis pathogenesis and future therapeutic or preventive avenues.
TL;DR: The data suggest that sustained microglial activation through TREM2 that does not result in strong amyloid removal may exacerbate Aβ-induced tau pathology, which may have important clinical implications.
Abstract: The results of this study show that chronic administration of a mouse TREM2 agonist antibody in a model of Aβ amyloidosis increases microglial activation, seeded neuritic plaque tau pathology, and neuritic dystrophy without affecting Aβ plaque burden or conformation.
TL;DR: Macrophage origin and functions in adipose tissue and how these features are modulated in obesity are discussed.
Abstract: As the first immune cells to colonize tissues and long-lived resident cells, macrophages play important roles in tissue functions during early development, homeostasis, and disease. Here, Chakarov et al. discuss macrophage origin and functions in adipose tissue and how these features are modulated in obesity.
TL;DR: Combining genetic, immunological, and clinical investigation, the surprisingly narrow disease susceptibility of IRF7 deficiency is highlighted and potential compensatory immunological mechanisms, including IFN-β and adaptive immunity are revealed.
Abstract: Campbell et al. describe seven IRF7-deficient patients with severe respiratory viral infection. Combining genetic, immunological, and clinical investigation, they highlight the surprisingly narrow disease susceptibility of IRF7 deficiency and reveal potential compensatory immunological mechanisms, including IFN-β and adaptive immunity.
TL;DR: It is inferred that sleep preserves clonal diversity by limiting neutral drift, and that sleep slows decay of the hematopoietic system by calibrating thehematopOietic epigenome, constraining inflammatory output, and maintaining clonal Diversity.
Abstract: Sleep interruption restructures the epigenome of hematopoietic stem and progenitor cells (HSPCs) and increases their proliferation, priming them for exaggerated inflammatory bursts and reducing hematopoietic clonal diversity through accelerated genetic drift. In humans, sleep restriction alters the HSPC epigenome and activates hematopoiesis.
TL;DR: The data suggest POT1(L259S) is a pathogenic driver of IPF and provide insights into gene therapy options.
Abstract: This study reports the first known family with pulmonary fibrosis carrying a heterozygous POT1 mutation. The family displays short telomeres, short telomere phenotypes, and genetic anticipation. The data suggest POT1(L259S) is a pathogenic driver of IPF and provide insights into gene therapy options.