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| Open AccesssynNotch-programmed iPSC-derived NK cells usurp TIGIT and CD73 activities for glioblastoma therapy
Given its immunosuppressive effect in glioblastoma (GBM), targeting the TIGIT-CD155 axis presents an attractive therapeutic strategy. Here, the authors develop an adoptive natural killer (iNK) cells therapy with anti-CD155 synNotch-inducible CD73 antibody production to reverse the effect of TIGIT-CD155 signaling for the treatment of GBM.
- Kyle B. Lupo
- , Xue Yao
- & Sandro Matosevic
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Article
| Open AccessAltered receptor binding, antibody evasion and retention of T cell recognition by the SARS-CoV-2 XBB.1.5 spike protein
New variants of SARS-CoV-2 virus can evolve such that antibodies that recognised previous versions are not able to recognise newer versions. Here the authors characterise antibody binding to the XBB.1.5 variant and how antibodies and T cells from persons infected with earlier versions of SARS-CoV-2 are able to recognise and/or bind to the XBB.1.5 spike protein.
- Dhiraj Mannar
- , James W. Saville
- & Sriram Subramaniam
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Article
| Open AccessCoordinated inflammatory responses dictate Marburg virus control by reservoir bats
The authors show pro-inflammatory responses are needed for Marburg virus control in its natural bat reservoir, and that if reduced, humanlike disease and shedding results, suggesting that natural immunomodulatory stressors may increase spillover risk.
- Jonathan C. Guito
- , Shannon G. M. Kirejczyk
- & Jonathan S. Towner
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Article
| Open AccessComparative transcriptomics coupled to developmental grading via transgenic zebrafish reporter strains identifies conserved features in neutrophil maturation
Maturation of innate immune cells is a graded stereotypic process which is often conserved across species. Here authors label distinct neutrophil leukocyte developmental stages via generating combinations of transgenic zebrafish reporter strains, followed by transcriptome analysis of different neutrophil maturation stages and comparison to the gene expression profile of developing neutrophils from humans and mice.
- Stefanie Kirchberger
- , Mohamed R. Shoeb
- & Martin Distel
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Article
| Open AccessQ586B2 is a crucial virulence factor during the early stages of Trypanosoma brucei infection that is conserved amongst trypanosomatids
Sleeping sickness caused by African trypanosome parasites induces a chronic, and potentially lethal, infection in humans. Here, the authors uncover a conserved protein, Q586B2, playing an important regulatory role in Trypanosomatid infection establishment.
- Benoit Stijlemans
- , Patrick De Baetselier
- & Carl De Trez
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Article
| Open AccessType 1 interferons and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice
Although continuous activity of Foxo transcription factors substantially increase the life span of species such as Hydra vulgaris, these proteins have never been implicated in mammalian aging. In this study, the authors demonstrate that, with age, Foxo1 is down-regulated in mouse T lymphocytes and associated with exhaustion.
- Aurélie Durand
- , Nelly Bonilla
- & Bruno Lucas
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Article
| Open AccessHuman cytomegalovirus exploits STING signaling and counteracts IFN/ISG induction to facilitate infection of dendritic cells
Human cytomegalovirus (HCMV) is a ubiquitous pathogen associated with morbidity and mortality in the immunocompromised or immunonaive context. Here the authors show that HCMV exploits STING signalling and subverts the interferon response to support infection of monocyte derive dendritic cells.
- Bibiana Costa
- , Jennifer Becker
- & Ulrich Kalinke
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Article
| Open AccessNINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress
Fevers are known to be both beneficial and detrimental in disease, but the fundamental innate immune mechanisms driving pathology in this context remain unclear. Here, the authors show that a combination of LPS and heat stress induces inflammatory cell death, PANoptosis, that is dependent on the executioner molecule Ninjurin 1 (Ninj1) to release inflammatory molecules and drive pathogenesis.
- Joo-Hui Han
- , Rajendra Karki
- & Thirumala-Devi Kanneganti
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Article
| Open AccessSerum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma
The reasons for why hepatocellular carcinoma (HCC) is unresponsive to anti-PD-1 inhibition in some patients is not fully understood. Here the authors use human samples and mice tumour models to implicate serum amyloid A and STAT3 signalling involvement in the resistance to anti-PD1 immunotherapy in HCC.
- Meng He
- , Yongxiang Liu
- & Ning Lyu
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Article
| Open AccessS-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens
The generation of reactive oxygen and nitrogen species is an critical part of host defense against microbial infection. Here, Jia et al, characterize the mechanisms by which reactive nitrogen species can modulate innate immunity.
- Mutian Jia
- , Li Chai
- & Wei Zhao
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Article
| Open AccessIntestinal stroma guides monocyte differentiation to macrophages through GM-CSF
Stromal cells are key players in immune cell homeostasis. Here, the authors decipher subset-specific human stromal responses in inflammatory bowel disease and suggest that intestinal PDGFRA+CD142−/low fibroblasts guide monocyte transition to macrophages in human gut through GM-CSF.
- Egle Kvedaraite
- , Magda Lourda
- & Mattias Svensson
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Article
| Open AccessNucleocapsid protein-specific monoclonal antibodies protect mice against Crimean-Congo hemorrhagic fever virus
There are limited treatment options for infection with Crimean-Congo hemorrhagic fever virus in humans. Here, the authors show that a monoclonal antibody targeting the highly conserved viral nucleocapsid protein provides protective effects in a mouse model of infection.
- Aura R. Garrison
- , Vanessa Moresco
- & Joseph W. Golden
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Article
| Open AccessMarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution
Three-dimensional analysis of the intact bone marrow within whole long bones remains very challenging. Here, the authors present a method that stabilizes the marrow and provides subcellular resolution of fluorescent signals throughout the murine femur.
- Till Fabian Mertens
- , Alina Tabea Liebheit
- & Anja Erika Hauser
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Article
| Open AccessPrior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection
Flavivirus infection or vaccination can induce cross-reactive immune responses. Here, the authors show how previous immunization with the tick-borne encephalitis virus vaccine affects the immune response to the yellow fever vaccine, suggesting that the yellow fever vaccine virus conceals epitopes shared with other flaviviruses in flavivirus-naive but not flavivirus-pre-exposed individuals.
- Antonio Santos-Peral
- , Fabian Luppa
- & Simon Rothenfusser
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Article
| Open AccessThe ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment
The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.
- Elizabeth L. Hardaker
- , Emilio Sanseviero
- & Simon T. Barry
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Article
| Open AccessNAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice
Circulating monocytes contribute to the transition to pain chronicity but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming, here the authors show that blood monocytes contribute to the emergence of chronic pain via a mechanism that requires a transient disruption of NAAA-regulated lipid signaling.
- Yannick Fotio
- , Alex Mabou Tagne
- & Daniele Piomelli
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Article
| Open AccessSingle-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model
Classical monocytes can differentiate into pro-inflammatory or pro-resolving macrophages. Here the authors characterise mouse macrophage differentiation and show that Ly6Chi classical monocytes can differentiate into Ly6Clo pro-resolving macrophages which are involved in the resolution of skin allergic inflammation.
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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Article
| Open AccessTargeted delivery of Fc-fused PD-L1 for effective management of acute and chronic colitis
Triggering the PD-1/PD-L1 immune checkpoint is an attractive therapeutic approach in inflammatory bowel disease, and PD-L1, conjugated to the Fc part of an immunoglobulin (PD-L1-Fc) has been shown to be effective in mouse models. Here authors show that fusing to reactive oxygen species (ROS)-responsive nanoparticles improves effect of PD-L1-Fc due to targeting to inflammation sites, while systemic toxicity is reduced.
- Xudong Tang
- , Yangyang Shang
- & Lei Chen
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Article
| Open AccessAdjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial
Immunotherapy using dendritic cell (DC)-based vaccination has been exploited in the clinic for cancer treatment. Here the authors report the results of a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived DC cell-based therapy in patients with stage IIIB and IIIC melanoma.
- Kalijn F. Bol
- , Gerty Schreibelt
- & I. Jolanda M. de Vries
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Article
| Open AccessImmune signature of Chlamydia vaccine CTH522/CAF®01 translates from mouse-to-human and induces durable protection in mice
Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate.
- Anja W. Olsen
- , Ida Rosenkrands
- & Frank Follmann
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Article
| Open AccessPorphyromonas gingivalis aggravates colitis via a gut microbiota-linoleic acid metabolism-Th17/Treg cell balance axis
Periodontitis is closely linked with inflammatory bowel disease (IBD) and may have overlapping characteristics. Here the authors show that a periodontal pathogen P. gingivalis promotes intestinal inflammation by affecting the microbiome metabolite linoleic acid and Th17/Treg cell balance in the intestine.
- Lu Jia
- , Yiyang Jiang
- & Yi Liu
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Article
| Open AccessM2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1
Adipose beiging is a positive biological change, which is often thought to be primarily sympathetically induced. Here, the authors show that M2 macrophages can independently promote beige adipogenesis, further revealing the adipocyte transcription factor Ets1 as a negative regulator of this process.
- Suyang Wu
- , Chen Qiu
- & Xiao Han
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Article
| Open AccessStructure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.
- Mathieu Ferrari
- , Matteo Righi
- & Martin Pule
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Article
| Open AccessGlobal evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection
Human Papillomaviruses (HPV) are classified in lineages based on their sequence. Here, the authors test neutralizing activity of sera from naturally infected women against vaccine-preventable HPV variants, delineating lineage-specific antibody responses.
- Gathoni Kamuyu
- , Filomeno Coelho da Silva
- & Simon Beddows
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Article
| Open AccessConverging and evolving immuno-genomic routes toward immune escape in breast cancer
Immune response during breast cancer progression remains to be explored. Here, the characterisation of sequential and parallel multiregion samples of an index patient and a cohort of metastatic triple-negative breast cancers reveals convergent immune evasion mechanisms and an increase in tumor genomic heterogeneity.
- Juan Blanco-Heredia
- , Carla Anjos Souza
- & Leticia De Mattos-Arruda
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Article
| Open AccessIntestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders
Interleukin (IL)-22 is critical in ameliorating obesity-induced metabolic disorders; however, it is unclear where IL-22 acts to mediate these outcomes. Here, the authors show in tissue-specific IL-22 receptor knockout mice a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating obesity-associated disorders.
- Stephen J. Gaudino
- , Ankita Singh
- & Pawan Kumar
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Article
| Open AccessEfficient encoding of large antigenic spaces by epitope prioritization with Dolphyn
Profiling antibody responses to vast antigenic spaces has been challenging using programmable phage display (PhIP-Seq). Here, authors develop a methodology for compressing large proteomic spaces and have discovered human antibodies targeting gut bacteria-infecting phages.
- Anna-Maria Liebhoff
- , Thiagarajan Venkataraman
- & H. Benjamin Larman
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Article
| Open AccessChronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release
Myotonic dystrophy type 2 is characterized by large CCUG repeats in the CNBP gene that result in myopathy. Here, the authors show that recognition of aberrant protein translation derived from these repeats leads to ER stress and mitochondrial DNA release, leading to cGAS/STING activation and type-I IFN responses.
- Sarah Rösing
- , Fabian Ullrich
- & Claudia Günther
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Article
| Open AccessRegulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue
Regulatory T cell (Treg) maintenance and function require IL-2, yet this cytokine is only present in low levels in vivo. In this study, the authors demonstrate that that Treg use heparanase to access IL-2 bound to heparan sulfate proteoglycans in the extracellular matrix of inflamed brain tissue in mice.
- Hunter A. Martinez
- , Ievgen Koliesnik
- & Hedwich F. Kuipers
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Article
| Open AccessA single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
Unlike most inflammatory fibrotic conditions, frozen shoulder is a spontaneously self-resolving human disease. Here authors study samples from frozen shoulder capsules by single cell RNA sequencing and by microculture modelling of cell-cell interactions to conclude that specific macrophage populations and their interaction with fibroblasts might promote fibrosis resolution.
- Michael T. H. Ng
- , Rowie Borst
- & Stephanie G. Dakin
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Article
| Open AccessDemographic and Clinical Factors Associated With SARS-CoV-2 Spike 1 Antibody Response Among Vaccinated US Adults: the C4R Study
The antibody response to COVID-19 vaccines varies among individuals. Here the authors find that older age, male sex, smoking, higher BMI, vaccine type, and certain comorbidities are associated with lower anti-S1 antibody levels after COVID-19 vaccinations, indicating that certain groups might benefit from higher frequency or doses of vaccination.
- John S. Kim
- , Yifei Sun
- & Elizabeth C. Oelsner
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Article
| Open AccessSingle-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis
Anti-integrin therapy inhibits lymphocyte trafficking in ulcerative colitis. Here Mennillo et al. use single-cell and spatial -omics to show modulation of mononuclear phagocytes and other networks, identifying gene sets related to treatment response.
- Elvira Mennillo
- , Yang Joon Kim
- & Michael G. Kattah
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Article
| Open AccessCOVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase
Less is known about SARS-CoV-2 infection in unstudied geographical areas such as sub-Saharan Africa. Here the authors use multi-omics to characterize the immune response to SARS-CoV-2 in Uganda and consider how people living with HIV immunologically differentially respond to the virus.
- Matthew J. Cummings
- , Barnabas Bakamutumaho
- & Max R. O’Donnell
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Article
| Open AccessMucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease
Here, through parallel profiling of the mucosal transcriptome and microbiome of intestinal biopsies derived from patients with IBD and from non-IBD controls, the authors characterize interactions between gene expression and microbiota composition associated with traits of patients with inflammatory bowel diseases. Peer Review Information: Nature Communications thanks Robert Häsler, and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.
- Shixian Hu
- , Arno R. Bourgonje
- & Rinse K. Weersma
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Article
| Open AccessNon-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer’s disease-associated pathology and cognition in mice
Meningeal lymphatic vessels have been associated with amyloid beta clearance, which is considered as a modulation target for Alzheimer’s disease (AD) treatment. Here, the authors show that transcranial light treatment can enhance meningeal lymphatic drainage in aged and AD model mice and improve AD-associated pathology and cognitive function.
- Miao Wang
- , Congcong Yan
- & Feifan Zhou
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Article
| Open AccessMosquito midgut stem cell cellular defense response limits Plasmodium parasite infection
Here, the authors study the cellular response of midgut progenitors in Anopheles stephensi to Plasmodium berghei infection. They show that midgut stem cells are able to detect Plasmodium oocysts and eliminate them in a Jak/STAT pathway dependent manner.
- Ana-Beatriz F. Barletta
- , Jamie C. Smith
- & Carolina Barillas-Mury
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Article
| Open AccessPAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma
MYC drives S-phase progression and immune invasion in pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms are not fully understood. Here, the authors show that the transcription elongation complex PAF1c controls the competition of different gene sets for RNA polymerase and elongation factors to regulate these MYC-associated mechanisms in PDAC.
- Abdallah Gaballa
- , Anneli Gebhardt-Wolf
- & Martin Eilers
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Article
| Open AccessCell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing
Cell softness protects cytotoxic T lymphocytes (CTL) from autolysis by own soluble factors such as perforin secreted for killing target cells. Here the authors show that softness can be induced by YAP activation, and that T leukemic cells are more sensitive to YAP inhibition than CTLs, thereby hinting YAP inhibitors as a potential therapy for T leukemia.
- Yabo Zhou
- , Dianheng Wang
- & Bo Huang
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Article
| Open AccessTGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo
Treatment with the clinical stage TGF-β inhibitor galunisertib promotes latency reversal of HIV/SIV. Here, using a treatment regimen similar to the one tested in clinical trials, the authors show how galunisertib affects immune cell function, increases SIV reactivation, and reduces the viral reservoir in macaques.
- Jinhee Kim
- , Deepanwita Bose
- & Elena Martinelli
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Article
| Open AccessGene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer
Immune checkpoint inhibitor treatment improves overall survival in metastatic urothelial cancer, but response of individual patients varies significantly. Authors here perform whole-genome DNA and bulk RNA sequencing on samples from metastatic tumours and based on these data, they set up a single metric, T cell-to-stroma enrichment (TSE) score, that reflects the relative abundance of T cells versus stromal cells and their products, accurately predicting therapeutic outcome.
- Maud Rijnders
- , J. Alberto Nakauma-González
- & Martijn P. Lolkema
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Article
| Open AccessEpigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma
The anti-CD38 monoclonal antibody Daratumumab is approved for the treatment of multiple myeloma but efficiency is curtailed by secondary resistance. Here authors show that the antibody-dependent cellular cytotoxicity, which is the main mechanism of action for Daratumumab, is regulated by KDM6A via Histone H3 K27 methylation of CD38 and CD48, downregulation of which leads to drug resistance.
- Jiye Liu
- , Lijie Xing
- & Kenneth C. Anderson
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Article
| Open AccessTYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes
TYK2 is a candidate susceptibility gene for type 1 diabetes (T1D) and a beneficial effect has been reported for TYK2 inhibitors for other autoimmune diseases. In this study, the authors generate Tyk2 KO mice on a NOD background and demonstrate that TYK2 signaling drives CD8+ T cell autoreactivity and T1D.
- Keiichiro Mine
- , Seiho Nagafuchi
- & Keizo Anzai
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Article
| Open AccessA general computational design strategy for stabilizing viral class I fusion proteins
The authors present a generalisable computational approach to stabilize class I fusion proteins in the prefusion state. The method was used to stabilize the fusion proteins of RSV, hMPV, and SARS-CoV-2 viruses, with the designs structurally validated and RSV F protein assessed in a neutralization assay.
- Karen J. Gonzalez
- , Jiachen Huang
- & Eva-Maria Strauch
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Article
| Open AccessDubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway
Here, Zhang et al. identify a metabolic axis by which Lys-producing commensal bacterium Dubosiella newyorkensis mediates a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in dendritic cells.
- Yanan Zhang
- , Shuyu Tu
- & Shu Jeffrey Zhu
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Article
| Open AccessHKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression
Aberrant expression of the human hexokinase HKDC1 has been observed in patients with cancer. Here the authors report that HKDC1 expression is associated with hepatocellular carcinoma progression and PD-L1 mediated immune evasion.
- Yi Zhang
- , Mingjie Wang
- & Ping Gao
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Article
| Open AccessApplying valency-based immuno-selection to generate broadly cross-reactive antibodies against influenza hemagglutinins
Here the authors develop a DNA vaccine, mixing 18 hemagglutinin (HA) subtypes monovalently into heterodimeric molecules, and show that it induces broadly reactive antibodies against subdominant HA epitopes and heterologous protection against influenza A viruses in mice.
- Daniëla Maria Hinke
- , Ane Marie Anderson
- & Ranveig Braathen
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Article
| Open AccessEFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death
Physiologically, the host suppresses intestinal epithelial cell death to prevent intestinal inflammation. Here, the authors show that EF-hand domain-containing protein D2 (EFHD2) endogenously suppresses intestinal epithelial cell death by blocking TNFR1 internalization and protects the intestine from excessive inflammation.
- Jiacheng Wu
- , Xiaoqing Xu
- & Xuetao Cao
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Article
| Open AccessA hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs
Here, English et al. show that after expanding in lymphoid tissues, CD4+ and CD8+ T cells recognising hepatic antigens migrate into specialised vascular liver areas where CD4+ T cells locally license hepatic dendritic cells and further expand CD8+ T cell numbers.
- Kieran English
- , Rain Kwan
- & Patrick Bertolino
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Article
| Open AccessT-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms
Endogenous retroviruses (ERV) can induce immune responses and the control of these viruses uses immune mechanisms also involved in autoimmunity. Here, the authors characterize the control of ERVs in mice and show age-associated B cell control and nucleic acid sensing TLR pathway involvement.
- Eileen Rauch
- , Timm Amendt
- & Philipp Yu
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