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Journal of Experimental Medicine
Journal Prestige (SJR): 8.615

Citation Impact (citeScore): 9
Number of Followers: 46

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

[3 journals]

Over a century of novel conceptual insights: The beginning of JEM ’s
125th anniversary year
- Authors: .
  PubDate: Wed, 23 Dec 2020 00:00:00 GMT
  DOI: 10.1084/jem.20202668
  Issue No: Vol. 218, No. 1 (2020)
Gatekeepers of the fetus: Characterization of placental macrophages
- Authors: Megli C; Coyne CB.
  Abstract: In this issue of JEM, Thomas et al. (https://doi.org/10.1084/jem.20200891) provide elegant technological and conceptual advances that further our understanding of the immune cells enriched at the maternal–fetal interface. Using new isolation strategies to better separate maternal- and fetal-derived cells, the authors identify previously undefined maternal-derived immune cells associated with the fetal-derived placenta and provide an in-depth analysis of the markers and characteristics of placental Hofbauer cells.
  PubDate: Mon, 21 Dec 2020 00:00:00 GMT
  DOI: 10.1084/jem.20202071
  Issue No: Vol. 218, No. 1 (2020)
Emerging paradigms in metastasis research
- Authors: Abdul Pari A; Singhal M, Augustin HG.
  Abstract: Historically, therapy of metastatic disease has essentially been limited to using strategies that were identified and established to shrink primary tumors. The limited efficacy of such treatments on overall patient survival stems from diverging intrinsic and extrinsic characteristics of a primary tumor and metastases originating therefrom. To develop better therapeutic strategies to treat metastatic disease, there is an urgent need to shift the paradigm in preclinical metastasis research by conceptualizing metastatic dissemination, colonization, and growth as spatiotemporally dynamic processes and identifying rate-limiting vulnerabilities of the metastatic cascade. Clinically, while metastatic colonization remains the most attractive therapeutic avenue, comprehensive understanding of earlier steps may unravel novel metastasis-restricting therapies for presurgical neoadjuvant application. Moving beyond a primary tumor-centric view, this review adopts a holistic approach to understanding the spatial and temporal progression of metastasis. After reviewing recent developments in metastasis research, we highlight some of the grand challenges and propose a framework to expedite mechanism-based discovery research feeding the translational pipeline.
  PubDate: Fri, 18 Dec 2020 00:00:00 GMT
  DOI: 10.1084/jem.20190218
  Issue No: Vol. 218, No. 1 (2020)
Lipid metabolism and cancer
- Authors: Bian X; Liu R, Meng Y, et al.
  Abstract: Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Cancer cells harness lipid metabolism to obtain energy, components for biological membranes, and signaling molecules needed for proliferation, survival, invasion, metastasis, and response to the tumor microenvironment impact and cancer therapy. Here, we summarize and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in cancer cells and introduce different approaches that have been clinically used to disrupt lipid metabolism in cancer therapy.
  PubDate: Fri, 18 Dec 2020 00:00:00 GMT
  DOI: 10.1084/jem.20201606
  Issue No: Vol. 218, No. 1 (2020)
The current landscape of single-cell transcriptomics for cancer
immunotherapy
- Authors: Guruprasad P; Lee Y, Kim K, et al.
  Abstract: Immunotherapies such as immune checkpoint blockade and adoptive cell transfer have revolutionized cancer treatment, but further progress is hindered by our limited understanding of tumor resistance mechanisms. Emerging technologies now enable the study of tumors at the single-cell level, providing unprecedented high-resolution insights into the genetic makeup of the tumor microenvironment and immune system that bulk genomics cannot fully capture. Here, we highlight the recent key findings of the use of single-cell RNA sequencing to deconvolute heterogeneous tumors and immune populations during immunotherapy. Single-cell RNA sequencing has identified new crucial factors and cellular subpopulations that either promote tumor progression or leave tumors vulnerable to immunotherapy. We anticipate that the strategic use of single-cell analytics will promote the development of the next generation of successful, rationally designed immunotherapeutics.
  PubDate: Fri, 18 Dec 2020 00:00:00 GMT
  DOI: 10.1084/jem.20201574
  Issue No: Vol. 218, No. 1 (2020)
B cells and cancer: To B or not to B'
- Authors: Fridman W; Petitprez F, Meylan M, et al.
  Abstract: Whereas T cells have been considered the major immune cells of the tumor microenvironment able to induce tumor regression and control cancer clinical outcome, a burst of recent publications pointed to the fact that B cells may also play a prominent role. Activated in germinal centers of tertiary lymphoid structures, B cells can directly present tumor-associated antigens to T cells or produce antibodies that increase antigen presentation to T cells or kill tumor cells, resulting in a beneficial clinical impact. Immune complexes can also increase inflammation, angiogenesis, and immunosuppression via macrophage and complement activation, resulting in deleterious impact.
  PubDate: Fri, 18 Dec 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200851
  Issue No: Vol. 218, No. 1 (2020)
Tumor-infiltrating dendritic cell states are conserved across solid human
cancers
- Authors: Gerhard GM; Bill R, Messemaker M, et al.
  Abstract: Dendritic cells (DCs) contribute a small fraction of the tumor microenvironment but are emerging as an essential antitumor component based on their ability to foster T cell immunity and immunotherapy responses. Here, we discuss our expanding view of DC heterogeneity in human tumors, as revealed with meta-analysis of single-cell transcriptome profiling studies. We further examine tumor-infiltrating DC states that are conserved across patients, cancer types, and species and consider the fundamental and clinical relevance of these findings. Finally, we provide an outlook on research opportunities to further explore mechanisms governing tumor-infiltrating DC behavior and functions.
  PubDate: Fri, 18 Dec 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200264
  Issue No: Vol. 218, No. 1 (2020)
Understanding adverse events of immunotherapy: A mechanistic perspective
- Authors: Burke KP; Grebinoski S, Sharpe AH, et al.
  Abstract: The treatment of many cancers has been revolutionized by immune checkpoint blockade (ICB) as a standard-of-care therapeutic. Despite many successes, a large proportion of patients treated with ICB agents experience immune-related adverse events (irAEs) in the form of clinical autoimmunity, ranging from mild to life threatening, that can limit cancer treatment. A mechanistic understanding of these irAEs is required to better treat or prevent irAEs and to predict those patients who are susceptible to irAEs. We propose several mechanisms that may contribute to the generation of irAEs: (1) preexisting susceptibility to autoimmunity, (2) aberrant presentation of “self” by the tumor, and (3) loss of tolerance driven by the tumor or tissue microenvironment.
  PubDate: Fri, 18 Dec 2020 00:00:00 GMT
  DOI: 10.1084/jem.20192179
  Issue No: Vol. 218, No. 1 (2020)
Correction: Dietary restriction improves repopulation but impairs lymphoid
differentiation capacity of hematopoietic stem cells in early aging
- Authors: Tang D; Tao S, Chen Z, et al.
  Abstract: The authors regret that in the original version of Fig. 1 B, the legend should have stated n = 3–5 mice per group, not 4–5 mice per group. In addition, the P value for the 1-mo CD150lo time point should have been **, P < 0.01, not ****, P < 0.0001. The corrected figure and legend are shown here. The authors also clarify that the P values in Fig. 2, E–G; Fig. 5, A–C and F–I; Fig. 6, F–J; Fig. 7, D–H; Fig. 8; and Fig. 9, A–C, E–K, and M–P depict results derived from the unpaired Student’s t test. The one-way ANOVA indicated in the legends was employed to confirm that the depicted differences were significant in multi-comparison testing. The errors in Fig. 1 appear in print and in PDFs downloaded before December 3, 2020.
  PubDate: Thu, 17 Dec 2020 00:00:00 GMT
  DOI: 10.1084/jem.2015110012042020C
  Issue No: Vol. 218, No. 1 (2020)
Correction: Transcription cofactor GRIP1 differentially affects myeloid
cell–driven neuroinflammation and response to IFN-β therapy
- Authors: Mimouna S; Rollins DA, Shibu G, et al.
  Abstract: Vol. 218, No. 1 10.1084/jem.20192386 October 12, 2020
  PubDate: Mon, 23 Nov 2020 00:00:00 GMT
  DOI: 10.1084/jem.2019238611162020C
  Issue No: Vol. 218, No. 1 (2020)
A new chapter in the CD8 T reg story
- Authors: Cantor H; Kim H.
  Abstract: CD8+ T reg cells play an important role in the maintenance of self-tolerance and can inhibit the development of autoimmune disease. In this issue of JEM, Mishra et al. (https://doi.org/10.1084/jem.20200030) reveal that TGF-β signaling and an Eomes-dependent genetic program contribute to CD8 T reg cell differentiation and function.
  PubDate: Thu, 12 Nov 2020 00:00:00 GMT
  DOI: 10.1084/jem.20201746
  Issue No: Vol. 218, No. 1 (2020)
Gut microbiome stability and dynamics in healthy donors and patients with
non-gastrointestinal cancers
- Authors: Byrd AL; Liu M, Fujimura KE, et al.
  Abstract: As microbial therapeutics are increasingly being tested in diverse patient populations, it is essential to understand the host and environmental factors influencing the microbiome. Through analysis of 1,359 gut microbiome samples from 946 healthy donors of the Milieu Intérieur cohort, we detail how microbiome composition is associated with host factors, lifestyle parameters, and disease states. Using a genome-based taxonomy, we found biological sex was the strongest driver of community composition. Additionally, bacterial populations shift across decades of life (age 20–69), with Bacteroidota species consistently increased with age while Actinobacteriota species, including Bifidobacterium, decreased. Longitudinal sampling revealed that short-term stability exceeds interindividual differences. By accounting for these factors, we defined global shifts in the microbiomes of patients with non-gastrointestinal tumors compared with healthy donors. Together, these results demonstrated that the microbiome displays predictable variations as a function of sex, age, and disease state. These variations must be considered when designing microbiome-targeted therapies or interpreting differences thought to be linked to pathophysiology or therapeutic response.
  PubDate: Wed, 11 Nov 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200606
  Issue No: Vol. 218, No. 1 (2020)
Placental inflammasome signaling: Protection for mother and baby
- Authors: Burgener S; Schroder K.
  Abstract: The second trimester of pregnancy is traditionally viewed as an immunosuppressive state. Megli et al. (https://doi.org/10.1084/jem.20200649) change this paradigm, showing that midgestation induces inflammasome signaling in placental trophoblasts to promote fetal and maternal antimicrobial defense. The placenta is thus a dynamic immunological organ.
  PubDate: Wed, 11 Nov 2020 00:00:00 GMT
  DOI: 10.1084/jem.20201738
  Issue No: Vol. 218, No. 1 (2020)
α-Synuclein modulates tau spreading in mouse brains
- Authors: Bassil F; Meymand ES, Brown HJ, et al.
  Abstract: α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson’s disease (PD) and Alzheimer’s disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate–derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.
  PubDate: Thu, 22 Oct 2020 00:00:00 GMT
  DOI: 10.1084/jem.20192193
  Issue No: Vol. 218, No. 1 (2020)
Phenotypic and functional characterization of first-trimester human
placental macrophages, Hofbauer cells
- Authors: Thomas JR; Appios A, Zhao X, et al.
  Abstract: Hofbauer cells (HBCs) are a population of macrophages found in high abundance within the stroma of the first-trimester human placenta. HBCs are the only fetal immune cell population within the stroma of healthy placenta. However, the functional properties of these cells are poorly described. Aligning with their predicted origin via primitive hematopoiesis, we find that HBCs are transcriptionally similar to yolk sac macrophages. Phenotypically, HBCs can be identified as HLA-DR−FOLR2+ macrophages. We identify a number of factors that HBCs secrete (including OPN and MMP-9) that could affect placental angiogenesis and remodeling. We determine that HBCs have the capacity to play a defensive role, where they are responsive to Toll-like receptor stimulation and are microbicidal. Finally, we also identify a population of placenta-associated maternal macrophages (PAMM1a) that adhere to the placental surface and express factors, such as fibronectin, that may aid in repair.
  PubDate: Mon, 19 Oct 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200891
  Issue No: Vol. 218, No. 1 (2020)
Exit from germinal center to become quiescent memory B cells depends on
metabolic reprograming and provision of a survival signal
- Authors: Inoue T; Shinnakasu R, Kawai C, et al.
  Abstract: A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38intBcl6hi/intEfnb1+ cells with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR that, in turn, contributed to their survival and development. We also found that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to adopt a memory B cell fate.
  PubDate: Mon, 12 Oct 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200866
  Issue No: Vol. 218, No. 1 (2020)
Transcription cofactor GRIP1 differentially affects myeloid cell–driven
neuroinflammation and response to IFN-β therapy
- Authors: Mimouna S; Rollins DA, Shibu G, et al.
  Abstract: Macrophages (MФ) and microglia (MG) are critical in the pathogenesis of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Glucocorticoids (GCs) and interferon β (IFN-β) are frontline treatments for MS, and disrupting each pathway in mice aggravates EAE. Glucocorticoid receptor–interacting protein 1 (GRIP1) facilitates both GR and type I IFN transcriptional actions; hence, we evaluated the role of GRIP1 in neuroinflammation. Surprisingly, myeloid cell–specific loss of GRIP1 dramatically reduced EAE severity, immune cell infiltration of the CNS, and MG activation and demyelination specifically during the neuroinflammatory phase of the disease, yet also blunted therapeutic properties of IFN-β. MФ/MG transcriptome analyses at the bulk and single-cell levels revealed that GRIP1 deletion attenuated nuclear receptor, inflammatory and, interestingly, type I IFN pathways and promoted the persistence of a homeostatic MG signature. Together, these results uncover the multifaceted function of type I IFN in MS/EAE pathogenesis and therapy, and an unexpectedly permissive role of myeloid cell GRIP1 in neuroinflammation.
  PubDate: Mon, 12 Oct 2020 00:00:00 GMT
  DOI: 10.1084/jem.20192386
  Issue No: Vol. 218, No. 1 (2020)
SHP2 inhibition diminishes KRAS G12C cycling and promotes tumor
microenvironment remodeling
- Authors: Fedele C; Li S, Teng K, et al.
  Abstract: KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site–specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.
  PubDate: Thu, 08 Oct 2020 00:00:00 GMT
  DOI: 10.1084/jem.20201414
  Issue No: Vol. 218, No. 1 (2020)
Qki is an essential regulator of microglial phagocytosis in demyelination
- Authors: Ren J; Dai C, Zhou X, et al.
  Abstract: The mechanism underpinning the regulation of microglial phagocytosis in demyelinating diseases is unclear. Here, we showed that the Quaking protein (Qki) in microglia was greatly induced by demyelination in the brains of both mice and humans. Deletion of the Quaking gene (Qk) in microglia severely impaired the clearance of myelin debris. Transcriptomic profiling indicated that depletion of Qki impaired total RNA levels and splicing of the genes involved in phagosome formation and maturation. RNA immunoprecipitation (RIP) confirmed the physical interactions between the Qki protein and the mRNAs of Qki targets that are involved in phagocytosis, indicating that Qki regulates their RNA stability. Both Qki depletion and inhibition of Qki target Cd36 greatly reduced the phagocytic activity of microglia and macrophages. The defective uptake and degradation of myelin debris caused by Qki depletion in microglia resulted in unresolved myelin debris that impaired axon integrity, oligodendrocyte maturation, and subsequent remyelination. Thus, our results demonstrate that Qki is an essential regulator of microglia’s phagocytic activity under demyelinating conditions.
  PubDate: Tue, 06 Oct 2020 00:00:00 GMT
  DOI: 10.1084/jem.20190348
  Issue No: Vol. 218, No. 1 (2020)
PD-1 restraint of regulatory T cell suppressive activity is critical for
immune tolerance
- Authors: Tan CL; Kuchroo JR, Sage PT, et al.
  Abstract: Inhibitory signals through the PD-1 pathway regulate T cell activation, T cell tolerance, and T cell exhaustion. Studies of PD-1 function have focused primarily on effector T cells. Far less is known about PD-1 function in regulatory T (T reg) cells. To study the role of PD-1 in T reg cells, we generated mice that selectively lack PD-1 in T reg cells. PD-1–deficient T reg cells exhibit an activated phenotype and enhanced immunosuppressive function. The in vivo significance of the potent suppressive capacity of PD-1–deficient T reg cells is illustrated by ameliorated experimental autoimmune encephalomyelitis (EAE) and protection from diabetes in nonobese diabetic (NOD) mice lacking PD-1 selectively in T reg cells. We identified reduced signaling through the PI3K–AKT pathway as a mechanism underlying the enhanced suppressive capacity of PD-1–deficient T reg cells. Our findings demonstrate that cell-intrinsic PD-1 restraint of T reg cells is a significant mechanism by which PD-1 inhibitory signals regulate T cell tolerance and autoimmunity.
  PubDate: Tue, 06 Oct 2020 00:00:00 GMT
  DOI: 10.1084/jem.20182232
  Issue No: Vol. 218, No. 1 (2020)
Nociceptors protect sickle cell disease mice from vaso-occlusive episodes
and chronic organ damage
- Authors: Xu C; Gulinello M, Frenette PS.
  Abstract: Sickle cell disease (SCD) is a common hereditary hematologic disorder. SCD patients suffer from acute vaso-occlusive episodes (VOEs), chronic organ damage, and premature death, with few therapeutic options. Although severe pain is a major clinical manifestation of SCD, it remains unknown whether nociception plays a role in SCD pathogenesis. To address this question, we generated nociceptor-deficient SCD mice and found, unexpectedly, that the absence of nociception led to more severe and more lethal VOE, indicating that somatosensory nerves protect SCD mice from VOE. Mechanistically, the beneficial effects of sensory nerves were induced by the neuropeptide calcitonin gene–related peptide (CGRP), which acted on hematopoietic cells. Additionally, oral capsaicin consumption, which can activate somatosensory nerves by binding to TRPV1, dramatically alleviated acute VOE and significantly prevented chronic liver and kidney damage in SCD mice. Thus, the manipulation of nociception may provide a promising approach to treat SCD.
  PubDate: Mon, 05 Oct 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200065
  Issue No: Vol. 218, No. 1 (2020)
Influenza infection fortifies local lymph nodes to promote lung-resident
heterosubtypic immunity
- Authors: Paik DH; Farber DL.
  Abstract: Influenza infection generates tissue-resident memory T cells (TRMs) that are maintained in the lung and can mediate protective immunity to heterologous influenza strains, but the precise mechanisms of local T cell–mediated protection are not well understood. In a murine heterosubtypic influenza challenge model, we demonstrate that protective lung T cell responses derive from both in situ activation of TRMs and the enhanced generation of effector T cells from the local lung draining mediastinal lymph nodes (medLNs). Primary infection fortified the medLNs with an increased number of conventional dendritic cells (cDCs) that mediate enhanced priming of T cells, including those specific for newly encountered epitopes; cDC depletion during the recall response diminished medLN T cell generation and heterosubtypic immunity. Our study shows that during a protective recall response, cDCs in a fortified LN environment enhance the breadth, generation, and tissue migration of effector T cells to augment lung TRM responses.
  PubDate: Thu, 01 Oct 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200218
  Issue No: Vol. 218, No. 1 (2020)
Helicobacter pylori metabolites exacerbate gastritis through C-type lectin
receptors
- Authors: Nagata M; Toyonaga K, Ishikawa E, et al.
  Abstract: Helicobacter pylori causes gastritis, which has been attributed to the development of H. pylori–specific T cells during infection. However, the mechanism underlying innate immune detection leading to the priming of T cells is not fully understood, as H. pylori evades TLR detection. Here, we report that H. pylori metabolites modified from host cholesterol exacerbate gastritis through the interaction with C-type lectin receptors. Cholesteryl acyl α-glucoside (αCAG) and cholesteryl phosphatidyl α-glucoside (αCPG) were identified as noncanonical ligands for Mincle (Clec4e) and DCAR (Clec4b1). During chronic infection, H. pylori–specific T cell responses and gastritis were ameliorated in Mincle-deficient mice, although bacterial burdens remained unchanged. Furthermore, a mutant H. pylori strain lacking αCAG and αCPG exhibited an impaired ability to cause gastritis. Thus H. pylori–specific modification of host cholesterol plays a pathophysiological role that exacerbates gastric inflammation by triggering C-type lectin receptors.
  PubDate: Tue, 29 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200815
  Issue No: Vol. 218, No. 1 (2020)
Activation of 4-1BBL + B cells with CD40 agonism and IFNγ elicits potent
immunity against glioblastoma
- Authors: Lee-Chang C; Miska J, Hou D, et al.
  Abstract: Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B cell–based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNγ stimulation. BVax migrates to key secondary lymphoid organs and is proficient at antigen cross-presentation, which promotes both the survival and the functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunological memory that prevented the growth of new tumors upon subsequent reinjection in cured mice. GBM patient–derived BVax was successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.
  PubDate: Tue, 29 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200913
  Issue No: Vol. 218, No. 1 (2020)
TGF-β and Eomes control the homeostasis of CD8 + regulatory T cells
- Authors: Mishra S; Liao W, Liu Y, et al.
  Abstract: In addition to Foxp3+ CD4+ regulatory T cells (CD4+ T reg cells), Foxp3− CD8+ regulatory T cells (CD8+ T reg cells) are critical to maintain immune tolerance. However, the molecular programs that specifically control CD8+ but not CD4+ T reg cells are largely unknown. Here, we demonstrate that simultaneous disruption of both TGF-β receptor and transcription factor Eomesodermin (Eomes) in T cells results in lethal autoimmunity due to a specific defect in CD8+ but not CD4+ T reg cells. Further, TGF-β signal maintains the regulatory identity, while Eomes controls the follicular location of CD8+ T reg cells. Both TGF-β signal and Eomes coordinate to promote the homeostasis of CD8+ T reg cells. Together, we have identified a unique molecular program designed for CD8+ T reg cells.
  PubDate: Tue, 29 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200030
  Issue No: Vol. 218, No. 1 (2020)
Histamine H 2 receptor negatively regulates oligodendrocyte
differentiation in neonatal hypoxic-ischemic white matter injury
- Authors: Jiang L; Cheng L, Chen H, et al.
  Abstract: Neonatal hypoxic-ischemic encephalopathy (HIE) with the pathological characteristic of white matter injury often leads to lifelong cognitive and neurobehavioral dysfunction, but relevant therapies to promote remyelination are still unavailable. We found that histamine H2 receptor (H2R) negatively regulated the oligodendrocyte differentiation rate without affecting the oligodendrocytes at the oligodendrocyte precursor cell stage or mature stage following oxygen-glucose deprivation in vitro. Notably, selective deletion of the H2R gene (Hrh2) in differentiating oligodendrocytes (Hrh2fl/fl;CNPase-Cre) improved their differentiation, remyelination, and functional recovery following neonatal hypoxia-ischemia in mice. The regulation of oligodendrocyte differentiation by H2R is mediated by binding with Axin2, which leads to up-regulation of the Wnt/β-catenin signaling pathway. Furthermore, H2R antagonists also promoted oligodendrocyte differentiation and remyelination and the recovery of cognition and motor functions following neonatal hypoxia-ischemia. Thus, histamine H2R in oligodendrocytes could serve as a novel and effective therapeutic target for the retard of oligodendrocyte differentiation and remyelination following neonatal hypoxia-ischemia. The H2R antagonists may have potential therapeutic value for neonatal HIE.
  PubDate: Tue, 29 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20191365
  Issue No: Vol. 218, No. 1 (2020)
Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity
- Authors: Xiao Y; Qureischi M, Dietz L, et al.
  Abstract: Posttranslational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is largely unexplored. The NFAT transcription factors play an essential role in antigen receptor-mediated gene regulation. SUMOylation of NFATc1 represses IL-2 in vitro, but its role in T cell–mediated immune responses in vivo is unclear. To this end, we generated a novel transgenic mouse in which SUMO modification of NFATc1 is prevented. Avoidance of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. Elevated IL-2 production in T cells promoted T reg expansion and suppressed autoreactive or alloreactive immune responses. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Then, Blimp-1 repressed IL-2 itself, as well as the induced, proliferation-associated survival factor Bcl2A1. Collectively, these data demonstrate that prevention of NFATc1 SUMOylation fine-tunes T cell responses toward lasting tolerance. Thus, targeting NFATc1 SUMOylation presents a novel and promising strategy to treat T cell–mediated inflammatory diseases.
  PubDate: Mon, 28 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20181853
  Issue No: Vol. 218, No. 1 (2020)
Inflammasome signaling in human placental trophoblasts regulates immune
defense against Listeria monocytogenes infection
- Authors: Megli C; Morosky S, Rajasundaram D, et al.
  Abstract: The human placenta is a dynamic organ that modulates physiological adaptations to pregnancy. To define the immunological signature of the human placenta, we performed unbiased profiling of secreted immune factors from human chorionic villi isolated from placentas at mid and late stages of pregnancy. We show that placental trophoblasts constitutively secrete the inflammasome-associated cytokines IL-1β and IL-18, which is blocked by NLRP3 inflammasome inhibitors and occurs without detectable gasdermin D cleavage. We further show that placenta-derived IL-1β primes monocytes for inflammasome induction to protect against Listeria monocytogenes infection. Last, we show that the human placenta responds to L. monocytogenes infection through additional inflammasome activation and that inhibition of this pathway sensitizes villi to infection. Our results thus identify the inflammasome as an important mechanism by which the human placenta regulates systemic and local immunity during pregnancy to defend against L. monocytogenes infection.
  PubDate: Fri, 25 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200649
  Issue No: Vol. 218, No. 1 (2020)
Spatiotemporal restriction of endothelial cell calcium signaling is
required during leukocyte transmigration
- Authors: Dalal PJ; Sullivan DP, Weber EW, et al.
  Abstract: Endothelial cell calcium flux is critical for leukocyte transendothelial migration (TEM), which in turn is essential for the inflammatory response. Intravital microscopy of endothelial cell calcium dynamics reveals that calcium increases locally and transiently around the transmigration pore during TEM. Endothelial calmodulin (CaM), a key calcium signaling protein, interacts with the IQ domain of IQGAP1, which is localized to endothelial junctions and is required for TEM. In the presence of calcium, CaM binds endothelial calcium/calmodulin kinase IIδ (CaMKIIδ). Disrupting the function of CaM or CaMKII with small-molecule inhibitors, expression of a CaMKII inhibitory peptide, or expression of dominant negative CaMKIIδ significantly reduces TEM by interfering with the delivery of the lateral border recycling compartment (LBRC) to the site of TEM. Endothelial CaMKII is also required for TEM in vivo as shown in two independent mouse models. These findings highlight novel roles for endothelial CaM and CaMKIIδ in transducing the spatiotemporally restricted calcium signaling required for TEM.
  PubDate: Thu, 24 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20192378
  Issue No: Vol. 218, No. 1 (2020)
Immunotherapy during the acute SHIV infection of macaques confers
long-term suppression of viremia
- Authors: Nishimura Y; Donau OK, Dias J, et al.
  Abstract: We report that combination bNAb immunotherapy initiated on day 3 post-infection (PI) maintained durable CD8+ T cell–mediated suppression of SHIVAD8 viremia and preinoculation levels of CD4+ T cells in 9 of 13 treated monkeys during nearly 6 yr of observation, as assessed by successive CD8+ T cell–depletion experiments. In an extension of that study, two treatment interventions (bNAbs alone or cART plus bNAbs) beginning on week 2 PI were conducted and conferred controller status to 7 of 12 monkeys that was also dependent on control mediated by CD8+ cells. However, the median time to suppression of plasma viremia following intervention on week 2 was markedly delayed (85 wk) compared with combination bNAb immunotherapy initiated on day 3 (39 wk). In both cases, the principal correlate of virus control was the induction of CD8+ T cellular immunity.
  PubDate: Wed, 23 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20201214
  Issue No: Vol. 218, No. 1 (2020)
Lineage-specific regulation of inducible and constitutive mast cells in
allergic airway inflammation
- Authors: Derakhshan T; Samuchiwal SK, Hallen N, et al.
  Abstract: Murine mast cells (MCs) contain two lineages: inducible bone marrow–derived mucosal MCs (MMCs) and constitutive embryonic-derived connective tissue MCs (CTMCs). Here, we use RNA sequencing, flow cytometry, and genetic deletion in two allergic lung inflammation models to define these two lineages. We found that inducible MCs, marked by β7 integrin expression, are highly distinct from airway CTMCs at rest and during inflammation and unaffected by targeted CTMC deletion. β7High MCs expand and mature during lung inflammation as part of a TGF-β–inducible transcriptional program that includes the MMC-associated proteases Mcpt1 and Mcpt2, the basophil-associated protease Mcpt8, granule components, and the epithelial-binding αE integrin. In vitro studies using bone marrow–derived MCs (BMMCs) identified a requirement for SCF in this TGF-β–mediated development and found that epithelial cells directly elicit TGF-β–dependent BMMC up-regulation of mMCP-1 and αE integrin. Thus, our findings characterize the expansion of a distinct inducible MC subset in C57BL/6 mice and highlight the potential for epithelium to direct MMC development.
  PubDate: Fri, 18 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200321
  Issue No: Vol. 218, No. 1 (2020)
A crucial role for Jagunal homolog 1 in humoral immunity and antibody
glycosylation in mice and humans
- Authors: Hagelkruys A; Wirnsberger G, Stadlmann J, et al.
  Abstract: Jagunal homolog 1 (JAGN1) has been identified as a critical regulator of neutrophil biology in mutant mice and rare-disease patients carrying JAGN1 mutations. Here, we report that Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) of antibody-producing cells as well as decreased antibody production and secretion. Consequently, mice lacking Jagn1 in B cells exhibit reduced serum immunoglobulin (Ig) levels at steady state and fail to mount an efficient humoral immune response upon immunization with specific antigens or when challenged with viral infections. We also demonstrate that Jagn1 deficiency in B cells results in aberrant IgG N-glycosylation leading to enhanced Fc receptor binding. Jagn1 deficiency in particular affects fucosylation of IgG subtypes in mice as well as rare-disease patients with loss-of-function mutations in JAGN1. Moreover, we show that ER stress affects antibody glycosylation. Our data uncover a novel and key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.
  PubDate: Tue, 15 Sep 2020 00:00:00 GMT
  DOI: 10.1084/jem.20200559
  Issue No: Vol. 218, No. 1 (2020)