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| 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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Article
| Open AccessEffectiveness of the second COVID-19 booster against Omicron: a large-scale cohort study in Chile
This study assesses the effectiveness of a second COVID-19 mRNA booster vaccine against severe disease using data from Chile. The authors find that the effectiveness of the second mRNA booster was high with a range of different background vaccination schemes, but there was evidence of waning over time.
- Alejandro Jara
- , Cristobal Cuadrado
- & Rafael Araos
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Article
| Open AccessCRISPR-Cas9 engineering of the RAG2 locus via complete coding sequence replacement for therapeutic applications
RAG2-SCID is a primary immunodeficiency caused by mutations in Recombination-activating gene 2 (RAG2). Here the authors report a RAG2 correction strategy that replaces the entire endogenous coding sequence (CDS) to maintain the endogenous spatiotemporal gene regulation and locus architecture.
- Daniel Allen
- , Orli Knop
- & Ayal Hendel
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Article
| Open AccessRespiratory mucosal immune memory to SARS-CoV-2 after infection and vaccination
Evidence from animal models suggest a vital role for mucosal vaccination in inducing protection from coronavirus infection. Here the authors examine the B and T cell responses at the lower airways, and contrast humoral and cellular immunity of people after infection and vaccination.
- Elena Mitsi
- , Mariana O. Diniz
- & Daniela M. Ferreira
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Article
| Open AccessFHL1 promotes chikungunya and o’nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design
FHL1A is a crucial host factor for alphavirus infection but its impact on pathogenesis is unclear. Here, the authors use a FHL1−/− knockout mouse model to show that the FHL1 splice variant impacts arthritis and myositis after chikungunya or o’nyong-nyong infections but not Ross River or mayaro virus infection.
- Wern Hann Ng
- , Xiang Liu
- & Suresh Mahalingam
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Article
| Open AccessImmune synapse formation promotes lipid peroxidation and MHC-I upregulation in licensed dendritic cells for efficient priming of CD8+ T cells
CD4+ T cells have been shown to be important in CD8+ T cell responses through a process of DC:T cell interaction. Here the authors further characterise this DC:T cell interaction and show that after CD4+ T cell help these post-synaptic DCs have increased lipid peroxidation and increased MHC class I proteins associated with increased cross-presentation function.
- Diego Calzada-Fraile
- , Salvador Iborra
- & Francisco Sánchez-Madrid
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Article
| Open AccessEbf3+ niche-derived CXCL12 is required for the localization and maintenance of hematopoietic stem cells
CAR cells act as HSC niche cells. Here the authors show that CXCL12 ablation in half CAR cells attracts HSCs from affected CAR cells to intact CAR cells whereas CXCL12 ablation in all CAR cells depletes balanced HSCs producing B cells at high levels.
- Taichi Nakatani
- , Tatsuki Sugiyama
- & Takashi Nagasawa
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Article
| Open AccessOrganoids transplantation attenuates intestinal ischemia/reperfusion injury in mice through L-Malic acid-mediated M2 macrophage polarization
Intestinal ischemia/reperfusion (I/R) injury is a life-threatening problem in surgeries. Here, authors report that intestinal organoids transplantation attenuates intestinal I/R injury in mice through L-Malic acid-mediated M2 macrophage polarization.
- Fang-Ling Zhang
- , Zhen Hu
- & Ke-Xuan Liu
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Article
| Open AccessBiomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy
Cancer immune therapy utilizing interleukin 15 (Il-15) is hampered by the short half-life and systemic toxic effects of the cytokine. Here authors introduce a biomimetic nanovaccine, in which Il-15 and tumor-associated antigenic peptide/MHC-I complexes are co-anchored to cell membrane vesicles of dendritic cell origin, which elicits antigen-specific T cell response leading to superior anti-tumour effect in syngeneic mouse tumour models.
- Kaiyuan Wang
- , Xuanbo Zhang
- & Jin Sun
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Article
| Open AccessAn interferon-integrated mucosal vaccine provides pan-sarbecovirus protection in small animal models
Here, the authors report the generation of a live but defective SARS-CoV-2 virus that is envelope-deficient and expresses human interferon beta. They show that nasal vaccination enhances mucosal and lung T cell response and provides pan-sarbecovirus protection in small animals.
- Chun-Kit Yuen
- , Wan-Man Wong
- & Kin-Hang Kok
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Article
| Open AccessSIgA structures bound to Streptococcus pyogenes M4 and human CD89 provide insights into host-pathogen interactions
Here, the authors used cryo-EM to explore secretory Immunoglobulin A interactions with bacterial and host receptors, uncovering unexpected binding stoichiometry and unappreciated functional consequences relevant to understanding host-pathogen interactions.
- Qianqiao Liu
- & Beth M. Stadtmueller
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Article
| Open AccessC-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity
Receptor dimerization can modulate immune responses during various microbial infections. Here, the authors show that C-type lectin receptor-2d (CLEC2D) negatively regulates antifungal immunity through forming homodimers or heterodimers with TLR2.
- Fan Li
- , Hui Wang
- & Xin-Ming Jia
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Article
| Open AccessInterferon-γ couples CD8+ T cell avidity and differentiation during infection
Although IFN-γ is known to regulate T cell function and expansion during virus-specific responses, its impact on T cells with varying avidity for antigen remains unclear. Here, the authors demonstrate that IFN-γ promotes the expansion of low-avidity CD8+ T cells during the effector phase, but favours those with high avidity in the memory pool.
- Lion F. K. Uhl
- , Han Cai
- & Audrey Gerard
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Article
| Open AccessActivation of coagulation and proinflammatory pathways in thrombosis with thrombocytopenia syndrome and following COVID-19 vaccination
Adenovirus-based vaccination for SARS-CoV-2 has a rare chance to cause thrombosis with thrombocytopenia (TTS). Here the authors compare proteomic and transcriptomic data from vaccinated participants with or without TTS to find distinct activations of coagulation and innate immune pathways in patient with TTS, or following initial or boosting vaccination.
- Malika Aid
- , Kathryn E. Stephenson
- & Dan H. Barouch
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Article
| Open AccessImmune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis
Immune checkpoint inhibitors (CPI) could effectively target cancers that are resistant to traditional therapy but may initiate immune related adverse effects, such as colitis. Here, authors characterise the gut immune microenvironment during CPI-colitis by bulk RNA sequencing, single-cell RNA sequencing and flow cytometry, and find that interleukin 23 plays an important role in promoting inflammation via cytotoxic polyfunctional IFNγ-producing lymphocytes.
- Jonathan W. Lo
- , Domenico Cozzetto
- & Nick Powell
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Article
| Open AccessSARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors
Although SARS-CoV2 epitope characterization has been the focus of extensive research, these efforts have largely focused on the spike protein. Here, the authors demonstrate that CD8+ T cell responses can be directed against a dominant nucleocapsid epitope and rely on a highly focused T cell receptor repertoire.
- Cecily Choy
- , Joseph Chen
- & Nan-Ping Weng
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Article
| Open AccessPathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections
Group A streptococcus causes a wide range of human diseases and significantly contributes to morbidity and mortality worldwide. Here, Toledo et al show how streptococcus alters the structure and function of endogenous and therapeutic antibodies during infection and how this is affected by the host microenvironment.
- Alejandro Gomez Toledo
- , Eleni Bratanis
- & Johan Malmström
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Article
| Open AccessDNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts
Epigenetic therapies are known to synergize with immunotherapies through the de-repression of endogenous retroviral element (ERV)-encoded promoters. Here the authors identify treatment-induced neoantigens and validate their ability to induce T cell response and anti-tumor effects in vitro and in patient samples.
- Ashish Goyal
- , Jens Bauer
- & Christoph Plass
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Article
| Open AccessStructure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir
The HIV-1 entry inhibitor temsavir prevents the interaction of the envelope glycoprotein with its cellular receptor. Here, authors apply CryoEM to show that HIV-1 clade AE resistance to temsavir is a combination of the residue at position 375 (His) and mutations in the gp120 mobile layers. Mutation of His375 to Ser/Thr and reversion of the layer mutations are required to restore temsavir sensitivity.
- Jérémie Prévost
- , Yaozong Chen
- & Marzena Pazgier
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Article
| Open AccessMicrophysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV± cancer
Current biological models for examining cancer immunobiology in a HIV infected context are lacking. Here the authors use a human-derived microphysiological model to represent the HIV immune system and assess the ability of transferred populations of NK cells in the targeting of tumours.
- Jose M. Ayuso
- , Mehtab Farooqui
- & David J. Beebe
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Article
| Open AccessAn innate granuloma eradicates an environmental pathogen using Gsdmd and Nos2
Pathogens often persist within granulomas which form to control infection. Here, Harvest et al describe an innate granuloma that eradicates a ubiquitous environmental pathogen without inducing adaptive immunity.
- Carissa K. Harvest
- , Taylor J. Abele
- & Edward A. Miao
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Article
| Open AccessThe transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells
Type 1 conventional dendritic cells (cDC1) play a pivotal role in the cross-presentation of antigens, enabling efficient CD8 + T cell response. Here authors show that the transcription factor Zeb1 essentially regulates this process via facilitating the reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytoplasm.
- Yan Wang
- , Quan Zhang
- & Nengming Xiao
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Article
| Open AccessA conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity
The authors identify feeblin, an inhibitory compound of the proinflammatory TLR7/8/9-IRF5 pathway with therapeutic potential, which acts by binding SLC15A4 via an allosteric mechanism mediating degradation of its signaling partner TASL.
- Andras Boeszoermenyi
- , Léa Bernaleau
- & Giulio Superti-Furga
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Article
| Open AccessStructural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling
Three structures of human SLC15A4 are presented in the outward-facing apo monomeric and dimeric states and the inward-facing TASL-bound state, revealing the molecular mechanism of SLC15A4-mediated TASL recruitment in human endolysosomal TLRs signalling.
- Xudong Chen
- , Min Xie
- & Maojun Yang
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Article
| Open AccessDe novo genome assembly depicts the immune genomic characteristics of cattle
The genomic organisation of the cattle genome has been assembled to a limited level of resolution. Here using long range nanopore sequencing the authors present a cattle genome assembly concentrating on characterising the immunogenomic loci, particularly T cell receptor (TR), immunoglobulin (IG) and MHC genes, from one animal.
- Ting-Ting Li
- , Tian Xia
- & Tao Li
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Article
| Open AccessObesity dysregulates the pulmonary antiviral immune response
Obesity is a risk factor for severe influenza infection. Here, Almond et al show that increased susceptibility is due to increased airway concentrations of the hormone leptin which dampens interferon responses and facilitates severe infection.
- Mark Almond
- , Hugo A. Farne
- & Aran Singanayagam
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Article
| Open AccessA spatial sequencing atlas of age-induced changes in the lung during influenza infection
Ageing is known to impair the immune response against infectious pathogens. Here, Kasmani et al. present a spatial and transcriptomic atlas of immune changes in the lungs of young and aged mice in response to influenza virus infection.
- Moujtaba Y. Kasmani
- , Paytsar Topchyan
- & Weiguo Cui
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Article
| Open AccessInfection- or AZD1222 vaccine-mediated immunity reduces SARS-CoV-2 transmission but increases Omicron competitiveness in hamsters
The impact of various immune statuses on SARS-CoV-2 transmission is unclear. Here, the authors used transmission chain experiments in hamsters to show better transmission prevention after intranasal vaccination and previous infection. Higher humoral responses against Delta may provide a competitive advantage to Omicron.
- Julia R. Port
- , Claude Kwe Yinda
- & Vincent J. Munster
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Article
| Open AccessDesign, structure and plasma binding of ancestral β-CoV scaffold antigens
Development of vaccines remains challenging because viral antigens can be unstable or aggregate. Here, authors present ancestral sequence reconstruction as a method to generate stable and soluble antigens using exclusively available sequence information.
- David Hueting
- , Karen Schriever
- & Per-Olof Syrén
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Article
| Open AccessStructural basis of dimerization of chemokine receptors CCR5 and CXCR4
Here, authors report chemokine receptors structures obtained using coarse-grained metadynamics. CCR5 and CXCR4 homo- and heterodimers differ in the conformations of ligand binding sites and of the G protein interaction interface, suggesting structural basis for the rational design of biased ligands.
- Daniele Di Marino
- , Paolo Conflitti
- & Vittorio Limongelli
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Article
| Open AccessPerinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells
Early life infections are known to impact and modulate the immune response in later life. Here the authors show that perinatal infection with murine cytomegalovirus results in a modified transcriptional profile and functionality in murine NK cells.
- Carmen Rožmanić
- , Berislav Lisnić
- & Ilija Brizić
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Article
| Open AccessFertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model
Successful engraftment of human hematopoietic stem cells during gene therapy requires myeloablative conditioning of the recipient, at the expense of toxicity. Authors show here that a single-dose of anti-CD117 antibody-drug conjugate achieves similar engraftment results as traditional multi-dose busulfan conditioning but preserves fertility in a non-human primate model.
- Naoya Uchida
- , Ulana Stasula
- & John F. Tisdale
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Article
| Open AccessComprehensive profiling of neutralizing polyclonal sera targeting coxsackievirus B3
Neutralizing antibodies are key to resolving viral infections and confer long-term protection. This work provides a detailed analysis of how murine and human sera neutralize a non-enveloped human virus, coxsackievirus B3, and how the virus can escape them.
- Beatriz Álvarez-Rodríguez
- , Javier Buceta
- & Ron Geller
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Article
| Open AccessSUN1/2 controls macrophage polarization via modulating nuclear size and stiffness
Stiffness and size of the nucleus may affect the function of specific cell types. Here the authors show that LPS treatment of macrophages affects the nucleus stiffness and size involving nuclear envelope proteins SUN1/2, chromatin accessibility and M1 associated gene expression.
- Shi Jiao
- , Chuanchuan Li
- & Zhaocai Zhou
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Article
| Open AccessKRAS G12V neoantigen specific T cell receptor for adoptive T cell therapy against tumors
Recent evidence suggests that KRAS mutations can be source of neoantigens and elicit T cell responses. Here the authors report the identification and characterization of KRAS-G12V specific TCRs for adoptive T cell immunotherapy.
- Dan Lu
- , Yuan Chen
- & George F. Gao
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Article
| Open AccessSingle-cell multi-omics analysis identifies two distinct phenotypes of newly-onset microscopic polyangiitis
Autoimmune vasculitis can be heterogeneous in terms of immune cell involvement. Here the authors use a single cell transcriptomics approach to characterise a group of microscopic polyangiitis patients that could be split into two groups typified by monocyte or Interferon associated gene expression.
- Masayuki Nishide
- , Kei Nishimura
- & Atsushi Kumanogoh
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Article
| Open AccessDefense against phytopathogens relies on efficient antimicrobial protein secretion mediated by the microtubule-binding protein TGNap1
Defining plant defense machinery against pathogens is significant in cell biology and crop yield. TGNap1, a TGN and microtubule-binding protein, is required for defense and efficient anti-microbial protein secretion, linking secretion and cytoskeleton.
- Deepak D. Bhandari
- , Dae Kwan Ko
- & Federica Brandizzi
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Article
| Open AccessHIV-1 treatment timing shapes the human intestinal memory B-cell repertoire to commensal bacteria
HIV-1 infection is known to impact the gut mucosa, effecting the microbiota and immune system, but early antiretroviral therapy is linked to partial reversal of this phenomena. Here the authors explore the impact of early commencement of antiretroviral therapy and show this can limit the abnormal responses of intestinal B cells associated with HIV-1 infection.
- Cyril Planchais
- , Luis M. Molinos-Albert
- & Hugo Mouquet
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Article
| Open AccessCreating resistance to avian influenza infection through genome editing of the ANP32 gene family
In chickens, influenza A virus relies on host protein ANP32A. Here the authors use CRISPR/Cas9 to generate homozygous gene edited chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction.
- Alewo Idoko-Akoh
- , Daniel H. Goldhill
- & Mike J. McGrew
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Article
| Open AccessSystematic identification of gene combinations to target in innate immune cells to enhance T cell activation
Determining targets for genetic engineering of immune cells remains a challenge. Here, we apply genome-wide CRISPR screens with a high-order Perturb-seq (named HMPCITE-seq) to identify gene combinations whose joint targeting improves innate immune cell function.
- Lei Xia
- , Anastasia Komissarova
- & Oren Parnas
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Article
| Open AccessFibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis
Fibroblast growth factor (FGF)18 plays pleiotropic roles, including bone development and carcinogenesis, however, its precise role in liver fibrosis remains incompletely understood. Here, the authors show that FGF18 promotes liver fibrosis by stimulating hepatic stellate cell proliferation, without concomitant upregulation of profibrotic genes.
- Yuichi Tsuchiya
- , Takao Seki
- & Hiroyasu Nakano
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Article
| Open AccessPolarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release
Microglia drastically change their morphology when reacting to pathological stimuli. Here, the authors study the molecular responses to stimulation and unravel cytoskeleton remodeling pathways that induce morphological and functional changes.
- Max Adrian
- , Martin Weber
- & Casper C. Hoogenraad
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Article
| Open AccessMucosal application of the broadly neutralizing antibody 10-1074 protects macaques from cell-associated SHIV vaginal exposure
HIV-1 can be transmitted by infected cells in body fluids and an efficient prophylaxis should prevent this. Here the authors show that the HIV-1 antibody 10-1074, when applied as topical vaginal gel, inhibits cell-associated transmission in non-human primates.
- Karunasinee Suphaphiphat
- , Delphine Desjardins
- & Mariangela Cavarelli
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