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Article
| Open AccessSynovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis
Mast cells have been shown to be involved with rheumatoid arthritis, but the mechanisms are not clear. Here using mouse models and making association with human patients, the authors show mast cells have an important function in the pathogenesis of rheumatoid arthritis, involving regulation of T cell responses and release of mast cell mediators.
- Yunxuan Lei
- , Xin Guo
- & Guangjie Chen
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Article
| Open AccessInnate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis
The evolutionally conserved Hippo pathway regulates essential developmental, homeostatic and regenerative processes, and is involved in the host defense against pathogens. Here authors show that in Drosophila Melanogaster and mammalian cells, innate immune stimuli activate Hippo via a pathway emanating from the Tak1 kinase and cascading down to Hippo via STRIPAK-Tao-Hpo signaling.
- Yinan Yang
- , Huijing Zhou
- & Bo Liu
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Article
| Open AccessIntegrative genotyping of cancer and immune phenotypes by long-read sequencing
Single-cell transcriptomics excel in cell subset classification and can be augmented by suitable genotype information. Here the authors devise a long-read sequencing workflow, termed nanoranger, for detection of molecular barcodes from single-cell cDNA and apply this to clonal tracking of acute myeloid leukemia and identification of complex immune phenotypes.
- Livius Penter
- , Mehdi Borji
- & Catherine J. Wu
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Article
| Open AccessIntegrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection
Amnesic screening methods are useful to discover host factors that are important for SARS-CoV2 infection. Here the authors use a CRISPR screen to identify three anti-viral factors, which are associated with the coagulation system, and two pro-viral candidates and then use individual genetic deletion experiments to characterise their effect.
- Jiakai Hou
- , Yanjun Wei
- & Weiyi Peng
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Article
| Open AccessTMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells
The immune receptor Transmembrane and immunoglobulin domain containing 2 (TMIGD2) mediates T-cell and nature killer cells co-stimulation upon B7-family HHLA2 engagement. Here, the authors show that TMIGD2 is expressed in Acute Myeloid Leukaemia stem cells regulating self-renewal and differentiation to facilitate leukemogenesis.
- Hao Wang
- , R. Alejandro Sica
- & Xingxing Zang
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Article
| Open AccessIL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity
Human natural killer T (NKT) cells have been proposed as a cellular platform for CAR engineering. Here the authors report that IL-12 engineering reprograms CAR-expressing NKT cells to long-lived Th1-polarized cells with potent anti-tumor activity in leukemia and neuroblastoma preclinical models.
- Elisa Landoni
- , Mark G. Woodcock
- & Gianpietro Dotti
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Article
| Open AccessPharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1
PD-L1 expression on the surface of cancer cells is believed to contribute to tumor immune evasion via triggering the inhibitory T cell co-receptor, PD-1, resulting in decreased T cell cytotoxicity. Here authors show that OTUB2 regulates PD-L1 expression via inhibition of its ubiquitin-mediated degradation, and that OTUB2 inhibition increases T cell cytotoxicity directed against tumors.
- Wenfeng Ren
- , Zilong Xu
- & Ningshao Xia
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Article
| Open AccessSerglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration
Aging-related intervertebral disc degeneration (IVDD) is a leading cause of lower back pain. Here, the authors perform scRNA-seq analysis of intervertebral disc cells from patients, and identify cell populations and mechanisms associated with IVDD.
- Fan Chen
- , Linchuan Lei
- & Jianru Wang
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Article
| Open AccessEpithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling
IL-17 mediated inflammation in the lung is mediated by different effector molecules. Here the authors show that the epigenetic regulator epithelial sirtuin 6 (Sirt6) is associated with lung inflammation in asthma patients and that Sirt6 contributes to promotion of inflammation in mouse asthma models.
- Jingyun Quan
- , Xiaoxia Wen
- & Tianwen Lai
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Article
| Open AccessCharacterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease
Targeting gluten antigens presents a plausible therapy option for celiac disease. Here the authors generate and characterize a broadly neutralizing antibody recognizing more than 25 gluten peptide:HLA-DQ2.5 complexes, with structural analyses implicating its mode of interaction, and with mouse in vivo studies supporting its therapeutic feasibility.
- Yuu Okura
- , Yuri Ikawa-Teranishi
- & Tomoyuki Igawa
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Article
| Open AccessPara-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.
- Benedict D. Michael
- , Cordelia Dunai
- & David K. Menon
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Article
| Open AccessDistinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination
The ability of BCG vaccination to prevent pulmonary tuberculosis could be improved by targeting mucosal immunity within the lung. Here the authors compare latent Mtb-infected donors with intradermal or oral BCG vaccine recipients to show distinct systemic and pulmonary immune responses are induced by differing routes of natural infection or vaccination.
- Richard F. Silver
- , Mei Xia
- & Daniel F. Hoft
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Article
| Open AccessUnique adipose tissue invariant natural killer T cell subpopulations control adipocyte turnover in mice
Invariant natural killer T (iNKT) cells have recently been reported to play a key role in adipose tissue homeostasis. Here, the authors show that adipose tissue iNKT cells mediate immune responses that control adipocyte turnover in mice.
- Sang Mun Han
- , Eun Seo Park
- & Jae Bum Kim
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Article
| Open AccessInflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC
Inflammasomes are multiprotein complexes, including the protein ASC, that assemble in response to inflammatory stimulation. Here the authors characterise the regulation of ASC during inflammasome formation and show the involvement of SUMOylation and zinc-finger and BTB domain-containing protein 16 (ZBTB16).
- Danfeng Dong
- , Yuzhang Du
- & Dakang Xu
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Article
| Open AccessNuclear RPSA senses viral nucleic acids to promote the innate inflammatory response
Innate immune responses are the first line of defence against viral pathogens. Here, Jiang et al show that the nuclear located 40S ribosomal protein SA senses viral nucleic acids to selectively enhance proinflammatory cytokine gene expression through epigenetic modification.
- Yan Jiang
- , Siqi Sun
- & Xuetao Cao
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Article
| Open AccessRecently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy
Marking of recently activated T cells may help further our understanding of immunity against Mycobacterium tuberculosis (Mtb). Here the authors use Nur77-GFP reporter mice infected with Mtb and systems data approaches to implicate OX40 as a marker for recently activated, functionally and transcriptome-wise distinct CD4 T cells, and as a potential target for immunotherapy.
- Abigail R. Gress
- , Christine E. Ronayne
- & Tyler D. Bold
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Article
| Open AccessAntigen recognition reinforces regulatory T cell mediated Leishmania major persistence
Upon skin infection with the parasite Leishmania major, a small group of infected cells remain present in healed skin. Here, Zayats et al. show that regulatory T cells focused towards parasite-derived proteins have strong suppressive capabilities and facilitate parasite persistence in vivo.
- Romaniya Zayats
- , Zhirong Mou
- & Thomas T. Murooka
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Article
| Open AccessAcetylation is required for full activation of the NLRP3 inflammasome
The NLRP3 inflammasome is activated in two steps, priming and assembly, in response to endogenous, microbial, and other environmental danger signals. Here authors show that the assembly step is regulated by acetylation, and inhibition of this post-translational modification prevents full activation of the inflammasome.
- Yening Zhang
- , Ling Luo
- & Kai Zhao
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Article
| Open AccessIntranasal mask for protecting the respiratory tract against viral aerosols
The spread of many infectious diseases substantially relies on aerosol transmission to the respiratory tract. Here, the authors design an intranasal mask with the ability to intercept viral aerosols, entrap and inactivate virus, thus preventing respiratory tract infection.
- Xiaoming Hu
- , Shuang Wang
- & Wei Wei
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Review Article
| Open AccessMolecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology
- Nieves Montenegro-Navarro
- , Claudia García-Báez
- & Melissa García-Caballero
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Article
| Open AccessActivation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis
Idiopathic Pulmonary Fibrosis (IPF) consists of lung inflammation and collagen deposition leading to reduced lung function and non-inducible mouse models are needed. Here the authors show a spontaneous mouse IPF model where Ifngr1-/-Rag2-/- mice show enhanced ILC2 activation and function along with pathology similar to IPF.
- Natsuko Otaki
- , Yasutaka Motomura
- & Kazuyo Moro
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Article
| Open AccessMaternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling
Treatment of pregnant animals with antibiotics can have unexpected effects on offspring. Here the authors use mouse models to show that antibiotic treatment of mothers leads to changes in ILC2 phenotype in neonatal lungs accompanied by changes in the microbiota and microbiota derived butyrate.
- Haixu Xu
- , Xianfu Yi
- & Jie Zhou
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Article
| Open AccessHigh monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials
Antibody Mediated Prevention (AMP) trials showed that the broadly neutralizing antibody VRC01 could prevent some HIV-1 acquisitions. Here the authors use VRC01 levels and the sensitivity of each acquired HIV virus to predict viral loads in the AMP studies and show that VRC01 influenced viral loads, though potency was lower in vivo than expected.
- Daniel B. Reeves
- , Bryan T. Mayer
- & Srilatha Edupuganti
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Article
| Open AccessAtherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation
Accumulation of lipid-laden macrophages in the arterial wall is a critical step in atherosclerosis. Here, the authors show that downregulation of Zeb1 in macrophages promotes lipid accumulation and atherosclerotic plaque formation while its restoration with macrophage-targeted nanoparticles reverses these effects.
- M. C. Martinez-Campanario
- , Marlies Cortés
- & Antonio Postigo
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Article
| Open AccessDPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages
Although macrophages infiltrating the skeletal muscles are known to be important in muscle growth and repair, much less is known about muscle-resident macrophages. Here, the authors identify a fibro-adipogenic progenitor niche involved in the maintenance of skeletal muscle-resident macrophages.
- Farshad Babaeijandaghi
- , Nasim Kajabadi
- & Fabio M. V. Rossi
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Article
| Open AccessBacterial-induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2
The role of interferon-γ (IFNγ) in anti-viral immunity has been unclear. Here the authors show that bacterial-induced or intranasally administered IFNγ effectively restricts SARS-CoV-2 infection in mice through effects on non-hematopoietic cells.
- Kerry L. Hilligan
- , Sivaranjani Namasivayam
- & Alan Sher
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Article
| Open AccessComplexEye: a multi-lens array microscope for high-throughput embedded immune cell migration analysis
Video microscopy is key in studying cell migration, but accomplishing this in a high-throughput manner is still challenging. Here, the authors present an array microscope that can track the movements of thousands of individual cells simultaneously, and that can be used for drug screening studies.
- Zülal Cibir
- , Jacqueline Hassel
- & Matthias Gunzer
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Article
| Open AccessHuman and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts
Difficulties can be encountered when translating research between cells from animals and humans because of gene expression differences. Here the authors perform an integrative transcriptomic analysis from human and mouse neutrophils and identify a core inflammation program shared across inflamed contexts.
- Nicolaj S. Hackert
- , Felix A. Radtke
- & Ricardo Grieshaber-Bouyer
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Article
| Open AccessIgG and IgM cooperate in coating of intestinal bacteria in IgA deficiency
IgA protects mucosal barriers by coating microorganisms, yet infection related complications are rare in human IgA deficiency. Authors here show that in humans lacking IgA, IgG assists IgM in coating of most bacterial families, thus contributing to gut mucosal defence.
- Carsten Eriksen
- , Janne Marie Moll
- & Susanne Brix
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Article
| Open AccessClonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells
The expansion of cells with TET2 mutations within the blood is associated with increased risk for all-cause mortality, development of leukemia and cardiovascular disease. Here authors show IL1 promotes the clonal expansion TET2 knockout cells, enhancing their self-renewal, promoting their myeloid bias and impairing an IL1 driven loss of methylation at lymphoid and erythroid regulatory elements.
- J. McClatchy
- , R. Strogantsev
- & A. Agarwal
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Article
| Open AccessT cell migration requires ion and water influx to regulate actin polymerization
The ability of T cells to migrate is a central component of their functionality and is known to require WNK1 kinase that is linked to the influx of ions into the cell. Here the authors show that T cell migration requires WNK1 mediated ion and water influx to swell the membrane of the leading edge and support actin polymerisation and forward motility.
- Leonard L. de Boer
- , Lesley Vanes
- & Victor L. J. Tybulewicz
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Article
| Open AccessEarly mucosal events promote distinct mucosal and systemic antibody responses to live attenuated influenza vaccine
Nasally delivered live attenuated influenza vaccines (LAIV) have been shown to be effective in vaccine trials yet immune responses are mostly measured in blood. Here the authors report a clinical trial in young adults and measure immune responses in the mucosa and blood to identify compartmentalised responses.
- Ryan S. Thwaites
- , Ashley S. S. Uruchurtu
- & Peter J. M. Openshaw
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Article
| Open AccessA lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection
The authors use lipid nanoparticles (LNPs) that predominantly accumulate in the lung to deliver mRNA encoding for the broadly neutralizing antibody 8-9D, and achieve superior inhibition of SARS-CoV-2 infection in mice compared to control LNPs.
- Wanbo Tai
- , Kai Yang
- & Gong Cheng
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Article
| Open AccessMetabolic tagging of extracellular vesicles and development of enhanced extracellular vesicle based cancer vaccines
Extracellular vesicles (EVs) have been actively explored for diagnostic and therapeutic applications. Here, the authors report a universal metabolic tagging technology to generate chemically tagged EVs from parent cells, modulate EV-cell interactions, and develop potent EV-based cancer vaccines.
- Rimsha Bhatta
- , Joonsu Han
- & Hua Wang
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Article
| Open AccessEnvironmental modulation of global epistasis in a drug resistance fitness landscape
Global epistasis can be used to reconstruct fitness landscapes and infer adaptive trajectories. Here, the authors investigate how environmental variation impacts patterns of global epistasis, finding that global epistasis in the malaria parasite P. falciparum can be modulated by drug concentration in the environment.
- Juan Diaz-Colunga
- , Alvaro Sanchez
- & C. Brandon Ogbunugafor
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Article
| Open AccessInvestigation of monoclonal antibody CSX-1004 for fentanyl overdose
Fentanyl continues to drive the opioid crisis by contributing to >70,000 deaths per year in the US. Here, the authors investigate a candidate medication for fentanyl overdose prevention (monoclonal antibody CSX-1004) demonstrating its mitigation of fentanyl’s effects in preclinical animal models.
- Paul T. Bremer
- , Emily L. Burke
- & Rajeev I. Desai
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Article
| Open AccessInterleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling
Paneth cell metaplasia (PCM) typically arises in diseases intrinsic to the gastrointestinal tract; however, whether extra intestinal diseases can trigger PCM and the mechanistic pathway by which PCM develops is unknown. Herein, the authors show in an inducible murine model of chronic myelogenous leukaemia that a systemic inflammatory state can trigger IL-33- mediated IL-9 production that leads to small intestinal remodelling and PCM.
- Chengyin Yuan
- , Aditya Rayasam
- & William R. Drobyski
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Article
| Open AccessInteraction dynamics between innate and adaptive immune cells responding to SARS-CoV-2 vaccination in non-human primates
Innate immune responses to mRNA vaccines are less well understood than adaptive immunity. Here, the authors comprehensively characterize the innate and adaptive immune responses to mRNA-1273 vaccinations in rhesus macaques and show how the vaccine activates interactions among components of the two systems.
- Chaim A. Schramm
- , Damee Moon
- & Daniel C. Douek
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Article
| Open AccessYoung infants display heterogeneous serological responses and extensive but reversible transcriptional changes following initial immunizations
Our understanding of the infant immune responses to routine vaccines remains limited. Here, the authors show that administration of routine vaccines to 2-month-old infants is associated with highly variable but limited antibody responses and mostly naïve-like immune cells with robust and transient expression of interferon genes.
- Nima Nouri
- , Raquel Giacomelli Cao
- & Octavio Ramilo
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Article
| Open AccessNeutralization of SARS-CoV-2 Omicron BQ.1, BQ.1.1 and XBB.1 variants following SARS-CoV-2 infection or vaccination in children
In this work, authors investigate the virus-neutralizing capacity in children against circulating BQ.1, BQ.1.1 and XBB.1 SARS-CoV-2 variants. Vaccination induced more neutralizing antibodies against BQ.1.1 and XBB.1 in youngest children ( < 5 years) compared with >5 years children.
- Lorenza Bellusci
- , Gabrielle Grubbs
- & Surender Khurana
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Article
| Open AccessIntrinsic factors and CD1d1 but not CD1d2 expression levels control invariant natural killer T cell subset differentiation
Invariant natural killer T (NKT) cells are defined into subset based on transcription expression and cytokine production, but differences in the subset distributions of these cells are seen between inbred mouse strains. Here the authors show that CD1d mediated TCR signals along with intrinsic signals impact this strain specific difference in the composition of the NKT cell compartment.
- Ludivine Amable
- , Luis Antonio Ferreira Martins
- & Kamel Benlagha
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Article
| Open AccessPyroptosis inhibiting nanobodies block Gasdermin D pore formation
Pyroptosis has been implicated in many diseases with aberrant inflammation. Here, Kopp et al. characterize single-chain nanobodies targeting the human gasdermin D protein as tools to inhibit pyroptosis.
- Anja Kopp
- , Gregor Hagelueken
- & Matthias Geyer
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Article
| Open AccessEngineered immunogens to elicit antibodies against conserved coronavirus epitopes
A pan-betacoronavirus vaccine will likely require the elicitation of antibodies against spike regions conserved across diverse coronaviruses. Here, authors computationally engineer and experimentally validate immunogens to elicit antibodies against two such spike regions.
- A. Brenda Kapingidza
- , Daniel J. Marston
- & Mihai L. Azoitei
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Article
| Open AccessDermis resident macrophages orchestrate localized ILC2 eosinophil circuitries to promote non-healing cutaneous leishmaniasis
Tissue resident macrophages are intricately involved in homeostatic processes but also in tissue repair. Here Lee and colleagues show dermis-resident macrophages are a source of thymic stromal lymphopoietin and CCL24, which act on type 2 innate lymphoid cells and eosinophils respectively, to maintain their M2 properties and promote non-healing cutaneous leishmaniasis.
- Sang Hun Lee
- , Byunghyun Kang
- & David L. Sacks
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Article
| Open AccessInterrogating ligand-receptor interactions using highly sensitive cellular biosensors
The interaction of membrane-resident proteins plays an essential role in biological processes. Here the authors describe cellular biosensors based on chimeric receptors, as a tool to study the interaction of receptor-ligand pairs such as immune checkpoint molecules or virus attachment proteins and their receptors.
- Maximilian A. Funk
- , Judith Leitner
- & Peter Steinberger
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Article
| Open AccessAdults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01
Small molecule drugs can affect clearance of monoclonal antibodies, but this hasn’t been assessed for oral HIV-1 pre-exposure prophylaxis. Here, the authors find that faster serum clearance of an experimental IgG1 monoclonal antibody, VRC01, is associated with use of tenofovir-emtricitabine, possibly explained by increased epithelial intestinal permeability.
- Yunda Huang
- , Lily Zhang
- & Maria P. Lemos
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Article
| Open AccessCAR+ and CAR− T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies
Phenotype of cells in the infusion product as well at specific post-infusion time points has been associated with clinical response to CD19 CAR T cells. Here the authors present a single-cell multi-omics analysis of pre- and post-infusion CAR+ and CAR- T cells from patients with relapsed or refractory B-ALL or LBCL who received CD19 CAR T therapy.
- Raymond Hall Yip Louie
- , Curtis Cai
- & Fabio Luciani
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Article
| Open AccessOVOL2 sustains postnatal thymic epithelial cell identity
The molecular mechanisms that maintain thymic epithelial cell (TEC) identity throughout life are incompletely understood. Here, the authors demonstrate that the transcription factor, Ovol2, maintains post-natal TECs by preventing their epithelial-to-mesenchymal transition.
- Xue Zhong
- , Nagesh Peddada
- & Bruce Beutler
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Article
| Open AccessSequential vaccinations with divergent H1N1 influenza virus strains induce multi-H1 clade neutralizing antibodies in swine
Seasonal influenza vaccines typically fail to induce cross-protective antibody responses. Here, Van Reeth et al. sequentially vaccinate pigs with diverse H1N1 viruses and show that this strategy induces antibodies against a panel of H1N1 strains from swine and humans and protects against antigenically mismatched strains.
- Kristien Van Reeth
- , Anna Parys
- & Elien Vandoorn
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