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Article
| Open AccessClothianidin seed-treatment has no detectable negative impact on honeybee colonies and their pathogens
There has been a lack of multi-year landscape-scale studies on the effect of neonicotinoids on honeybee health. Here, Osterman et al. show that clothianidin exposure via seed-treated rapeseed has no negative impact on honeybee colony development, microbial pathogens/symbionts or immune gene expression.
- Julia Osterman
- , Dimitry Wintermantel
- & Joachim R. de Miranda
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Article
| Open AccessJapanese encephalitis virus neuropenetrance is driven by mast cell chymase
How Japanese encephalitis virus (JEV) penetrates the blood-brain barrier (BBB) remains unclear. Here, using a genetic mouse model and a virulent JEV strain, the authors show that perivascular mast cells (MC) mediate JEV neuroinvasion and identify the MC-protease chymase as a potential therapeutic target.
- Justin T. Hsieh
- , Abhay P. S. Rathore
- & Ashley L. St. John
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Article
| Open AccessIntestinal non-canonical NFκB signaling shapes the local and systemic immune response
Microfold cells (M-cell) are specialized cells of the intestine that sample luminal microbiota and dietary antigens. Here the authors show that epithelial non-canonical NFκB signalling, as induced by NIK, is important for M-cells maintenance, yet constitutive NIK activation is associated with gut inflammation and inflammatory bowel disease.
- Sadeesh K. Ramakrishnan
- , Huabing Zhang
- & Yatrik M. Shah
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Article
| Open AccessLymphocyte innateness defined by transcriptional states reflects a balance between proliferation and effector functions
Innate T cells (ITC) contain many subsets and are poised to promptly respond to antigens and pathogens, but how this poised state is maintained is still unclear. Here the authors perform single-cell RNA-seq to align the various ITC subsets along an ‘innateness gradient’ that is associated with changes in proliferation and effector functions.
- Maria Gutierrez-Arcelus
- , Nikola Teslovich
- & Patrick J. Brennan
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Article
| Open AccessCorticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition
Corticosteroids are host-directed drugs that enhance survival of tuberculosis patients through unclear mechanisms. Here, Gräb et al. show that corticosteroids inhibit necrotic death of cells infected with Mycobacterium tuberculosis by facilitating MKP-1-dependent dephosphorylation of p38 MAPK.
- Jessica Gräb
- , Isabelle Suárez
- & Jan Rybniker
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Article
| Open AccessSelection of immunoglobulin elbow region mutations impacts interdomain conformational flexibility in HIV-1 broadly neutralizing antibodies
Somatic mutations within antibody framework regions (FWR) can alter structural flexibility, but their role in maturation of broadly neutralizing antibodies (bnAbs) is unclear. Here the authors show how FWR mutations impact interdomain conformational flexibility and paratope plasticity during bnAb development.
- Rory Henderson
- , Brian E. Watts
- & S. Munir Alam
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Article
| Open AccessMosaic deletion patterns of the human antibody heavy chain gene locus shown by Bayesian haplotyping
High-throughput sequencing and analyzes of antibody repertoire provide important information on immune responses, but current methodologies are limited in sequence assembly precision and haplotype inference validity. Here the authors propose a new Bayesian haplotyping method, and attest its broad application with a large, multi-individual dataset.
- Moriah Gidoni
- , Omri Snir
- & Gur Yaari
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Article
| Open AccessSympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A
Diverse interactions between the nervous and immune systems have been shown, but specific mechanistic insights are still lacking. Here the authors show, using both mouse inflammation models and clinical correlation, that adrenergic nerve may ameliorate inflammation by inducing repulsive guidance molecule A signalling.
- Andreas Körner
- , Martin Schlegel
- & Valbona Mirakaj
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Article
| Open AccessHematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation
Transplantation of allogeneic bone marrow helps establish chimerism that may induce tolerance to tissue grafts. Here the authors show that a CD117-antibody-drug-conjugate helps precondition the recipients for inducing mixed chimerism and allo-tolerance without clear adverse effects or the need for chronic immune suppression.
- Zhanzhuo Li
- , Agnieszka Czechowicz
- & Philip M. Murphy
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Article
| Open AccessSelective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation
Hematopoietic stem cell (HSC) transplantation is a desirable treatment for many non-malignant and malignant diseases, but its use requires preconditioning of recipients with irradiation or chemotherapy that often induces high toxicity. Here the authors show that antibody-drug-conjugate to CD117, a HSC marker, allows specific and efficient preconditioning for HSC therapy.
- Agnieszka Czechowicz
- , Rahul Palchaudhuri
- & Derrick J. Rossi
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Article
| Open AccessTGFβ/BMP immune signaling affects abundance and function of C. elegans gut commensals
Host genetics modulates gut microbiota composition, which in turn affects host health, but little is known about the specific genes involved. Here, Berg et al. show that TGFβ/BMP immune signalling affects abundance and function of commensal Enterobacter species in C. elegans.
- Maureen Berg
- , David Monnin
- & Michael Shapira
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Article
| Open AccessTargets of complement-fixing antibodies in protective immunity against malaria in children
Antibodies against Plasmodium falciparum merozoites that fix complement can inhibit blood-stage replication. Here, Reiling et al. show that complement-fixing antibodies strongly correlate with protective immunity in children, identify the merozoite targets, and predict antigen combinations that should result in strong protection.
- Linda Reiling
- , Michelle J. Boyle
- & James G. Beeson
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Article
| Open AccessVirus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy
The immunosuppressive tumor environment and the lack of functional anti-tumor immunity are major limiting factors in immunotherapy. Here the authors show that human and mouse tumors are infiltrated by virus-specific memory T cells, which can be harnessed by viral peptides to induce local and systemic anti-tumor immunity and synergize with checkpoint blockade.
- Pamela C. Rosato
- , Sathi Wijeyesinghe
- & David Masopust
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Article
| Open AccessSatb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation
A chromatin remodelling factor Satb1 is essential for T cell lineage development in the thymus. Here the authors show that while Satb1 is dispensable for the differentiation of Th17 cells and their response to gut commensals, it plays a critical role in pathogenic Th17 effector function in EAE by directly activating Bhlhe40 and modulating PD-1.
- Keiko Yasuda
- , Yohko Kitagawa
- & Keiji Hirota
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Article
| Open AccessRemodeling of secretory lysosomes during education tunes functional potential in NK cells
Natural killer (NK) cells are functionally calibrated against self MHC during a process termed education. Here the authors show that NK cell education is associated with the accumulation of dense-core secretory lysosomes for expedited release of granzyme B and Ca2+ flux upon target recognition and NK cell activation.
- Jodie P. Goodridge
- , Benedikt Jacobs
- & Karl-Johan Malmberg
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Article
| Open AccessThe cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells
Metabolic pathways are increasingly recognized as crucial determinants of T cell function. Here the authors show that the balance between IFNγ and IL-10 production in human CD4 T cells is modulated by the cholesterol biosynthetic pathway.
- Esperanza Perucha
- , Rossella Melchiotti
- & Andrew P. Cope
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Article
| Open AccessRunx/Cbfβ complexes protect group 2 innate lymphoid cells from exhausted-like hyporesponsiveness during allergic airway inflammation
Group 2 innate lymphoid cells (ILC2) are important mediators for allergy, but how ILC2 are regulated under chronic inflammation is still unclear. Here the authors show that Runx transcription factors, which normally suppresses ILC2 activation at steady state, help promote ILC2 activation and type 2 cytokine production in lung allergy mouse models.
- Chizuko Miyamoto
- , Satoshi Kojo
- & Takashi Ebihara
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Article
| Open AccessCKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ
In atherosclerotic plaques, transformation of macrophages into foam cells is a key step in initiating the inflammatory response. Here Fan et al. show that casein kinase 2-interacting protein-1 (CKIP-1) limits foam cell formation and atherosclerosis by preventing expression of the scavenger receptor LOX-1 through REGγ-mediated degradation of Oct-1.
- Jiao Fan
- , Lifeng Liu
- & Lingqiang Zhang
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Article
| Open AccessMemory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patients
Adoptive cell therapy (ACT) using neoantigen-specific T cells can lead to tumor regression. Here the authors use an in vitro stimulation approach to isolate tumor specific memory T cells from peripheral blood of metastatic epithelial cancer patients targeting unique as well as shared mutations in the KRAS oncogene.
- Gal Cafri
- , Rami Yossef
- & Steven A. Rosenberg
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Article
| Open AccessDiverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages
Transcription factors of the AP-1 family can play diverse roles despite recognizing the same DNA sequence. Here the authors investigate the DNA binding activities of AP-1 members in mouse macrophages and apply a machine learning approach to identify motifs predicted to drive factor-specific binding profiles.
- Gregory J. Fonseca
- , Jenhan Tao
- & Christopher K. Glass
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Article
| Open AccessNeuropathological correlates and genetic architecture of microglial activation in elderly human brain
The consequences of microglial activation in the aging human brain remain unknown. This study quantified microglial morphology and density in the elderly human brain to show that cortical microglial activation strongly associates with AD pathogenesis and may be an upstream contributor to cognitive decline via the accumulation of tau pathology.
- Daniel Felsky
- , Tina Roostaei
- & Philip L. De Jager
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Article
| Open AccessA child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation
Some perinatally HIV infected children who have received early antiretroviral therapy (ART) show long-term sustained virological control after ART cessation. Here the authors describe a case who, at age 9.5 years, shows normal CD4:CD8 T cell ratios and has no detectable levels of replication-competent virus.
- Avy Violari
- , Mark F. Cotton
- & Caroline T. Tiemessen
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Article
| Open AccessThe lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation
The transcription factor Foxp3 and Stat5 modulate lineage stability and function of regulatory T (Treg) cells to promote immune homeostasis. Here the authors show that O-GlcNAcylation of Foxp3 and Stat5, mediated by O-GlcNAc transferase (OGT), is essential for Treg-mediate immune balance, with Treg-specific deficiency of OGT leading to severe autoimmunity.
- Bing Liu
- , Oscar C. Salgado
- & Hai-Bin Ruan
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Article
| Open AccessEfficient oral vaccination by bioengineering virus-like particles with protozoan surface proteins
Giardia lamblia express a dense coat of variant-specific surface proteins (VSPs) on trophozoites that protects the parasite inside the host´s intestine. Here the authors show that stability and immunomodulatory properties of VSPs can be exploited to both protect and adjuvant vaccine antigens for oral administration.
- Marianela C. Serradell
- , Lucía L. Rupil
- & Hugo D. Luján
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Article
| Open AccessCross-lineage protection by human antibodies binding the influenza B hemagglutinin
Immune recognition of Influenza B virus (IBV) is poorly understood. Here, Liu et al. use flow cytometry to characterize IBV-specific memory B cell responses following seasonal vaccination and show that elicited cross-reactive antibodies can protect against infection, providing a platform for vaccine design.
- Yi Liu
- , Hyon-Xhi Tan
- & Adam K. Wheatley
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Article
| Open AccessMalonylation of GAPDH is an inflammatory signal in macrophages
Host metabolic reprogramming plays a role in functional responses against pathogens. Here, the authors characterise malonylated proteins in macrophages and show that malonylation of the glycolytic enzyme GAPDH impacts cytokine production by modulating both its enzymatic activity and RNA-binding capacity.
- Silvia Galván-Peña
- , Richard G. Carroll
- & Luke A. O’Neill
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Article
| Open AccessTCR microclusters form spatially segregated domains and sequentially assemble in calcium-dependent kinetic steps
Engagement of T cell receptors (TCRs) induces the formation of microclusters that mediate the downstream signalling events. Here the authors show, using high resolution TIRF-SIM and live cell imaging, that ZAP70 and LAT are recruited to TCR with distinct kinetics, with the delayed ZAP70-TCR association modulated by TCR-induced calcium flux.
- Jason Yi
- , Lakshmi Balagopalan
- & Lawrence E. Samelson
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Article
| Open AccessInterferon lambda protects the female reproductive tract against Zika virus infection
Zika virus infections can cause devastating congenital birth defects but the underlying interactions with the host immune system are not well understood. Here, the authors examine the immune basis of vaginal protection and susceptibility to Zika viral infection, and identify a hormonal dependent role for interferon-lambda-mediated protection against disease.
- Elizabeth A. Caine
- , Suzanne M. Scheaffer
- & Michael S. Diamond
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Article
| Open AccessFetal-derived macrophages dominate in adult mammary glands
Tissue-resident macrophages are highly specialized phagocytes that serve multiple functions. Here, using high-dimension analyses and fate-mapping experiments, the authors show that fetal liver-derived macrophages dominate the mammary gland in neonatal and adult, and display characteristic phenotypes and functions.
- Norma Jäppinen
- , Inês Félix
- & Marko Salmi
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Article
| Open AccessNeuroinflammation-induced lymphangiogenesis near the cribriform plate contributes to drainage of CNS-derived antigens and immune cells
Lymphangiogenesis occurs in the context of systemic inflammation and development but has not been reported for the lymphatics that surround the CNS. Here the authors show that in the context of experimental autoimmune encephatlitis, lymphangiogenesis occurs at the cribriform plate, but not the meninges, and contributes to immune cell and antigen drainage.
- Martin Hsu
- , Aditya Rayasam
- & Zsuzsanna Fabry
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Article
| Open AccessATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens
The generation of protective secretory IgA is a desired outcome of oral vaccination. Here, the authors show that the depletion of intestinal ATP significantly improves the production and response of high-affinity IgA against both live and inactivated oral vaccines.
- Michele Proietti
- , Lisa Perruzza
- & Fabio Grassi
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Article
| Open AccessBreakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice
Chronic hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC) and is associated with immune tolerance to HBV. Here the authors show, in a transgenic mouse model, that rescuing T cells function via inhibition of co-inhibitory receptor TIGIT results in HCC development via supporting inflammation.
- Lu Zong
- , Hui Peng
- & Zhigang Tian
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Article
| Open AccessMature IgDlow/- B cells maintain tolerance by promoting regulatory T cell homeostasis
B cells produce antibodies to mediate various immune functions, but are also reported to negatively regulate immune responses. Here, the authors show that a subset of mature B cells expressing low levels of IgD, present in both mice and human, may pursue this regulatory function indirectly by inducing the proliferation of regulatory T cells via GITRL.
- Avijit Ray
- , Mohamed I. Khalil
- & Bonnie N. Dittel
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Article
| Open AccessExpression of novel long noncoding RNAs defines virus-specific effector and memory CD8+ T cells
Long noncoding RNA (lncRNA) genes do not encode protein products yet are emerging as key regulators of cellular processes such as transcription and translation. Here, by examining lncRNA profiles from human and mouse CD8 T cells, the authors show that stages of CD8+ T cell differentiation are defined by expression of lncRNA genes.
- William H. Hudson
- , Nataliya Prokhnevska
- & Haydn T. Kissick
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Article
| Open AccessCD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy
Targeting the immune-stimulatory receptor 4-1BB has only yielded modest benefit in cancer treatment. In this study, the authors show that CD73 expression on effector T cells sustained by TGF-β drives tumor resistance to anti-4-1BB therapy and therefore TGF- β blockade can be used to overcome such resistance.
- Siqi Chen
- , Jie Fan
- & Bin Zhang
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Article
| Open AccessPost-exposure immunotherapy for two ebolaviruses and Marburg virus in nonhuman primates
Current experimental monoclonal antibodies (mAbs) for Ebola virus (EBOV) post-exposure immunotherapy are ineffective against Sudan (SUDV) or Marburg virus (MARV). Here, authors develop cocktails of mAbs that protect nonhuman primates against EBOV, SUDV, and MARV infection when given four days post infection.
- Jennifer M. Brannan
- , Shihua He
- & M. Javad Aman
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Article
| Open AccessEnhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway
Urolithins are microbial metabolites derived from food polyphenols. Here, Singh et al. show that urolithin A and a synthetic analogue enhance gut barrier function via Nrf2-dependent pathways and mitigate inflammation and colitis in mice, highlighting a potential application for inflammatory bowel diseases.
- Rajbir Singh
- , Sandeep Chandrashekharappa
- & Venkatakrishna R. Jala
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Article
| Open AccessMolecular recognition of the native HIV-1 MPER revealed by STED microscopy of single virions
The Membrane-Proximal External Region (MPER) of the HIV Env gp41 subunit is a target for broadly neutralizing antibodies. Here, the authors apply super-resolution stimulated emission depletion (STED) microscopy on single virions and provide insights into how the MPER epitope is recognized.
- Pablo Carravilla
- , Jakub Chojnacki
- & José L. Nieva
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Article
| Open AccessA T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids
CD1 proteins present lipid antigens to T cells via the T cell receptor. Here the authors describe T cell reactivity to human membrane lipid moieties and provide structural data to define a molecular mechanism of promiscuous recognition of self-derived phospholipids.
- Adam Shahine
- , Peter Reinink
- & Ildiko Van Rhijn
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Article
| Open AccessMicroglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits
The potential links between infections and neurodegenerative disorders are unclear. Here, Wu et al. present a mouse model of low-grade candidemia characterized by highly localized cerebritis, accumulation of amyloid precursor protein and beta peptides, and mild memory impairment that resolves with fungal clearance.
- Yifan Wu
- , Shuqi Du
- & David B. Corry
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Article
| Open AccessPRMT5 is essential for B cell development and germinal center dynamics
Protective antibody responses depend critically on proper B cell development and differentiation at multiple stages. Here the authors show that a protein arginine methyltransferase, Prmt5 uses multiples pathways to prevent death of immature B cells, yet modulates, in p53-independent manners, the survival and differentiation of mature B cells.
- Ludivine C. Litzler
- , Astrid Zahn
- & Javier M. Di Noia
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Article
| Open AccessUlcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
The severity of ulcerative colitis, and response to treatment, is highly variable. Here, the authors examine rectal gene expression signatures and faecal microbiomes of children and adults with the disease and provide new insights in to pathogenesis.
- Yael Haberman
- , Rebekah Karns
- & Lee A. Denson
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Article
| Open AccessRORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients
The role of innate T cell subsets in the pathogenesis of spondyloarthritis (SpA) is not well understood. Here, the authors examine the role of invariant natural killer T (iNKT) and γδ-T cells in SpA and show that disease-derived iNKT and γδ-T cells have unique and Th17-skewed phenotype and gene expression profiles within inflamed joints.
- Koen Venken
- , Peggy Jacques
- & Dirk Elewaut
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Article
| Open AccessMolecular and functional heterogeneity of IL-10-producing CD4+ T cells
Tr1 cells are considered an immunosuppressive CD4 T cell population producing IL-10. Here the authors show that IL-10 is insufficient for Tr1 immunosuppression, define surface markers and transcriptional program of the immunosuppressive subset within Tr1, and reveal its deficiency in patients with IBD.
- Leonie Brockmann
- , Shiwa Soukou
- & Samuel Huber
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Article
| Open AccessBroad CD8+ T cell cross-recognition of distinct influenza A strains in humans
Mutations within immunological epitope containing regions of influenza A virus can impair the established immune response between influenza strains and could impact rational vaccine design. Here Grant et al. examine the presence, structural impact and cross reactivity of two human immunodominant influenza epitope variants.
- Emma J. Grant
- , Tracy M. Josephs
- & Katherine Kedzierska
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Article
| Open AccessA miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset
A decrease in the fraction of non-classical monocytes is a hallmark of chronic myelomonocytic leukaemia. Taking advantage of this abnormal situation, the authors identify a mechanistic link between miR-150 and TET3 as being involved in monocyte subset generation.
- Dorothée Selimoglu-Buet
- , Julie Rivière
- & Eric Solary
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Article
| Open AccessEzh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf
Ezh2 is an histone methyltransferase that catalyzes H3K27me3. Here the authors show that Ezh2 promotes T follicular helper (TFH) differentiation and helper activity, by cooperating with Tcf1 to activate Bcl6 transcription and epigenetically repressing p19Arf, an antagonist of Bcl6 function and TFH cell survival.
- Fengyin Li
- , Zhouhao Zeng
- & Hai-Hui Xue
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Article
| Open AccessA virus-encoded type I interferon decoy receptor enables evasion of host immunity through cell-surface binding
Secreted cytokine decoy receptors encoded by viruses can act as potent immune evasion proteins modulating antiviral immunity. Here Hernaez et al. show that cell surface binding is required for efficient evasion of the host response by a secreted virus encoded type I IFN decoy receptor of vaccinia and ectromelia virus using an in vivo model of infection.
- Bruno Hernáez
- , Juan Manuel Alonso-Lobo
- & Antonio Alcamí
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Article
| Open AccessField-level clothianidin exposure affects bumblebees but generally not their pathogens
The potential impact of neonicotinoid field exposure on bumblebee microbiota remains unclear. In a landscape—scale study, Wintermantel et al. show that whilst exposure to clothianidin impacts Bombus terrestris performance, it does not affect levels of gut bacteria, viruses or intracellular parasites.
- Dimitry Wintermantel
- , Barbara Locke
- & Joachim R. de Miranda
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