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Journal of Experimental Medicine
Journal Prestige (SJR): 8.615

Citation Impact (citeScore): 9
Number of Followers: 45

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ISSN (Print) 0022-1007 - ISSN (Online) 1540-9538
Published by Rockefeller University Press

[3 journals]

Beyond genes and transcription factors: A potential mechanism for the
pathogenesis of cerebral cavernous malformations
- Authors: Muller WA.
  Abstract: In this issue of JEM, Hong et al. (https://doi.org/10.1084/jem.20200140) identify a major step in the pathogenesis of cerebral cavernous malformations (CCMs), which at the same time offers insight into potential therapy for this disease.
  PubDate: Thu, 17 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200858
  Issue No: Vol. 217, No. 10 (2020)
Gut microbiota, NLR proteins, and intestinal homeostasis
- Authors: Guo H; Gibson SA, Ting JY.
  Abstract: The gastrointestinal tract harbors a highly complex microbial community, which is referred to as gut microbiota. With increasing evidence suggesting that the imbalance of gut microbiota plays a significant role in the pathogenesis of multiple diseases, interactions between the host immune system and the gut microbiota are now attracting emerging interest. Nucleotide-binding and leucine-rich repeat–containing receptors (NLRs) encompass a large number of innate immune sensors and receptors, which mediate the activation of Caspase-1 and the subsequent release of mature interleukin-1β and interleukin-18. Several family members have been found to restrain rather than activate inflammatory cytokines and immune signaling. NLR family members are central regulators of pathogen recognition, host immunity, and inflammation with utmost importance in human diseases. In this review, we focus on the potential roles played by NLRs in controlling and shaping the microbiota community and discuss how the functional axes interconnecting gut microbiota with NLRs impact the modulation of colitis, inflammatory bowel diseases, and colorectal cancer.
  PubDate: Thu, 17 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20181832
  Issue No: Vol. 217, No. 10 (2020)
Immune asynchrony in COVID-19 pathogenesis and potential immunotherapies
- Authors: Zhou T; Su T, Mudianto T, et al.
  Abstract: The outbreak of coronavirus disease 2019 (COVID-19) is an unprecedented global health crisis. Tissue and peripheral blood analysis indicate profound, aberrant myeloid cell activation, cytokine storm, and lymphopenia, with unknown immunopathological mechanisms. Spatiotemporal control of the quality and quantity of the antiviral immune responses involves synchronized cellular and molecular cascades and cross-talk between innate and adaptive immunity. Dysregulated responses in immunity, such as at the stages of immune sensing, alarming, polarization, and resolution, may contribute to disease pathology. Herein, we approach SARS-CoV-2 through an immunomodulatory lens, discussing possible mechanisms of the asynchronized antiviral immune response and proposing potential therapeutic strategies to correct the dysregulation.
  PubDate: Thu, 10 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200674
  Issue No: Vol. 217, No. 10 (2020)
A third Notch in colorectal cancer progression and metastasis
- Authors: Koch U; Radtke F.
  Abstract: In this issue of JEM, Varga et al. (https://doi.org/10.1084/jem.20191515) describe a mouse model of invasive and metastatic colorectal cancer (CRC) closely resembling the human consensus molecular subtype (CMS) 4 associated with the poorest overall survival of the four CMSs. Transcriptomic and bioinformatic analysis combined with pharmacological and genetic studies identified Notch3 as a promoter of tumor progression and metastasis. NOTCH3 expression was up-regulated in CMS4 CRC patients and associated with tumor staging, lymph node and distant metastasis. These findings feature NOTCH3 as putative therapeutic target for advanced CMS4 CRC patients.
  PubDate: Wed, 26 Aug 2020 00:00:00 GMT
  DOI: 10.1084/jem.20201017
  Issue No: Vol. 217, No. 10 (2020)
Neutralizing hepatitis B
- Authors: Robbiani DF.
  Abstract: Despite an effective vaccine, hepatitis B virus (HBV) remains a major public health threat since chronic infection leads to liver disease and cancer. Hehle et al. (https://doi.org/10.1084/jem.20200840) discovered human-derived antibodies that potently neutralize the virus. Will this help a cure'
  PubDate: Thu, 13 Aug 2020 00:00:00 GMT
  DOI: 10.1084/jem.20201261
  Issue No: Vol. 217, No. 10 (2020)
AKT-dependent NOTCH3 activation drives tumor progression in a model of
mesenchymal colorectal cancer
- Authors: Varga J; Nicolas A, Petrocelli V, et al.
  Abstract: Recently, a transcriptome-based consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to individualize CRC therapy. However, the lack of animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here, we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances tumor invasion and metastasis in Trp53ΔIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane. Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four CMSs. Trp53ΔIECAktE17K tumor cells are characterized by Notch3 up-regulation, and treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. In CRC patients, NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically up-regulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.
  PubDate: Tue, 04 Aug 2020 00:00:00 GMT
  DOI: 10.1084/jem.20191515
  Issue No: Vol. 217, No. 10 (2020)
Ganglioneuromas are driven by activated AKT and can be therapeutically
targeted with mTOR inhibitors
- Authors: Tao T; Shi H, Wang M, et al.
  Abstract: Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is a need for well-tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma and therefore limit surgical morbidity. Here, we found that an AKT–mTOR–S6 pathway was active in human ganglioneuroma but not neuroblastoma samples. Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Inhibition of the downstream AKT target, mTOR, in zebrafish with ganglioneuroma effectively reduced the tumor burden. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of mTOR inhibitors as a means to shrink large ganglioneuromas before resection in order to reduce surgical morbidity.
  PubDate: Wed, 29 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20191871
  Issue No: Vol. 217, No. 10 (2020)
A committed tissue-resident memory T cell precursor within the circulating
CD8 + effector T cell pool
- Authors: Kok L; Dijkgraaf FE, Urbanus J, et al.
  Abstract: An increasing body of evidence emphasizes the role of tissue-resident memory T cells (TRM) in the defense against recurring pathogens and malignant neoplasms. However, little is known with regard to the origin of these cells and their kinship to other CD8+ T cell compartments. To address this issue, we followed the antigen-specific progeny of individual naive CD8+ T cells to the T effector (TEFF), T circulating memory (TCIRCM), and TRM pools by lineage-tracing and single-cell transcriptome analysis. We demonstrate that a subset of T cell clones possesses a heightened capacity to form TRM, and that enriched expression of TRM–fate-associated genes is already apparent in the circulating TEFF offspring of such clones. In addition, we demonstrate that the capacity to generate TRM is permanently imprinted at the clonal level, before skin entry. Collectively, these data provide compelling evidence for early stage TRM fate decisions and the existence of committed TRM precursor cells in the circulatory TEFF compartment.
  PubDate: Wed, 29 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20191711
  Issue No: Vol. 217, No. 10 (2020)
Liver X receptors are required for thymic resilience and T cell output
- Authors: Chan CT; Fenn AM, Harder NK, et al.
  Abstract: The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)—a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity—critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ’s functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ’s indispensable roles in adaptive immunity.
  PubDate: Mon, 27 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200318
  Issue No: Vol. 217, No. 10 (2020)
Profiling HPV-16–specific T cell responses reveals broad antigen
reactivities in oropharyngeal cancer patients
- Authors: Bhatt KH; Neller MA, Srihari S, et al.
  Abstract: Cellular immunotherapeutics targeting the human papillomavirus (HPV)–16 E6 and E7 proteins have achieved limited success in HPV-positive oropharyngeal cancer (OPC). Here we have conducted proteome-wide profiling of HPV-16–specific T cell responses in a cohort of 66 patients with HPV-associated OPC and 22 healthy individuals. Unexpectedly, HPV-specific T cell responses from OPC patients were not constrained to the E6 and E7 antigens; they also recognized E1, E2, E4, E5, and L1 proteins as dominant targets for virus-specific CD8+ and CD4+ T cells. Multivariate analysis incorporating tumor staging, treatment status, and smoking history revealed that treatment status had the most significant impact on HPV-specific CD8+ and CD4+ T cell immunity. Specifically, the breadth and overall strength of HPV-specific T cell responses were significantly higher before the commencement of curative therapy than after therapy. These data provide the first glimpse of the overall human T cell response to HPV in a clinical setting and offer groundbreaking insight into future development of cellular immunotherapies for HPV-associated OPC patients.
  PubDate: Mon, 27 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200389
  Issue No: Vol. 217, No. 10 (2020)
PKM2 promotes Th17 cell differentiation and autoimmune inflammation by
fine-tuning STAT3 activation
- Authors: Damasceno L; Prado D, Veras F, et al.
  Abstract: Th17 cell differentiation and pathogenicity depend on metabolic reprogramming inducing shifts toward glycolysis. Here, we show that the pyruvate kinase M2 (PKM2), a glycolytic enzyme required for cancer cell proliferation and tumor progression, is a key factor mediating Th17 cell differentiation and autoimmune inflammation. We found that PKM2 is highly expressed throughout the differentiation of Th17 cells in vitro and during experimental autoimmune encephalomyelitis (EAE) development. Strikingly, PKM2 is not required for the metabolic reprogramming and proliferative capacity of Th17 cells. However, T cell–specific PKM2 deletion impairs Th17 cell differentiation and ameliorates symptoms of EAE by decreasing Th17 cell–mediated inflammation and demyelination. Mechanistically, PKM2 translocates into the nucleus and interacts with STAT3, enhancing its activation and thereby increasing Th17 cell differentiation. Thus, PKM2 acts as a critical nonmetabolic regulator that fine-tunes Th17 cell differentiation and function in autoimmune-mediated inflammation.
  PubDate: Wed, 22 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20190613
  Issue No: Vol. 217, No. 10 (2020)
Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and
cytokine response to antigen
- Authors: Poholek CH; Raphael I, Wu D, et al.
  Abstract: The STAT3 signaling pathway is required for early Th17 cell development, and therapies targeting this pathway are used for autoimmune disease. However, the role of STAT3 in maintaining inflammatory effector Th17 cell function has been unexplored. Th17ΔSTAT3 mice, which delete STAT3 in effector Th17 cells, were resistant to experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Th17 cell numbers declined after STAT3 deletion, corresponding to reduced cell cycle. Th17ΔSTAT3 cells had increased IL-6–mediated phosphorylation of STAT1, known to have antiproliferative functions. Th17ΔSTAT3 cells also had reduced mitochondrial membrane potential, which can regulate intracellular Ca2+. Accordingly, Th17ΔSTAT3 cells had reduced production of proinflammatory cytokines when stimulated with myelin antigen but normal production of cytokines when TCR-induced Ca2+ flux was bypassed with ionomycin. Thus, early transcriptional roles of STAT3 in developing Th17 cells are later complimented by noncanonical STAT3 functions that sustain pathogenic Th17 cell proliferation and cytokine production.
  PubDate: Wed, 22 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20191761
  Issue No: Vol. 217, No. 10 (2020)
Cancer cell CCR2 orchestrates suppression of the adaptive immune response
- Authors: Fein MR; He X, Almeida AS, et al.
  Abstract: C-C chemokine receptor type 2 (CCR2) is expressed on monocytes and facilitates their recruitment to tumors. Though breast cancer cells also express CCR2, its functions in these cells are unclear. We found that Ccr2 deletion in cancer cells led to reduced tumor growth and approximately twofold longer survival in an orthotopic, isograft breast cancer mouse model. Deletion of Ccr2 in cancer cells resulted in multiple alterations associated with better immune control: increased infiltration and activation of cytotoxic T lymphocytes (CTLs) and CD103+ cross-presenting dendritic cells (DCs), as well as up-regulation of MHC class I and down-regulation of checkpoint regulator PD-L1 on the cancer cells. Pharmacological or genetic targeting of CCR2 increased cancer cell sensitivity to CTLs and enabled the cancer cells to induce DC maturation toward the CD103+ subtype. Consistently, Ccr2−/− cancer cells did not induce immune suppression in Batf3−/− mice lacking CD103+ DCs. Our results establish that CCR2 signaling in cancer cells can orchestrate suppression of the immune response.
  PubDate: Wed, 15 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20181551
  Issue No: Vol. 217, No. 10 (2020)
Transmembrane TNF drives osteoproliferative joint inflammation reminiscent
of human spondyloarthritis
- Authors: Kaaij MH; van Tok MN, Blijdorp IC, et al.
  Abstract: TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). It remains incompletely understood how TNF can lead to different disease phenotypes such as destructive peripheral polysynovitis in RA versus axial and peripheral osteoproliferative inflammation in SpA. We observed a marked increase of transmembrane (tm) versus soluble (s) TNF in SpA versus RA together with a decrease in the enzymatic activity of ADAM17. In contrast with the destructive polysynovitis observed in classical TNF overexpression models, mice overexpressing tmTNF developed axial and peripheral joint disease with synovitis, enthesitis, and osteitis. Histological and radiological assessment evidenced marked endochondral new bone formation leading to joint ankylosis over time. SpA-like inflammation, but not osteoproliferation, was dependent on TNF-receptor I and mediated by stromal tmTNF overexpression. Collectively, these data indicate that TNF can drive distinct inflammatory pathologies. We propose that tmTNF is responsible for the key pathological features of SpA.
  PubDate: Tue, 14 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200288
  Issue No: Vol. 217, No. 10 (2020)
FcRn is a CD32a coreceptor that determines susceptibility to IgG immune
complex–driven autoimmunity
- Authors: Hubbard JJ; Pyzik M, Rath T, et al.
  Abstract: IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) γ-receptors (FcγRs). Of these, the highly prevalent FcγRIIa (CD32a) histidine (H)-131 variant (CD32aH) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32aR) variant, CD32aH more avidly bound human (h) IgG1 IC and formed a ternary complex with the neonatal Fc receptor (FcRn) under acidic conditions. In primary human and mouse cells, both CD32a variants required FcRn to induce innate and adaptive immune responses to hIgG1 ICs, which were augmented in the setting of CD32aH. Conversely, FcRn induced responses to IgG IC independently of classical FcγR, but optimal responses required FcRn and FcγR. Finally, FcRn blockade decreased inflammation in a rheumatoid arthritis model without reducing circulating autoantibody levels, providing support for FcRn’s direct role in IgG IC-associated inflammation. Thus, CD32a and FcRn coregulate IgG IC-mediated immunity in a manner favoring the CD32aH variant, providing a novel mechanism for its disease association.
  PubDate: Mon, 13 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200359
  Issue No: Vol. 217, No. 10 (2020)
Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of
versican
- Authors: Hong CC; Tang AT, Detter MR, et al.
  Abstract: Cerebral cavernous malformations (CCMs) form following loss of the CCM protein complex in brain endothelial cells due to increased endothelial MEKK3 signaling and KLF2/4 transcription factor expression, but the downstream events that drive lesion formation remain undefined. Recent studies have revealed that CCM lesions expand by incorporating neighboring wild-type endothelial cells, indicative of a cell nonautonomous mechanism. Here we find that endothelial loss of ADAMTS5 reduced CCM formation in the neonatal mouse model. Conversely, endothelial gain of ADAMTS5 conferred early lesion genesis in the absence of increased KLF2/4 expression and synergized with KRIT1 loss of function to create large malformations. Lowering versican expression reduced CCM burden, indicating that versican is the relevant ADAMTS5 substrate and that lesion formation requires proteolysis but not loss of this extracellular matrix protein. These findings identify endothelial secretion of ADAMTS5 and cleavage of versican as downstream mechanisms of CCM pathogenesis and provide a basis for the participation of wild-type endothelial cells in lesion formation.
  PubDate: Fri, 10 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200140
  Issue No: Vol. 217, No. 10 (2020)
Deciphering and predicting CD4 + T cell immunodominance of influenza virus
hemagglutinin
- Authors: Cassotta A; Paparoditis P, Geiger R, et al.
  Abstract: The importance of CD4+ T helper (Th) cells is well appreciated in view of their essential role in the elicitation of antibody and cytotoxic T cell responses. However, the mechanisms that determine the selection of immunodominant epitopes within complex protein antigens remain elusive. Here, we used ex vivo stimulation of memory T cells and screening of naive and memory T cell libraries, combined with T cell cloning and TCR sequencing, to dissect the human naive and memory CD4+ T cell repertoire against the influenza pandemic H1 hemagglutinin (H1-HA). We found that naive CD4+ T cells have a broad repertoire, being able to recognize naturally processed as well as cryptic peptides spanning the whole H1-HA sequence. In contrast, memory Th cells were primarily directed against just a few immunodominant peptides that were readily detected by mass spectrometry–based MHC-II peptidomics and predicted by structural accessibility analysis. Collectively, these findings reveal the presence of a broad repertoire of naive T cells specific for cryptic H1-HA peptides and demonstrate that antigen processing represents a major constraint determining immunodominance.
  PubDate: Thu, 09 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200206
  Issue No: Vol. 217, No. 10 (2020)
Mutations in the exocyst component EXOC2 cause severe defects in human
brain development
- Authors: Van Bergen NJ; Ahmed S, Collins F, et al.
  Abstract: The exocyst, an octameric protein complex, is an essential component of the membrane transport machinery required for tethering and fusion of vesicles at the plasma membrane. We report pathogenic variants in an exocyst subunit, EXOC2 (Sec5). Affected individuals have severe developmental delay, dysmorphism, and brain abnormalities; variability associated with epilepsy; and poor motor skills. Family 1 had two offspring with a homozygous truncating variant in EXOC2 that leads to nonsense-mediated decay of EXOC2 transcript, a severe reduction in exocytosis and vesicle fusion, and undetectable levels of EXOC2 protein. The patient from Family 2 had a milder clinical phenotype and reduced exocytosis. Cells from both patients showed defective Arl13b localization to the primary cilium. The discovery of mutations that partially disable exocyst function provides valuable insight into this essential protein complex in neural development. Since EXOC2 and other exocyst complex subunits are critical to neuronal function, our findings suggest that EXOC2 variants are the cause of the patients’ neurological disorders.
  PubDate: Wed, 08 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20192040
  Issue No: Vol. 217, No. 10 (2020)
Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes
- Authors: Mosialou I; Shikhel S, Luo N, et al.
  Abstract: Regulation of food intake is a recently identified endocrine function of bone that is mediated by Lipocalin-2 (LCN2). Osteoblast-secreted LCN2 suppresses appetite and decreases fat mass while improving glucose metabolism. We now show that serum LCN2 levels correlate with insulin levels and β-cell function, indices of healthy glucose metabolism, in obese mice and obese, prediabetic women. However, LCN2 serum levels also correlate with body mass index and insulin resistance in the same individuals and are increased in obese mice. To dissect this apparent discrepancy, we modulated LCN2 levels in mice. Silencing Lcn2 expression worsens metabolic dysfunction in genetic and diet-induced obese mice. Conversely, increasing circulating LCN2 levels improves metabolic parameters and promotes β-cell function in mouse models of β-cell failure acting as a growth factor necessary for β-cell adaptation to higher metabolic load. These results indicate that LCN2 up-regulation is a protective mechanism to counteract obesity-induced glucose intolerance by decreasing food intake and promoting adaptive β-cell proliferation.
  PubDate: Wed, 08 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20191261
  Issue No: Vol. 217, No. 10 (2020)
PDGFA-associated protein 1 protects mature B lymphocytes from
stress-induced cell death and promotes antibody gene diversification
- Authors: Delgado-Benito V; Berruezo-Llacuna M, Altwasser R, et al.
  Abstract: The establishment of protective humoral immunity is dependent on the ability of mature B cells to undergo antibody gene diversification while adjusting to the physiological stressors induced by activation with the antigen. Mature B cells diversify their antibody genes by class switch recombination (CSR) and somatic hypermutation (SHM), which are both dependent on efficient induction of activation-induced cytidine deaminase (AID). Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation and ensures efficient antibody diversification by promoting their survival and optimal function.
  PubDate: Wed, 01 Jul 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200137
  Issue No: Vol. 217, No. 10 (2020)
Single-cell analysis of germinal-center B cells informs on lymphoma cell
of origin and outcome
- Authors: Holmes AB; Corinaldesi C, Shen Q, et al.
  Abstract: In response to T cell–dependent antigens, mature B cells are stimulated to form germinal centers (GCs), the sites of B cell affinity maturation and the cell of origin (COO) of most B cell lymphomas. To explore the dynamics of GC B cell development beyond the known dark zone and light zone compartments, we performed single-cell (sc) transcriptomic analysis on human GC B cells and identified multiple functionally linked subpopulations, including the distinct precursors of memory B cells and plasma cells. The gene expression signatures associated with these GC subpopulations were effective in providing a sc-COO for ∼80% of diffuse large B cell lymphomas (DLBCLs) and identified novel prognostic subgroups of DLBCL.
  PubDate: Tue, 30 Jun 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200483
  Issue No: Vol. 217, No. 10 (2020)
Potent human broadly neutralizing antibodies to hepatitis B virus from
natural controllers
- Authors: Hehle V; Beretta M, Bourgine M, et al.
  Abstract: Rare individuals can naturally clear chronic hepatitis B virus (HBV) infection and acquire protection from reinfection as conferred by vaccination. To examine the protective humoral response against HBV, we cloned and characterized human antibodies specific to the viral surface glycoproteins (HBsAg) from memory B cells of HBV vaccinees and controllers. We found that human HBV antibodies are encoded by a diverse set of immunoglobulin genes and recognize various conformational HBsAg epitopes. Strikingly, HBsAg-specific memory B cells from natural controllers mainly produced neutralizing antibodies able to cross-react with several viral genotypes. Furthermore, monotherapy with the potent broadly neutralizing antibody Bc1.187 suppressed viremia in vivo in HBV mouse models and led to post-therapy control of the infection in a fraction of animals. Thus, human neutralizing HBsAg antibodies appear to play a key role in the spontaneous control of HBV and represent promising immunotherapeutic tools for achieving HBV functional cure in chronically infected humans.
  PubDate: Wed, 24 Jun 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200840
  Issue No: Vol. 217, No. 10 (2020)