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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]
  • Takes one to B1a: Dismantling the origin of mantle cell lymphoma

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      Authors: Beaudin A.
      Abstract: Therapeutic discovery for mantle cell lymphoma (MCL) has been hindered by a lack of preclinical mouse models that recapitulate human disease. In this issue, Pieters and colleagues (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202280) establish a novel mouse model of MCL driven by overexpression of cyclin D2 and identify fetal-derived B1a cells as putative cell of origin for MCL.
      PubDate: Thu, 16 Sep 2021 00:00:00 GMT
      DOI: 10.1084/jem.20211482
      Issue No: Vol. 218, No. 10 (2021)
       
  • A fungal antigenic driver for Löfgren’s syndrome sarcoidosis

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      Authors: Lim CX; Weichhart T.
      Abstract: Löfgren’s syndrome is an acute form of sarcoidosis that is characterized by the activation of CD4+ T helper cells. In this issue of JEM, Greaves et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210785) identified a peptide derived from an airborne mold species that stimulates T cells of Löfgren’s syndrome patients in an HLA-DR3–restricted manner. An increased serum IgG antibody response to the full-length protein was also observed in those patients, indicating that the fungus Aspergillus nidulans might be the elusive microbial agent that drives acute sarcoidosis.
      PubDate: Mon, 13 Sep 2021 00:00:00 GMT
      DOI: 10.1084/jem.20211572
      Issue No: Vol. 218, No. 10 (2021)
       
  • Autoimmunity affecting the biliary tract fuels the immunosurveillance of
           cholangiocarcinoma

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      Authors: Paillet J; Plantureux C, Lévesque S, et al.
      Abstract: Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.
      PubDate: Wed, 08 Sep 2021 00:00:00 GMT
      DOI: 10.1084/jem.20200853
      Issue No: Vol. 218, No. 10 (2021)
       
  • Blood transcriptomics reveal the evolution and resolution of the immune
           response in tuberculosis

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      Authors: Tabone O; Verma R, Singhania A, et al.
      Abstract: Blood transcriptomics have revealed major characteristics of the immune response in active TB, but the signature early after infection is unknown. In a unique clinically and temporally well-defined cohort of household contacts of active TB patients that progressed to TB, we define minimal changes in gene expression in incipient TB increasing in subclinical and clinical TB. While increasing with time, changes in gene expression were highest at 30 d before diagnosis, with heterogeneity in the response in household TB contacts and in a published cohort of TB progressors as they progressed to TB, at a bulk cohort level and in individual progressors. Blood signatures from patients before and during anti-TB treatment robustly monitored the treatment response distinguishing early and late responders. Blood transcriptomics thus reveal the evolution and resolution of the immune response in TB, which may help in clinical management of the disease.
      PubDate: Tue, 07 Sep 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210915
      Issue No: Vol. 218, No. 10 (2021)
       
  • Alveolar macrophages and epithelial cells: The art of living together

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      Authors: Clements D; Idoyaga J.
      Abstract: In this issue of JEM, Gschwend et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210745) reveal the indispensable role of alveolar epithelial cells type 2 in controlling the density of alveolar macrophages. This study highlights the intricate crosstalk that lung stroma and macrophages undergo to maintain homeostasis.
      PubDate: Tue, 07 Sep 2021 00:00:00 GMT
      DOI: 10.1084/jem.20211583
      Issue No: Vol. 218, No. 10 (2021)
       
  • Neutrophil-specific gain-of-function mutations in Nlrp3 promote
           development of cryopyrin-associated periodic syndrome

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      Authors: Stackowicz J; Gaudenzio N, Serhan N, et al.
      Abstract: Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as “cryopyrin-associated periodic syndromes” (CAPS). Treatment of CAPS patients with IL-1–targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.
      PubDate: Fri, 03 Sep 2021 00:00:00 GMT
      DOI: 10.1084/jem.20201466
      Issue No: Vol. 218, No. 10 (2021)
       
  • Helios represses megakaryocyte priming in hematopoietic stem and
           progenitor cells

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      Authors: Cova G; Taroni C, Deau M, et al.
      Abstract: Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte gene expression program in cells as early as the stem cell stage. Helios binding promotes chromatin compaction, notably at the regulatory regions of platelet-specific genes recognized by the Gata2 and Runx1 transcriptional activators, implicated in megakaryocyte priming. Helios null HSPCs are biased toward the megakaryocyte lineage at the expense of the lymphoid and partially resemble cells of aging animals. We propose that Helios acts as a guardian of HSPC pluripotency by continuously repressing the megakaryocyte fate, which in turn allows downstream lymphoid priming to take place. These results highlight the importance of negative and positive priming events in lineage commitment.
      PubDate: Mon, 30 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20202317
      Issue No: Vol. 218, No. 10 (2021)
       
  • Imatinib augments standard malaria combination therapy without added
           toxicity

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      Authors: Chien H; Pantaleo A, Kesely KR, et al.
      Abstract: To egress from its erythrocyte host, the malaria parasite, Plasmodium falciparum, must destabilize the erythrocyte membrane by activating an erythrocyte tyrosine kinase. Because imatinib inhibits erythrocyte tyrosine kinases and because imatinib has a good safety profile, we elected to determine whether coadministration of imatinib with standard of care (SOC) might be both well tolerated and therapeutically efficacious in malaria patients. Patients with uncomplicated P. falciparum malaria from a region in Vietnam where one third of patients experience delayed parasite clearance (DPC; continued parasitemia after 3 d of therapy) were treated for 3 d with either the region’s SOC (40 mg dihydroartemisinin + 320 mg piperaquine/d) or imatinib (400 mg/d) + SOC. Imatinib + SOC–treated participants exhibited no increase in number or severity of adverse events, a significantly accelerated decline in parasite density and pyrexia, and no DPC. Surprisingly, these improvements were most pronounced in patients with the highest parasite density, where serious complications and death are most frequent. Imatinib therefore appears to improve SOC therapy, with no obvious drug-related toxicities.
      PubDate: Thu, 26 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210724
      Issue No: Vol. 218, No. 10 (2021)
       
  • Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells
           before and after birth

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      Authors: Gschwend J; Sherman SM, Ridder F, et al.
      Abstract: Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and nonimmune cells and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular cross talk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected in both immune cells, including group 2 innate lymphoid cells and γδ T cells, as well as AT2s. AMs were unaffected by constitutive deletion of hematopoietic Csf2 and basophil depletion. Instead, AT2 lineage-specific constitutive and inducible Csf2 deletion revealed the nonredundant function of AT2-derived GM-CSF in instructing AM fate, establishing the postnatal AM compartment, and maintaining AMs in adult lungs. This AT2-AM relationship begins during embryogenesis, where nascent AT2s timely induce GM-CSF expression to support the proliferation and differentiation of fetal monocytes contemporaneously seeding the tissue, and persists into adulthood, when epithelial GM-CSF remains restricted to AT2s.
      PubDate: Wed, 25 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210745
      Issue No: Vol. 218, No. 10 (2021)
       
  • JAML promotes CD8 and γδ T cell antitumor immunity and is a novel target
           for cancer immunotherapy

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      Authors: McGraw JM; Thelen F, Hampton EN, et al.
      Abstract: T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation signals required to promote TIL responses are less well characterized. Here we show that the antitumor activity of CD8 and γδ TIL is supported by interactions between junctional adhesion molecule–like protein (JAML) on T cells and its ligand coxsackie and adenovirus receptor (CXADR) within tumor tissue. Loss of JAML through knockout in mice resulted in accelerated tumor growth that was associated with an impaired γδ TIL response and increased CD8 TIL dysfunction. In mouse tumor models, therapeutic treatment with an agonistic anti-JAML antibody inhibited tumor growth, improved γδ TIL activation, decreased markers of CD8 TIL dysfunction, and significantly improved response to anti–PD-1 checkpoint blockade. Thus, JAML represents a novel therapeutic target to enhance both CD8 and γδ TIL immunity.
      PubDate: Tue, 24 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20202644
      Issue No: Vol. 218, No. 10 (2021)
       
  • Characterization of human FDCs reveals regulation of T cells and antigen
           presentation to B cells

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      Authors: Heesters BA; van Megesen K, Tomris I, et al.
      Abstract: Stromal-derived follicular dendritic cells (FDCs) are essential for germinal centers (GCs), the site where B cells maturate their antibodies. FDCs present native antigen to B cells and maintain a CXCL13 gradient to form the B cell follicle. Yet despite their essential role, the transcriptome of human FDCs remains undefined. Using single-cell RNA sequencing and microarray, we provided the transcriptome of these enigmatic cells as a comprehensive resource. Key genes were validated by flow cytometry and microscopy. Surprisingly, marginal reticular cells (MRCs) rather than FDCs expressed B cell activating factor (BAFF). Furthermore, we found that human FDCs expressed TLR4 and can alter antigen availability in response to pathogen-associated molecular patterns (PAMPs). High expression of PD-L1 and PD-L2 on FDCs activated PD1 on T cells. In addition, we found expression of genes related to T cell regulation, such as HLA-DRA, CD40, and others. These data suggest intimate contact between human FDCs and T cells.
      PubDate: Mon, 23 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210790
      Issue No: Vol. 218, No. 10 (2021)
       
  • The early interferon catches the SARS-CoV-2

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      Authors: Decker T.
      Abstract: Interferons establish innate antiviral immunity. Two recent papers in JEM by Lopez et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20211211) and Cheemarla et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210583) show that an appropriate supply of antiviral interferon enables epithelial cells of the nasopharyngeal mucosa to inhibit SARS-CoV-2 growth and that interferon-induced mucosal genes serve as biomarkers of infection.
      PubDate: Mon, 23 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20211667
      Issue No: Vol. 218, No. 10 (2021)
       
  • TREM2-dependent lipid droplet biogenesis in phagocytes is required for
           remyelination

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      Authors: Gouna G; Klose C, Bosch-Queralt M, et al.
      Abstract: Upon demyelinating injury, microglia orchestrate a regenerative response that promotes myelin repair, thereby restoring rapid signal propagation and protecting axons from further damage. Whereas the essential phagocytic function of microglia for remyelination is well known, the underlying metabolic pathways required for myelin debris clearance are poorly understood. Here, we show that cholesterol esterification in male mouse microglia/macrophages is a necessary adaptive response to myelin debris uptake and required for the generation of lipid droplets upon demyelinating injury. When lipid droplet biogenesis is defective, innate immune cells do not resolve, and the regenerative response fails. We found that triggering receptor expressed on myeloid cells 2 (TREM2)–deficient mice are unable to adapt to excess cholesterol exposure, form fewer lipid droplets, and build up endoplasmic reticulum (ER) stress. Alleviating ER stress in TREM2-deficient mice restores lipid droplet biogenesis and resolves the innate immune response. Thus, we conclude that TREM2-dependent formation of lipid droplets constitute a protective response required for remyelination to occur.
      PubDate: Mon, 23 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210227
      Issue No: Vol. 218, No. 10 (2021)
       
  • Correction: Early nasal type I IFN immunity against SARS-CoV-2 is
           compromised in patients with autoantibodies against type I IFNs

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      Authors: Lopez J; Mommert M, Mouton W, et al.
      Abstract: Vol. 218, No. 10 10.1084/jem.20211211 August 6, 2021
      PubDate: Fri, 20 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.2021121108132021c
      Issue No: Vol. 218, No. 10 (2021)
       
  • Single-cell imaging of T cell immunotherapy responses in vivo

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      Authors: Yan C; Yang Q, Zhang S, et al.
      Abstract: T cell immunotherapies have revolutionized treatment for a subset of cancers. Yet, a major hurdle has been the lack of facile and predicative preclinical animal models that permit dynamic visualization of T cell immune responses at single-cell resolution in vivo. Here, optically clear immunocompromised zebrafish were engrafted with fluorescent-labeled human cancers along with chimeric antigen receptor T (CAR T) cells, bispecific T cell engagers (BiTEs), and antibody peptide epitope conjugates (APECs), allowing real-time single-cell visualization of T cell–based immunotherapies in vivo. This work uncovered important differences in the kinetics of T cell infiltration, tumor cell engagement, and killing between these immunotherapies and established early endpoint analysis to predict therapy responses. We also established EGFR-targeted immunotherapies as a powerful approach to kill rhabdomyosarcoma muscle cancers, providing strong preclinical rationale for assessing a wider array of T cell immunotherapies in this disease.
      PubDate: Fri, 20 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210314
      Issue No: Vol. 218, No. 10 (2021)
       
  • MERTK on mononuclear phagocytes regulates T cell antigen recognition at
           autoimmune and tumor sites

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      Authors: Lindsay RS; Whitesell JC, Dew KE, et al.
      Abstract: Understanding mechanisms of immune regulation is key to developing immunotherapies for autoimmunity and cancer. We examined the role of mononuclear phagocytes during peripheral T cell regulation in type 1 diabetes and melanoma. MERTK expression and activity in mononuclear phagocytes in the pancreatic islets promoted islet T cell regulation, resulting in reduced sensitivity of T cell scanning for cognate antigen in prediabetic islets. MERTK-dependent regulation led to reduced T cell activation and effector function at the disease site in islets and prevented rapid progression of type 1 diabetes. In human islets, MERTK-expressing cells were increased in remaining insulin-containing islets of type 1 diabetic patients, suggesting that MERTK protects islets from autoimmune destruction. MERTK also regulated T cell arrest in melanoma tumors. These data indicate that MERTK signaling in mononuclear phagocytes drives T cell regulation at inflammatory disease sites in peripheral tissues through a mechanism that reduces the sensitivity of scanning for antigen leading to reduced responsiveness to antigen.
      PubDate: Fri, 20 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20200464
      Issue No: Vol. 218, No. 10 (2021)
       
  • CD4 + T cells in the lungs of acute sarcoidosis patients recognize an
           Aspergillus nidulans epitope

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      Authors: Greaves SA; Ravindran A, Santos RG, et al.
      Abstract: Löfgren’s syndrome (LS) is an acute form of sarcoidosis characterized by a genetic association with HLA-DRB1*03 (HLA-DR3) and an accumulation of CD4+ T cells of unknown specificity in the bronchoalveolar lavage (BAL). Here, we screened related LS-specific TCRs for antigen specificity and identified a peptide derived from NAD-dependent histone deacetylase hst4 (NDPD) of Aspergillus nidulans that stimulated these CD4+ T cells in an HLA-DR3–restricted manner. Using ELISPOT analysis, a greater number of IFN-γ– and IL-2–secreting T cells in the BAL of DR3+ LS subjects compared with DR3+ control subjects was observed in response to the NDPD peptide. Finally, increased IgG antibody responses to A. nidulans NDPD were detected in the serum of DR3+ LS subjects. Thus, our findings identify a ligand for CD4+ T cells derived from the lungs of LS patients and suggest a role of A. nidulans in the etiology of LS.
      PubDate: Thu, 19 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210785
      Issue No: Vol. 218, No. 10 (2021)
       
  • Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice

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      Authors: Pieters T; T’Sas S, Vanhee S, et al.
      Abstract: Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with poor long-term overall survival. Currently, MCL research and development of potential cures is hampered by the lack of good in vivo models. MCL is characterized by recurrent translocations of CCND1 or CCND2, resulting in overexpression of the cell cycle regulators cyclin D1 or D2, respectively. Here, we show, for the first time, that hematopoiesis-specific activation of cyclin D2 is sufficient to drive murine MCL-like lymphoma development. Furthermore, we demonstrate that cyclin D2 overexpression can synergize with loss of p53 to form aggressive and transplantable MCL-like lymphomas. Strikingly, cyclin D2–driven lymphomas display transcriptional, immunophenotypic, and functional similarities with B1a B cells. These MCL-like lymphomas have B1a-specific B cell receptors (BCRs), show elevated BCR and NF-κB pathway activation, and display increased MALT1 protease activity. Finally, we provide preclinical evidence that inhibition of MALT1 protease activity, which is essential for the development of early life–derived B1a cells, can be an effective therapeutic strategy to treat MCL.
      PubDate: Wed, 18 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20202280
      Issue No: Vol. 218, No. 10 (2021)
       
  • Hepatic FGF21 preserves thermoregulation and cardiovascular function
           during bacterial inflammation

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      Authors: Huen SC; Wang A, Feola K, et al.
      Abstract: Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor 21 (FGF21), and decreases survival. Consistent with this observation, FGF21-deficient mice are more susceptible to mortality from endotoxemia and polybacterial peritonitis. Here, we report that increased circulating FGF21 during bacterial inflammation is hepatic derived and required for survival through the maintenance of thermogenesis, energy expenditure, and cardiac function. FGF21 signaling downstream of its obligate coreceptor, β-Klotho (KLB), is required in bacterial sepsis. However, FGF21 modulates thermogenesis and chronotropy independent of the adipose, forebrain, and hypothalamus, which are operative in cold adaptation, suggesting that in bacterial inflammation, either FGF21 signals through a novel, undescribed target tissue or concurrent signaling of multiple KLB-expressing tissues is required.
      PubDate: Wed, 18 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20202151
      Issue No: Vol. 218, No. 10 (2021)
       
  • The germinal center reaction depends on RNA methylation and divergent
           functions of specific methyl readers

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      Authors: Grenov AC; Moss L, Edelheit S, et al.
      Abstract: Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required for GC maintenance through the differential functions of m6A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation–related genes. The m6A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m6A reader, YTHDF2, indirectly regulated the expression of the oxidative phosphorylation gene program. Our findings demonstrate how two independent gene networks that support critical GC functions are modulated by m6A through distinct mRNA binders.
      PubDate: Tue, 17 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210360
      Issue No: Vol. 218, No. 10 (2021)
       
  • The RAG1 N-terminal region regulates the efficiency and pathways of
           synapsis for V(D)J recombination

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      Authors: Beilinson HA; Glynn RA, Yadavalli A, et al.
      Abstract: Immunoglobulin and T cell receptor gene assembly depends on V(D)J recombination initiated by the RAG1-RAG2 recombinase. The RAG1 N-terminal region (NTR; aa 1–383) has been implicated in regulatory functions whose influence on V(D)J recombination and lymphocyte development in vivo is poorly understood. We generated mice in which RAG1 lacks ubiquitin ligase activity (P326G), the major site of autoubiquitination (K233R), or its first 215 residues (Δ215). While few abnormalities were detected in R1.K233R mice, R1.P326G mice exhibit multiple features indicative of reduced recombination efficiency, including an increased Igκ+:Igλ+ B cell ratio and decreased recombination of Igh, Igκ, Igλ, and Tcrb loci. Previous studies indicate that synapsis of recombining partners during Igh recombination occurs through two pathways: long-range scanning and short-range collision. We find that R1Δ215 mice exhibit reduced short-range Igh and Tcrb D-to-J recombination. Our findings indicate that the RAG1 NTR regulates V(D)J recombination and lymphocyte development by multiple pathways, including control of the balance between short- and long-range recombination.
      PubDate: Tue, 17 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210250
      Issue No: Vol. 218, No. 10 (2021)
       
  • Persistent RNA virus infection is short-lived at the single-cell level but
           leaves transcriptomic footprints

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      Authors: Reuther P; Martin K, Kreutzfeldt M, et al.
      Abstract: Several RNA viruses can establish life-long persistent infection in mammalian hosts, but the fate of individual virus-infected cells remains undefined. Here we used Cre recombinase–encoding lymphocytic choriomeningitis virus to establish persistent infection in fluorescent cell fate reporter mice. Virus-infected hepatocytes underwent spontaneous noncytolytic viral clearance independently of type I or type II interferon signaling or adaptive immunity. Viral clearance was accompanied by persistent transcriptomic footprints related to proliferation and extracellular matrix remodeling, immune responses, and metabolism. Substantial overlap with persistent epigenetic alterations in HCV-cured patients suggested a universal RNA virus-induced transcriptomic footprint. Cell-intrinsic clearance occurred in cell culture, too, with sequential infection, reinfection cycles separated by a period of relative refractoriness to infection. Our study reveals that systemic persistence of a prototypic noncytolytic RNA virus depends on continuous spread and reinfection. Yet undefined cell-intrinsic mechanisms prevent viral persistence at the single-cell level but give way to profound transcriptomic alterations in virus-cleared cells.
      PubDate: Mon, 16 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210408
      Issue No: Vol. 218, No. 10 (2021)
       
  • Enhanced cGAS-STING–dependent interferon signaling associated with
           mutations in ATAD3A

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      Authors: Lepelley A; Della Mina E, Van Nieuwenhove E, et al.
      Abstract: Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain–containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.
      PubDate: Fri, 13 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20201560
      Issue No: Vol. 218, No. 10 (2021)
       
  • Early nasal type I IFN immunity against SARS-CoV-2 is compromised in
           patients with autoantibodies against type I IFNs

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      Authors: Lopez J; Mommert M, Mouton W, et al.
      Abstract: IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3–dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.
      PubDate: Fri, 06 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20211211
      Issue No: Vol. 218, No. 10 (2021)
       
  • Eosinophils are part of the granulocyte response in tuberculosis and
           promote host resistance in mice

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      Authors: Bohrer AC; Castro E, Hu Z, et al.
      Abstract: Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions and autopsy granulomas. An influx of eosinophils is also evident in infected zebrafish, mice, and nonhuman primate granulomas, where they are functionally activated and degranulate. Importantly, using complementary genetic models of eosinophil deficiency, we demonstrate that in mice, eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings uncover an unexpected recruitment of eosinophils to the infected lung tissue and a protective role for these cells in the control of Mtb infection in mice.
      PubDate: Wed, 04 Aug 2021 00:00:00 GMT
      DOI: 10.1084/jem.20210469
      Issue No: Vol. 218, No. 10 (2021)
       
 
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