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| Open AccessShp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells
The phosphatase Shp-2 was implicated in NK cell education due to its reported association with inhibitory receptors, but its function in this context is unclear. Here the authors show that Shp-2 is not required for NK cell function, but is necessary for IL-15-induced metabolic burst and expansion.
- Charlène Niogret
- , S. M. Shahjahan Miah
- & Greta Guarda
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Article
| Open AccessGenomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma
Burkitt lymphoma (BL) is the most common pediatric B-cell lymphoma. Here, within the International Cancer Genome Consortium, the authors performed whole genome and transcriptome sequencing of 39 sporadic BL, describing the landscape of mutations, structural variants, and mutational processes that underpin this disease how alterations on different cellular levels cooperate in deregulating key pathways and complexes.
- Cristina López
- , Kortine Kleinheinz
- & Reiner Siebert
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Article
| Open AccessSpecialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma
Pancreatic ductal adenocarcinoma is characterized by a highly immunosuppressive tumour microenvironment. Here, the authors show that specialized subsets of tumour-infiltrating dendritic cells induce distinct CD4+ T cell programs and specifically identify a CD103–CD11b+ subset which induces tumor-promoting FoxP3– Type-1 regulatory T cells.
- Rocky M. Barilla
- , Brian Diskin
- & George Miller
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Article
| Open AccessIL-4 together with IL-1β induces antitumor Th9 cell differentiation in the absence of TGF-β signaling
CD4+ helper T cells producing IL-9 (Th9) have been implicated in anti-tumor immunity, with Th9 differentiation inducible in vitro via IL-4 and TGFβ treatment. Here the authors show that replacing TGFβ with IL-1β induces a distinct IL-9+ CD4+ population that have strong cytotoxic and anti-tumor activity in preclinical mouse models.
- Gang Xue
- , Guangxu Jin
- & Yong Lu
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Article
| Open AccessBone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT
Allogeneic hematopoietic cell transplantation is the standard treatment of acute myeloid leukemia, but many patients relapse. Here the authors show increased markers of exhaustion and cancer antigen specificity within bone marrow-residing memory T cells precede and potentially predict the relapse.
- Maddalena Noviello
- , Francesco Manfredi
- & Chiara Bonini
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Article
| Open AccessMicrobial recognition by GEF-H1 controls IKKε mediated activation of IRF5
The transcription factor IRF5 is essential for immune defense against pathogens. Here, the authors show that the microtubule-associated factor GEF-H1 plays a critical role in host defense against Listeria monocytogenes in macrophages via activation of the IRF5 kinase IKKε.
- Yun Zhao
- , Rachid Zagani
- & Hans-Christian Reinecker
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Article
| Open AccessNeutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
The pathogenesis of heparin-induced thrombocytopenia and thrombosis (HIT) is mediated by heparin-reactive autoantibodies binding to platelets (thrombocytes). Here the authors show neutrophil activation and NETosis are elevated in patients with HIT, and are essential for thrombosis in HIT mouse models.
- José Perdomo
- , Halina H. L. Leung
- & Beng H. Chong
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Article
| Open AccessLarge-scale network analysis reveals the sequence space architecture of antibody repertoires
Analysis of large-scale immune repertoire architecture remains a challenge. Here, the authors introduce an approach to construct similarity networks from high-throughput antibody repertoire sequencing data, and show that the networks are redundant, robust and reproducible across individuals.
- Enkelejda Miho
- , Rok Roškar
- & Sai T. Reddy
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Article
| Open AccessMolecular mechanism for the control of virulent Toxoplasma gondii infections in wild-derived mice
Toxoplasma gondii virulence in wild-derived mice is restricted by Immunity-Related GTPases (IRG). Here, the authors show specific binding of the IRG tandem protein Irgb2-b1 with the virulence effector ROP5, and provide insights into how different ROP5 isoforms and IRG alleles shape virulence among T. gondii strains.
- Mateo Murillo-León
- , Urs B. Müller
- & Tobias Steinfeldt
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Article
| Open AccessTissue resident and follicular Treg cell differentiation is regulated by CRAC channels
Regulatory T (Treg) cells are important for maintaining immune homeostasis. Here the authors show that STIM1 and STIM2, which activate the Ca2+ channel ORAI1, are essential for the differentiation of peripheral Treg cells into tissue-resident and follicular Treg cells and their ability to limit autoimmunity in mice.
- Martin Vaeth
- , Yin-Hu Wang
- & Stefan Feske
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Article
| Open AccessDynamic molecular changes during the first week of human life follow a robust developmental trajectory
The first week of life impacts health for all of life, but the mechanisms are little-understood. Here the authors extract multi-omic data from small volumes of blood to study the dynamic molecular changes during the first week of life, revealing a robust developmental trajectory common to different populations.
- Amy H. Lee
- , Casey P. Shannon
- & Tobias R. Kollmann
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Article
| Open AccessA late B lymphocyte action in dysfunctional tissue repair following kidney injury and transplantation
Allograft can induces local chronic inflammation, but how this feeds back to regulating late immunity is still not clear. Here the authors show, by charactering B cell transcriptome landscape dynamic in human allografts and in mouse kidneys transitioning from acute to chronic injury, that late B cell activation is associated with renal dysfunction and inflammation.
- Pietro E. Cippà
- , Jing Liu
- & Andrew P. McMahon
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Article
| Open AccessSystematic comparison of respiratory syncytial virus-induced memory B cell responses in two anatomical compartments
Here, the authors isolate over 800 RSV F-specific antibodies from paired nasopharyngeal tonsil and peripheral blood samples from four young children undergoing adenoidectomy and find that adenoid derived antibodies have overall higher binding affinities and neutralization potencies.
- Laila Shehata
- , Wendy F. Wieland-Alter
- & Laura M. Walker
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Article
| Open AccessGenome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02
Frontal fibrosing alopecia (FFA) features lichenoid cutaneous inflammation and scarring hair loss. Here, Tziotzios et al. identify four genetic loci associated with FFA by GWAS followed by Bayesian fine-mapping, co-localisation and HLA imputation which highlights HLA-B*07:02 as a risk factor.
- Christos Tziotzios
- , Christos Petridis
- & John A. McGrath
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Article
| Open AccessVaccination to prevent T cell subversion can protect against persistent hepacivirus infection
Development of a HCV vaccine is hampered by a lack of appropriate small animal models. Here, Hartlage et al. describe a rat model of hepacivirus persistence and show that persistence can be prevented by vaccination with viral non-structural proteins.
- Alex S. Hartlage
- , Satyapramod Murthy
- & Amit Kapoor
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Article
| Open AccessNeutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair
Neutrophils and macrophages are both involved in the initiation of inflammation, but whether and how they may participate in inflammation resolution is unclear. Here the authors show that neutrophils may mediate the conversion of macrophage into a pro-resolution phenotype via reactive oxygen species production to promote liver repair.
- Wenting Yang
- , Yuandong Tao
- & Li Tang
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Article
| Open AccessUfbp1 promotes plasma cell development and ER expansion by modulating distinct branches of UPR
IRE1 and PERK, both important mediators of the unfold protein response pathway, are differentially regulated during plasma cell differentiation. Here the authors show that an ufmylation target, Ufbp1, suppresses PERK to stimulate plasma cell development and is induced by the IRE1/XBP1 pathway to promote ER expansion .
- Huabin Zhu
- , Brinda Bhatt
- & Nagendra Singh
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Article
| Open AccessEssential and non-overlapping IL-2Rα-dependent processes for thymic development and peripheral homeostasis of regulatory T cells
Interleukin-2 (IL-2) signaling is required for regulatory T (Treg) cell differentiation in the thymus, but its function in peripheral Tregs is still unclear. Here the authors show, using inducible deletion of IL-2 receptor subunit CD25, that IL-2 signaling is essential for maintaining peripheral Treg homeostasis, but dispensable for lineage stability.
- Kevin H. Toomer
- , Jen Bon Lui
- & Thomas R. Malek
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Article
| Open AccessMolecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire
For T cells, functional antigen receptors are selected in the thymus from a pre-selection repertoire by interaction with self MHCs. Here the authors show that specific, non-germline coded features located in the complementarity determining region 3 of the pre-selection antigen receptors are essential for the selection of MHC-restricted repertoire.
- Jinghua Lu
- , François Van Laethem
- & Peter D. Sun
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Article
| Open AccessHelical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9
Amphihelical antimicrobial peptides (AMPs) are bactericidal host defense factors, but their function as immunomodulators is emerging. Here the authors show that several AMPs organize DNA into periodic nanocrystals by self-assembling into superhelical protofibril scaffolds, which potentiates DNA sensing by TLR9.
- Ernest Y. Lee
- , Changsheng Zhang
- & Gerard C. L. Wong
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Article
| Open AccessA small secreted protein triggers a TLR2/4-dependent inflammatory response during invasive Candida albicans infection
The interplay between fungal pathogens and the innate immune system remains incompletely understood. Here, Wang et al. show that a small protein secreted by Candida albicans induces a TLR2- and TLR4-mediated inflammatory response in a mouse infection model.
- Wenjuan Wang
- , Zihou Deng
- & Jiangye Chen
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Article
| Open AccessTissue-resident Eomes+ NK cells are the major innate lymphoid cell population in human infant intestine
Innate lymphoid cells (ILC), including natural killer (NK) cells, are important innate immune regulators. Here the authors show that, in human infant intestines, CD103+Eomes+ NK cells are the predominant ILC population, but are replaced gradually by Eomes+ T cells, while NKp44+ NK cells persist in adult intestines.
- Adrian F. Sagebiel
- , Fenja Steinert
- & Madeleine J. Bunders
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Article
| Open AccessImpact of pre-existing dengue immunity on human antibody and memory B cell responses to Zika
Here, Andrade et al. assess the memory B cell (MBC) and antibody response to Zika virus (ZIKV) in individuals with and without prior dengue virus (DENV) infection and find that ZIKV infection elicits a robust and specific MBC response that is only modestly affected by the number of prior DENV infections.
- Paulina Andrade
- , Ciara Gimblet-Ochieng
- & Eva Harris
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Article
| Open AccessSTAT1 signaling shields T cells from NK cell-mediated cytotoxicity
The JAK-STAT signaling pathway is important for cytokine responses and CD4 T-cell differentiation. Here the authors show that Stat1 also serves to protect CD4 T cells from natural killer cell-mediated killing, potentially by promoting the expression of Nlrc5 and MHC-I, to preserve the induction of experimental colitis via the adoptive transfer of CD4 T cells.
- Yu Hui Kang
- , Amlan Biswas
- & Scott B. Snapper
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Article
| Open AccessDefining the structural basis for human alloantibody binding to human leukocyte antigen allele HLA-A*11:01
Anti-human leukocyte antigen (HLA) antibodies are important mediators of alloresponses, but structural insights on antibody:HLA interaction are still lacking. Here the authors provide a 2.4 Å structure of antibody:HLA complex, and also analyse HLA features important for other HLA-interacting molecules, to enhance our understanding of alloimmunity.
- Yue Gu
- , Yee Hwa Wong
- & Paul A. MacAry
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Article
| Open AccessOrthobunyavirus spike architecture and recognition by neutralizing antibodies
Orthobunyaviruses (OBVs) cause severe disease in humans and farm animals, but the molecular basis for infection is not fully understood. Here, the authors present crystal structures of free and antibody-bound OBV envelope glycoproteins and show that their domains enable efficient immunization in a mouse model.
- Jan Hellert
- , Andrea Aebischer
- & Félix A. Rey
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Article
| Open AccessOutcomes of controlled human malaria infection after BCG vaccination
Immune activation induces long-term alterations of setpoints, impacting responses to subsequent unrelated stimuli. Here the authors show that volunteers vaccinated with BCG respond to controlled human malaria infection with increased clinical symptoms and an inverse correlation between immune activation markers and parasitemia.
- Jona Walk
- , L. Charlotte J. de Bree
- & Robert W. Sauerwein
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Article
| Open AccessGenetic programming of macrophages generates an in vitro model for the human erythroid island niche
In vitro differentiation of red blood cells (RBCs) is a desirable therapy for various disorders. Here the authors develop a culture system using stem cell-derived macrophages to show that inducible expression of a transcription factor, KLF1, enhances RBC production, potentially through the induction of three soluble factors, ANGPTL7, IL33 and SERPINB2.
- Martha Lopez-Yrigoyen
- , Cheng-Tao Yang
- & Lesley M. Forrester
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Article
| Open AccessIntegrated systems approach defines the antiviral pathways conferring protection by the RV144 HIV vaccine
The RV144 vaccine trial showed reduced risk of HIV-1 acquisition, but mechanisms underlying protection are poorly understood. Here, Fourati et al. assess the transcriptomic profile of blood collected from 223 vaccinees and 40 placebo recipients and identify IRF7 as a mediator of protection.
- Slim Fourati
- , Susan Pereira Ribeiro
- & Rafick-Pierre Sékaly
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Article
| Open AccessRole of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming
Fibroblasts can be directly reprogrammed to cardiomyocytes, but reprogramming is less efficient for adult compared to embryonic fibroblasts. Here, the authors find that inhibition of inflammation and Cox-2-prostaglandin-cAMP-IL-1β signaling enhances reprogramming efficiency of adult, but not embryonic fibroblasts.
- Naoto Muraoka
- , Kaori Nara
- & Masaki Ieda
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Article
| Open AccessAssociation study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations
The burden of asthma varies between ancestries, but GWAS have so far focused on mainly European ancestry populations. Here, Daya et al. perform GWAS for asthma in 14,654 individuals of African ancestry and, besides confirming previously known loci, identify two potentially African ancestry-specific loci.
- Michelle Daya
- , Nicholas Rafaels
- & Maria Yazdanbakhsh
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Article
| Open AccessCD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens
Autoreactive T cells are suspected to destroy hypocretin-producing neurons in narcolepsy. Here the authors detect CD8 T cells recognizing narcolepsy-related proteins in healthy individuals and in patients with narcolepsy, and show that the frequency of self-reactive CD8 T cells differs between patients and controls sharing the same HLA-II risk allele.
- Natasja Wulff Pedersen
- , Anja Holm
- & Birgitte Rahbek Kornum
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Article
| Open AccessAdenosine deaminase-1 delineates human follicular helper T cell function and is altered with HIV
Follicular helper T cells are critical in the generation of the antibody response. Here the authors show that adenosine deaminase is involved in the Tfh program and ensuring the provision of B cell help.
- Virginie Tardif
- , Roshell Muir
- & Elias K. Haddad
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Article
| Open AccessLong non-coding RNAs discriminate the stages and gene regulatory states of human humoral immune response
Long non-coding RNAs (lncRNA) constitute a large fraction of human transcriptome, and are reported, individually, for context-specific regulatory functions. Here the authors expand our understanding by providing a systemic, unbiased annotation of lncRNA to establish an atlas of lncRNA landscape during the induction of human humoral immune responses.
- Xabier Agirre
- , Cem Meydan
- & Ari Melnick
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Article
| Open AccessDifferential organization of tonic and chronic B cell antigen receptors in the plasma membrane
Signalling of the B cell receptor (BCR) is pivotal for survival and activation of naïve B cells. Here the authors show, using super-resolution microscopy techniques, that BCRs exist primarily as monomers and dimers in resting B cells, and oligomerize only on stimulation, thereby implicating a function of BCR clustering patterns on B cell biology.
- Maria Angela Gomes de Castro
- , Hanna Wildhagen
- & Felipe Opazo
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Article
| Open AccessHIV-1 vaccination by needle-free oral injection induces strong mucosal immunity and protects against SHIV challenge
Oral vaccination is a potential option to elicit systemic and mucosal immunity against HIV. Here, Jones et al. show that oral vaccination with a modified needle-free injector induces protective immunity against SHIV in non-human primates and is superior to topical application of vaccines to oral tissues.
- Andrew T. Jones
- , Xiaoying Shen
- & Rama Rao Amara
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Article
| Open AccessPD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals
The immune checkpoint molecule PD-1 is expressed on a fraction of CD4+ T cells latently infected with HIV, but whether PD-1 plays a functional role in reservoir persistence remains unknown. Here, Fromentin et al. show that PD-1 blockade potentiates latency reversal ex vivo in CD4+ T cells from ART suppressed individuals.
- Rémi Fromentin
- , Sandrina DaFonseca
- & Nicolas Chomont
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Article
| Open AccessPrecise tuning of gene expression levels in mammalian cells
Analogue regulation of gene expression is important for normal function in mammals but existing genetic technologies are designed to achieve ON/OFF control. Here the authors develop synthetic microRNA silencing-mediated fine-tuners (miSFITs) to precisely control target gene expression levels.
- Yale S. Michaels
- , Mike B. Barnkob
- & Tudor A. Fulga
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Article
| Open AccessThe short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes
Short-chain fatty acids (SCFAs) have immunomodulatory effects, but the underlying mechanisms are still unclear. Here the authors show that a SCFA, pentanoate, suppresses autoimmune inflammation in mouse models of colitis and multiple sclerosis via epigenetic modulation of immune cell metabolic and functional pathways.
- Maik Luu
- , Sabine Pautz
- & Alexander Visekruna
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Article
| Open AccessA functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPα expression
SIRPa is most commonly known as a phagocytosis inhibitory receptor expressed by myeloid cells. Here the authors show SIRPa is expressed on a subset of CD8+ T cells with higher proliferative and effector activity during the chronic phase of the immune response to viral infection.
- Lara M. Myers
- , Michal Caspi Tal
- & Kim J. Hasenkrug
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Article
| Open AccessThe Tec kinase ITK is essential for ILC2 survival and epithelial integrity in the intestine
Signals mediating tissue-specific control of immune cell fate and function remain largely uncharacterized. Here the authors uncover a requirement of ITK, a kinase mediating TCR signaling, for IL-2-dependent ILC2 cell survival specifically in the intestine.
- Hyoung-Soo Cho
- , Andrea Reboldi
- & Leslie J. Berg
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Article
| Open AccessCapturing the inherent structural dynamics of the HIV-1 envelope glycoprotein fusion peptide
The fusion peptide (FP) of HIV envelope (Env) is critical in the cell entry process. Here, Kumar et al. present crystal structures of B41 SOSIP.664 Env trimer and show the dynamic nature of the FP and proximal region, which likely relates to conformational rearrangements required for membrane fusion.
- Sonu Kumar
- , Anita Sarkar
- & Ian A. Wilson
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Article
| Open AccessMacrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis
Immune cells produce reactive oxygen species (ROS) to eliminate pathogens, but cell-spontaneous death and ageing may also be induced. Here the authors show that, upon sensing ROS, Mst1/2 kinases modulate the activity of Nrf2 transcription factor and downstream genetic programs to protect mouse macrophages from death and ageing.
- Ping Wang
- , Jing Geng
- & Lanfen Chen
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Article
| Open AccessPLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
Phospholipase C β (PLCβ) exhibits immuno-modulatory functions but its role in antiviral innate responses is unclear. Here, the authors provide evidence that PLCβ2 down regulates enterovirus-induced pro-inflammatory responses via inhibition of TAK1 activation, and suggest PLC as a potential therapeutic target.
- Lin Wang
- , Yilong Zhou
- & Baoxue Ge
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Article
| Open AccessDiversity within the adenovirus fiber knob hypervariable loops influences primary receptor interactions
Adenovirus based (AdV) vectors are promising platforms for therapeutics and vaccines, but receptor usage of serotypes in clinical development remains unclear. Here, based on crystal structures and modeling, Baker et al. show that HAdV-D26/48 fiber knob protein interacts weakly with CAR but not with CD46 or DSG2.
- Alexander T. Baker
- , Alexander Greenshields-Watson
- & Alan L. Parker
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Article
| Open AccessLongitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion
How HIV reservoirs are shaped over time on antiviral therapy is poorly understood. Here, the authors analyze the dynamics of the HIV reservoir by longitudinal proviral sequencing revealing that HIV reservoir expression can contribute to its clearance and paradoxically even to its persistence.
- Marilia Rita Pinzone
- , D. Jake VanBelzen
- & Una O’Doherty
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Article
| Open AccessPathogenic function of bystander-activated memory-like CD4+ T cells in autoimmune encephalomyelitis
T cells express specific T cell receptors (TCR) to recognise antigens and initiate adaptive immune responses. Here the authors show, in a mouse model of autoimmune encephalomyelitis, that memory-like CD4 T cells expressing unrelated TCR can also infiltrate the spinal cord and contribute to autoimmunity.
- Hong-Gyun Lee
- , Jae-Ung Lee
- & Je-Min Choi
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Article
| Open AccessCostimulation of type-2 innate lymphoid cells by GITR promotes effector function and ameliorates type 2 diabetes
Type-2 innate lymphoid cells (ILC2s) are an immune population secreting Th2 cytokines playing a role in the regulation of adipose metabolic homeostasis. Here the authors show that engagement of GITR, a member of the TNF superfamily, in activated ILC2s is protective against insulin resistance in both a preventive and a therapeutic manner in the context of obesity.
- Lauriane Galle-Treger
- , Ishwarya Sankaranarayanan
- & Omid Akbari
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Article
| Open AccessHectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation
Ubiquitination may control protein stability or function. Here the authors show that an ubiquitination enzyme, Hectd3, ubiquitinates Stat3 and Malt1 to modulate their function but not degradation in T cells, and thereby promoting the differentiation of pathogenic Th17 cells and susceptibility to a mouse model of multiple sclerosis.
- Jonathan J. Cho
- , Zhiwei Xu
- & Dorina Avram
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