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Article
| Open AccessSEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway
Interferon-gamma (IFN-γ) is an important but not exclusive proinflammatory mediator in macrophages. Here authors show that IFN-γ-independent macrophage autoactivation involves endoplasmic reticulum (ER) stress which in turn induces the GTP-binding protein Septin2 to limit inflammation via a negative feedback loop.
- Beibei Fu
- , Yan Xiong
- & Haibo Wu
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Article
| Open AccessTh17-associated cytokines IL-17 and IL-23 in inflamed skin of Darier disease patients as potential therapeutic targets
The use of IL-17/IL-23 blocking therapy for rare inflammatory skin diseases needs proof of principle data for larger clinical trials. Here the authors show that patients with Darier disease have enhanced Th17 cells and, using IL-17/IL-23 blockers, they show that the immune gene signatures are altered in localised skin biopsies.
- Monika Ettinger
- , Teresa Burner
- & Wolfram Hoetzenecker
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Article
| Open AccessTOFIMS mass spectrometry-based immunopeptidomics refines tumor antigen identification
MS-based immunopeptidomics provides direct evidence for HLA peptide-antigen presentation, which is indispensable for therapeutic use. Here the authors present an ion mobility MS-based immunopeptidome workflow, largely expand benign reference databases and enables next generation tumor antigen discovery.
- Naomi Hoenisch Gravel
- , Annika Nelde
- & Juliane S. Walz
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Article
| Open AccessHigh-sensitive spatially resolved T cell receptor sequencing with SPTCR-seq
Understanding T cell behaviour in cancers is vital for improving immunotherapies. Here, the authors present spatially resolved T cell receptor sequencing (SPTCR-seq), a technology that annotates T cell receptors within the tumour ecosystem.
- Jasim Kada Benotmane
- , Jan Kueckelhaus
- & Dieter Henrik Heiland
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Article
| Open AccessSingle cell transcriptomics shows that malaria promotes unique regulatory responses across multiple immune cell subsets
The use of single cell sequencing has enabled more detailed analysis of the immune response to infection. Here the authors characterise the immune response to malaria infection in an endemic region using single cell transcriptomics indicating regulatory signatures associated with infection.
- Nicholas L. Dooley
- , Tinashe G. Chabikwa
- & Michelle J. Boyle
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Article
| Open AccessFatty acid desaturation and lipoxygenase pathways support trained immunity
Cellular functional states are supported by metabolic pathways, including lipid metabolism. Here, authors examine the contribution of differential biosynthesis of lipid mediators to innate immune memory (or trained immunity), in human monocytes following Bacillus Calmette-Guérin (BCG) vaccination.
- Anaísa V. Ferreira
- , Juan Carlos Alarcon-Barrera
- & Martin Giera
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Article
| Open AccessMucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease
Mucosal associated invariant T (MAIT) cells reside in barrier organs, but their contribution to inflammatory processes in the kidneys is not fully known. Here authors find by single cell RNA sequencing that among the different MAIT cell subtypes found at steady state, a population with MAIT17 signature is expanded in both human crescentic glomerulonephritis and its mouse model, and these cells may play protective role in the disease.
- Ann-Christin Gnirck
- , Marie-Sophie Philipp
- & Jan-Eric Turner
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Article
| Open AccessInterferon stimulated immune profile changes in a humanized mouse model of HBV infection
There is increasing evidence that treatment of hepatitis B with interferon alpha can be beneficial. Here, Wang et al, present a type 1 interferon receptor humanized mouse model and characterize it as a platform in which to study interferon function in vivo.
- Yaping Wang
- , Liliangzi Guo
- & Feng Li
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Article
| Open AccessDietary L-Tryptophan consumption determines the number of colonic regulatory T cells and susceptibility to colitis via GPR15
Environmental factors such as diet have been shown to be involved with the development of colitis. Here the authors show that L-tryptophan promotes the development of GPR15+ Treg cells via the host IDO1/2 pathway and that tryptophan consumption in mice reduces severity of colitis in a C. rodentium mouse model.
- Nguyen T. Van
- , Karen Zhang
- & Sangwon V. Kim
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Article
| Open AccessTLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase
Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.
- Gang Liu
- , Tatt Jhong Haw
- & Philip M. Hansbro
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Article
| Open AccessDeciphering a critical role of uterine epithelial SHP2 in parturition initiation at single cell resolution
The mechanism of parturition initiation remains elusive. Here, authors show that epithelium is an underestimated site for parturition initiation via epithelial PGF2a regulated by SHP2-COX1/COX2.
- Meng Liu
- , Mengjun Ji
- & Wenbo Deng
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Article
| Open AccessRNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis
The function of METTL3 and RNA methylation is important in various biological processes. Here the authors show that METTL3 is reduced in childhood asthma patients and that conditional knockout of Mettl3 in mouse myeloid cells enhances Th2 response and allergic asthma associated with changes in macrophage function.
- Xiao Han
- , Lijuan Liu
- & Yufeng Zhou
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Article
| Open AccessNanomedicine-based co-delivery of a calcium channel inhibitor and a small molecule targeting CD47 for lung cancer immunotherapy
Lung cancer is characterized by an immunosuppressive microenvironment, limiting responses to immunotherapies. Here the authors report the design of a pH-responsive nanomedicine for the co-delivery of a T-type calcium channel inhibitor and of a small molecule targeting CD47, promoting anti-tumor immune responses in orthotopic lung cancer preclinical models.
- Yuedong Guo
- , Qunqun Bao
- & Jianlin Shi
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Article
| Open AccessThe E3 ligase Riplet promotes RIG-I signaling independent of RIG-I oligomerization
Riplet conjugates K63-Ub chain to RIG-I in order to induce a robust antiviral response, but the mechanism of action remains unclear. Here, the authors show that Riplet recognizes RIG-I regardless of its RNA-bound status and promotes RIG-I signaling independent of RIG-I oligomerization.
- Wenshuai Wang
- , Benjamin Götte
- & Anna Marie Pyle
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Matters Arising
| Open AccessReply to: Failure to apply standard limit-of-detection or limit-of-quantitation criteria to specialized pro-resolving mediator analysis incorrectly characterizes their presence in biological samples
- Jesmond Dalli
- & Esteban A. Gomez
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Article
| Open AccessCryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization
The authors characterized puncta in the ASC complex by correlative light microscopy and cryo-ET in cells and propose an ultrastructure of the ASC filament network.
- Yangci Liu
- , Haoming Zhai
- & Yorgo Modis
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Article
| Open AccessNULISA: a proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing
Unlocking the blood proteome requires exquisite sensitivity and multiplexing to detect low and high abundance proteins simultaneously. Here the authors describe a 200-plex immunoassay with attomolar sensitivity to detect important low abundance proteins in inflammatory diseases and COVID-19.
- Wei Feng
- , Joanne C. Beer
- & Xiao-Jun Ma
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Article
| Open AccessSingle cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs
Mathematical tools can be used to help identify pathological features from images of diseased lungs. Here, the authors used mathematical tools combined with high resolution multiplex imaging mass cytometry to show an association between immature neutrophils, CD8 T cells and proliferating alveolar epithelial cells in areas of maximal alveolar damage in COVID-19 lungs.
- Praveen Weeratunga
- , Laura Denney
- & Ling-Pei Ho
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Article
| Open AccessThemis2 regulates natural killer cell memory function and formation
Innate immunity represents the first line of defence against pathogens, but certain innate cells are capable of memory formation, albeit with different and lesser-known mechanisms than adoptive immune cells. Here authors show that Themis2 regulates both memory NK cell development and function, via distinct downstream pathways.
- Tsukasa Nabekura
- , Elfira Amalia Deborah
- & Akira Shibuya
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Article
| Open AccessThe alarmin IL33 orchestrates type 2 immune-mediated control of thymus regeneration
Although thymic function declines with age, the thymus also has the ability to regenerate following injury. Here, the authors demonstrate that IL-33 and type-2 innate lymphoid cells trigger the expansion of eosinophils following radiation injury, which in turn produce IL-4 to stimulate the recovery of the thymus mesenchyme during thymus regeneration.
- Emilie J. Cosway
- , Kieran D. James
- & Graham Anderson
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Article
| Open AccessMicroglia are not protective against cryptococcal meningitis
Cryptococcal meningitis is a life-threatening fungal infection. Here, Mohamed et al find that brain resident microglia do not provide protection against this infection and instead are a site where the fungus may access the micronutrient copper.
- Sally H. Mohamed
- , Man Shun Fu
- & Rebecca A. Drummond
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Article
| Open AccessInadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility
It is still unclear why HIV-1 vaccines targeting MPER induce antibodies that fail to bind HIV. Here, the authors show that antibodies targeting membrane-proximal linear epitopes of virion spike proteins must generate relevant antibody paratopes and approach angles to ligate their quarry in a topologically restricted site.
- Kemin Tan
- , Junjian Chen
- & Mikyung Kim
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Article
| Open AccessUnlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering
Vγ9Vδ2 (Vδ2) T cells have been proposed as cell carriers for off-the-shelf CAR therapies. Here the authors describe CD16 as a biomarker for the selection of Vδ2 T cells with high levels of cytotoxicity and report the anti-tumor activity of engineered CD16high Vδ2 T cells in ovarian cancer preclinical models.
- Derek Lee
- , Zachary Spencer Dunn
- & Lili Yang
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Article
| Open AccessDetermining zebrafish dorsal organizer size by a negative feedback loop between canonical/non-canonical Wnts and Tlr4/NFκB
Dorsal organizer initiates the dorsal-ventral axis formation in vertebrates. Here, the authors demonstrate that Tlr4/NFκB-mediated negative feedback regulation of Wnt/β-catenin signaling determines the precise size of the zebrafish dorsal organizer.
- Juqi Zou
- , Satoshi Anai
- & Tohru Ishitani
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Article
| Open AccessImmuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients
Efficacy of dendritic cell (DC)-based vaccines remains unsatisfactory. Here the authors analyse the transcriptomic and immune-metabolic profiles of DCs from patients enrolled in a DC vaccine trial in late-stage melanoma, suggesting that the metabolic profile of DC is associated with the immunostimulatory potential of the cancer vaccine.
- Juraj Adamik
- , Paul V. Munson
- & Lisa H. Butterfield
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Article
| Open AccessProbabilities of developing HIV-1 bNAb sequence features in uninfected and chronically infected individuals
Successful induction of broadly neutralizing antibodies is a main challenge in HIV vaccine development. The authors provide a framework to determine probabilities of antibody sequence development and show that uninfected and chronically infected individuals have the same chances to develop HIV-1 neutralizing antibodies.
- Christoph Kreer
- , Cosimo Lupo
- & Florian Klein
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Article
| Open AccessFoxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity
Cell lineage specification involves substantial chromatin conformation reorganization. Here, the authors integrate in-situ Hi-C and PLAC-seq to map the dynamic changes in 3D chromatin structure during Treg cell differentiation. Furthermore, the authors further characterize the role of Foxp3 in the establishment of Treg-specific chromatin interactions by different Foxp3-mutant mouse lines.
- Zhi Liu
- , Dong-Sung Lee
- & Jesse R. Dixon
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Article
| Open AccessAn FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission
Here the authors develop a mucosal SARS-CoV-2 vaccine and show immunogenicity and protection in mice as well as reduced virus transmission in hamsters. This protein vaccine consists of a stabilized spike protein fused to monomeric IgG Fc, supporting its transport across epithelial barriers by binding to the neonatal Fc receptor.
- Weizhong Li
- , Tao Wang
- & Xiaoping Zhu
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Article
| Open AccessEvolutionary design of explainable algorithms for biomedical image segmentation
Deep learning frameworks require large human-annotated datasets for training and the resulting ‘black box’ models are difficult to interpret. Here, the authors present Kartezio; a modular Cartesian Genetic Programming-based computational strategy that generates fully transparent and easily interpretable image processing pipelines.
- Kévin Cortacero
- , Brienne McKenzie
- & Sylvain Cussat-Blanc
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Article
| Open AccessTissue-resident B cells orchestrate macrophage polarisation and function
The function of B cells in peripheral blood and secondary lymphoid organs has long been appreciated but whether and how they contribute to tissue immune homeostasis is lesser known. Non-lymphoid organs harbour tissue-resident B cells that include a substantial population of B-1 cells and promote homeostatic anti-inflammatory macrophage polarization via IL-10, with profound effects on bacterial clearance during local infection.
- Ondrej Suchanek
- , John R. Ferdinand
- & Menna R. Clatworthy
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Article
| Open AccessCell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function
During the activation and migration of T cells volume changes occur in response to osmolality cues which is not fully understood. Here the authors characterize the function of volume regulated ion channels in T cells and show that these channels regulate TCR sensitivity, thymic selection and TCR repertoire.
- Yuman Wang
- , Zaiqiao Sun
- & Ning Wu
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Article
| Open AccessA combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates
Protein antigens, such as HIV envelope protein, require adjuvants for high immunogenicity. Here the authors show that a combined adjuvant approach with slow antigen delivery and potent ISCOMs adjuvant primes robust germinal center activity and humoral immunity in non-human primates. pSer-modified antigen shifts immunodominance to allow subdominant epitope-targeting of rare B cells.
- Ivy Phung
- , Kristen A. Rodrigues
- & Shane Crotty
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Article
| Open Accessc-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity
Although T cells proliferate at an exceptionally fast rate following activation, the mechanisms sustaining such fast proliferation remain unclear. Here, the authors demonstrate that c-Myc upregulates the E3 ubiquitin ligase Cul4b to reduce replication stress in CD8+ T cells, allowing massive clonal expansion and viral clearance.
- Asif A. Dar
- , Dale D. Kim
- & Paula M. Oliver
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Article
| Open AccessIL-21R-STAT3 signalling initiates a differentiation program in uterine tissue-resident NK cells to support pregnancy
Uterine natural killer (NK) cells support tissue homeostasis in the uterus during pregnancy, but it is not fully known how they differentiate into potentially cytotoxic effector cells while avoiding tissue damage. Here authors show that Il21 receptor signalling via STAT3 activation governs their differentiation, while an apoptotic cell death program ensures that harm is limited.
- Mengwei Han
- , Luni Hu
- & Chao Zhong
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Article
| Open AccessRational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin
Therapeutic modulation of Janus kinase family enzymes is an established approach for inflammatory and autoimmune skin diseases. Here the authors rationally design small interfering RNAs to enable single Janus kinase targeting and test this new therapeutic approach in a skin disease model for maintaining efficacy and improving selectivity.
- Qi Tang
- , Hassan H. Fakih
- & John E. Harris
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Article
| Open AccessIL-17 signalling is critical for controlling subcutaneous adipose tissue dynamics and parasite burden during chronic murine Trypanosoma brucei infection
Trypanosome brucei is known to colonise the subcutaneous white adipose tissue and the interaction with the cellular locale could play key roles in pathogenesis and host response. Here the author’s use single cell approaches and in vivo animal models, and show a role for IL-17 in the adipose tissue response and parasite burden in a chronic murine model of infection.
- Matthew C. Sinton
- , Praveena R. G. Chandrasegaran
- & Juan F. Quintana
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Article
| Open AccessAerosol delivery of SARS-CoV-2 human monoclonal antibodies in macaques limits viral replication and lung pathology
Here the authors deliver aerosolized human monoclonal antibodies to SARS-CoV-2-infected rhesus macaques and show that the treatment significantly reduces viral RNA and infectious virus in the respiratory tracts, limits lung pathology, and decreases inflammatory cytokines.
- Daniel N. Streblow
- , Alec J. Hirsch
- & Nancy L. Haigwood
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Article
| Open AccessDistinct receptor binding domain IgG thresholds predict protective host immunity across SARS-CoV-2 variants and time
Evidence from trials suggests SARS-CoV-2 binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether this is accurate in the context of variants of concerns, or in the event of prior infection or vaccination remains unclear. Authors explore the performance of receptor binding domain IgG thresholds in predicting a level of neutralising capacity that has demonstrated protection against infection in vaccine trials
- Grace Kenny
- , Sophie O’Reilly
- & Patrick Mallon
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Article
| Open AccessA2AR eGFP reporter mouse enables elucidation of A2AR expression dynamics during anti-tumor immune responses
Adenosine is an immunosuppressive metabolite known to limit anti-tumor immune responses. Here the authors report the characterization of an adenosine A2A receptor (A2AR) eGFP reporter mouse, providing immunological insights into the biology of A2AR expression in the context of anti-tumor immunity.
- Kirsten L. Todd
- , Junyun Lai
- & Paul A. Beavis
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Article
| Open AccessARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.
- Maximilian Hirschenberger
- , Alice Lepelley
- & Konstantin M. J. Sparrer
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Article
| Open AccessDefining neutralization and allostery by antibodies against COVID-19 variants
Here, Tulsian et al. identified the effect of biologically relevant full-length IgG binding on the Spike protein from different SARS-CoV-2 variants to comprehensively understand the mechanisms of antibody evasion, towards the development of better antiviral strategies.
- Nikhil Kumar Tulsian
- , Raghuvamsi Venkata Palur
- & Paul Anthony MacAry
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Article
| Open AccessPeripheral helper-T-cell-derived CXCL13 is a crucial pathogenic factor in idiopathic multicentric Castleman disease
Idiopathic multicentric Castleman disease (CD) is a rare and potentially fatal lymphoproliferative disorder. Authors here establish a mouse xenotransplantation model of the “not otherwise specified” subtype of the disease and show that the chemokine CXCL13 plays a pivotal role in the pathogenesis and likely produced by peripheral helper cells, which expand upon engraftment.
- Takuya Harada
- , Yoshikane Kikushige
- & Kazuyuki Yoshizaki
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Article
| Open AccessAntigen presentation by B cells enables epitope spreading across an MHC barrier
Increasing evidence suggests that antigen presentation by B cells is critical to the initiation of autoimmunity. Here, the authors demonstrate that tolerance breakdown is initiated outside of germinal centres and that B cells can directly instruct T cells to break tolerance and propagate autoimmune responses.
- Cecilia Fahlquist-Hagert
- , Thomas R. Wittenborn
- & Søren E. Degn
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Article
| Open AccessContinually recruited naïve T cells contribute to the follicular helper and regulatory T cell pools in germinal centers
B cell clonal expansion and affinity maturation takes place in germinal centers (GC) and is orchestrated by follicular T cells. Here authors show that naïve conventional T cells are continuously recruited to the GCs during the GC reaction and develop into follicular helper and regulatory T cells, thus quantitatively contribute to remodelling the GC overtime.
- Julia Merkenschlager
- , Riza-Maria Berz
- & Michel C. Nussenzweig
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Article
| Open AccessAn in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases
Immune checkpoints are critical in maintaining self-tolerance and their therapeutic modulation can be achieved in autoimmune diseases. Here the authors present an in situ dual-anchoring approach that targets PD-L1 and show effects in animal models of autoimmunity.
- Shenqiang Wang
- , Ying Zhang
- & Jicheng Yu
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Article
| Open AccessHIV-1 diverts cortical actin for particle assembly and release
HIV-1 assembles and buds from the host cell membrane of infected T lymphocytes. Here, Dibsy et al. characterise the role of cortical actin, viral Gag and host factor Arpin in virion assembly and release.
- Rayane Dibsy
- , Erwan Bremaud
- & Delphine Muriaux
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Article
| Open AccessAntiviral responses in a Jamaican fruit bat intestinal organoid model of SARS-CoV-2 infection
Bats are natural reservoirs for several zoonotic viruses including SARS-CoV-2 thus there is a need to better define bat antiviral responses. Here, Hashimi et al. profile antiviral responses to SARS-CoV-2 in bat intestinal organoids finding that interferon and regenerative responses where induced.
- Marziah Hashimi
- , T. Andrew Sebrell
- & Diane Bimczok
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Article
| Open AccessA tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development
Within gastrointestinal tissues, tuft cells, a rare population of chemo-sensory epithelial cells, can promote the activation of type 2 innate lymphoid cells (ILC2s). Here the authors show that tuft cells and ILC2s are increased during gastric cancer development and that the pharmacologic inhibition of tuft cell derived IL25 or ILC2-produced IL13 reduces gastric tumor growth.
- Ryan N. O’Keefe
- , Annalisa L. E. Carli
- & Michael Buchert
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Article
| Open AccessMitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming
Exhaustion is the functional deterioration of T cells following chronic stimulation. Here, Wu et al. show that mitochondrial dysfunction drives T cell exhaustion by inhibiting HIF-1α degradation and transcriptional metabolic reprogramming.
- Hao Wu
- , Xiufeng Zhao
- & Martin Vaeth
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