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| Open AccessDemographic and Clinical Factors Associated With SARS-CoV-2 Spike 1 Antibody Response Among Vaccinated US Adults: the C4R Study
The antibody response to COVID-19 vaccines varies among individuals. Here the authors find that older age, male sex, smoking, higher BMI, vaccine type, and certain comorbidities are associated with lower anti-S1 antibody levels after COVID-19 vaccinations, indicating that certain groups might benefit from higher frequency or doses of vaccination.
- John S. Kim
- , Yifei Sun
- & Elizabeth C. Oelsner
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Article
| Open AccessCell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing
Cell softness protects cytotoxic T lymphocytes (CTL) from autolysis by own soluble factors such as perforin secreted for killing target cells. Here the authors show that softness can be induced by YAP activation, and that T leukemic cells are more sensitive to YAP inhibition than CTLs, thereby hinting YAP inhibitors as a potential therapy for T leukemia.
- Yabo Zhou
- , Dianheng Wang
- & Bo Huang
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| Open AccessTYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes
TYK2 is a candidate susceptibility gene for type 1 diabetes (T1D) and a beneficial effect has been reported for TYK2 inhibitors for other autoimmune diseases. In this study, the authors generate Tyk2 KO mice on a NOD background and demonstrate that TYK2 signaling drives CD8+ T cell autoreactivity and T1D.
- Keiichiro Mine
- , Seiho Nagafuchi
- & Keizo Anzai
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Article
| Open AccessA hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs
Here, English et al. show that after expanding in lymphoid tissues, CD4+ and CD8+ T cells recognising hepatic antigens migrate into specialised vascular liver areas where CD4+ T cells locally license hepatic dendritic cells and further expand CD8+ T cell numbers.
- Kieran English
- , Rain Kwan
- & Patrick Bertolino
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Article
| Open AccessT-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms
Endogenous retroviruses (ERV) can induce immune responses and the control of these viruses uses immune mechanisms also involved in autoimmunity. Here, the authors characterize the control of ERVs in mice and show age-associated B cell control and nucleic acid sensing TLR pathway involvement.
- Eileen Rauch
- , Timm Amendt
- & Philipp Yu
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Article
| Open AccessA monoclonal antibody targeting a large surface of the receptor binding motif shows pan-neutralizing SARS-CoV-2 activity
Characterisation of monoclonal antibodies against SARS-CoV-2 are useful for potential therapeutics or to understand more about the immune response to this virus. Here the authors characterise a monoclonal antibody that has a broad range of reactivity against SARS-CoV-2 variants and measure how it binds to its specific target region of the receptor binding domain.
- Leire de Campos-Mata
- , Benjamin Trinité
- & Giuliana Magri
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Article
| Open AccessA Gamma-adapted subunit vaccine induces broadly neutralizing antibodies against SARS-CoV-2 variants and protects mice from infection
Here the authors show that a Gamma-based subunit vaccine induces broadly neutralizing antibodies against SARS-CoV-2 variants including Omicron, induces cellular immune responses, and protects mice from infection with Omicron BA.5 SARS-CoV-2.
- Lorena M. Coria
- , Juan Manuel Rodriguez
- & Juliana Cassataro
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| Open AccessEnhancing antibody responses by multivalent antigen display on thymus-independent DNA origami scaffolds
Three-dimensional DNA origami constructs can be used to deliver vaccine antigens in a multi-valent form. Here the authors design a DNA origami system for SARS-CoV-2 proteins and characterize in mice the immune response and protective capacity of generated antibodies, finding that the construct itself is not immunogenic.
- Eike-Christian Wamhoff
- , Larance Ronsard
- & Mark Bathe
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Article
| Open AccessHumoral profiles of toddlers and young children following SARS-CoV-2 mRNA vaccination
Nziza et al. profile anti-SARS-CoV-2 antibody responses in infants and toddlers after mRNA vaccination and demonstrate a strong functional activation of humoral immunity in this age group when compared with adults and naturally infected children.
- Nadège Nziza
- , Yixiang Deng
- & Lael M. Yonker
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Article
| Open AccessCaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses
Calmodulin-dependent kinase 4 (CaMK4) has been implicated in humoral immunity. Here, the authors demonstrate that CaMK4 expression controls the differentiation of T follicular helper cells, leading to the expansion of pathogenic B cells in systemic lupus erythematosus.
- Marc Scherlinger
- , Hao Li
- & George C. Tsokos
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Article
| Open AccessIdentification of a highly conserved neutralizing epitope within the RBD region of diverse SARS-CoV-2 variants
Most recent SARS-CoV-2 variants showed exceptional immune evasion properties. Here, the authors identify a highly conserved epitope within the RBD targeted by a broad spectrum neutralizing antibody BA7535 that shows therapeutic antiviral potency in mouse studies.
- Yanqun Wang
- , An Yan
- & Jincun Zhao
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Article
| Open AccessIdentification of differentially recognized T cell epitopes in the spectrum of tuberculosis infection
T cells play critical roles in the immune pathology of tuberculosis. Here the authors perform a proteome-wide screen of T cell antigens and reactivity to mycobacterium tuberculosis at different stages of infection.
- Sudhasini Panda
- , Jeffrey Morgan
- & Cecilia S. Lindestam Arlehamn
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| Open AccessHuman coronavirus OC43-elicited CD4+ T cells protect against SARS-CoV-2 in HLA transgenic mice
The origin of SARS-CoV-2 cross-reactive T cells in unexposed humans is unclear. Here, the authors use HLA transgenic mouse models of sequential infections with human coronavirus OC43 and SARSCoV-2 and show that OC43 elicits cross-protective immunity against SARS-CoV-2, which partially depends on CD4 + T cells.
- Rúbens Prince dos Santos Alves
- , Julia Timis
- & Sujan Shresta
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| Open AccessMARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer
Detection of neoepitopes from tumours is time consuming and requires the integration of genomic and/or RNA sequencing expression data. Here, the authors propose a machine learning method to enable direct identification of additional, tumour-specific sequences using mass spectrometry through integration of de novo peptide sequencing scores, MHC class I binding prediction, and peptide retention time prediction.
- Hanqing Liao
- , Carolina Barra
- & Nicola Ternette
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Article
| Open Accessi-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists
In contrast to their clinical success as inhibitors and targeting agents, antibodies have generally been ineffective as receptor agonists. Here, Romei et al. leverage a natural homotypic interface to tune antibody geometry, enabling optimization of agonist activity for multiple therapeutic targets.
- Matthew G. Romei
- , Brandon Leonard
- & Greg A. Lazar
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Article
| Open AccessThe CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells
CD8 + T cells are central players in anti-tumour immunity. Here authors identify Cul5, a ubiquitin E3 ligase as an important inhibitor of CD8 + T cell anti-tumour cytotoxicity and persistence via involvement with both T cell receptor and cytokine-regulated central pathways.
- Xiaofeng Liao
- , Wenxue Li
- & Dianqing Wu
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Article
| Open AccessHLA class I peptide polymorphisms contribute to class II DQβ0603:DQα0103 antibody specificity
Bead-based assays to assess the donor-specific antibody profile of solid organ transplant patients often produce discordant results relative to cell-based alternatives. In this study, the authors demonstrate that, for some MHC class-II-specific antibodies, discordance can be attributed to recognition of the MHC class-I-derived peptides bound to MHC class-II molecules.
- N. Remi Shih
- , Thoa Nong
- & Jar-How Lee
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Article
| Open AccessEarly antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8+ T-cells
HIV remission has been seen in people living with HIV after the cessation of antiretroviral therapy and is termed post treatment control. Here Passaes and colleagues present an SIV model that shows early initiation of antiretroviral therapy after SIV infection is linked to improved post treatment control upon cessation of antiviral therapy and associates with the expansion of an enhanced memory pool of CD8 + T cells‘.
- Caroline Passaes
- , Delphine Desjardins
- & Asier Sáez-Cirión
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Article
| Open AccessProstaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment
CD8+ T cells reprogram their metabolism in response to the gut environment. Upon sensing of PGE2, gut CD8+ T cells reduce their mitochondrial content, an event that ultimately shapes the pool of CD8+ T cells in the intestinal tissue.
- Matteo Villa
- , David E. Sanin
- & Erika L. Pearce
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Article
| Open AccessN-linked Fc glycosylation is not required for IgG-B-cell receptor function in a GC-derived B-cell line
IgG molecules are glycosylated at a conserved asparagine residue of their constant region, and this modification is essential for the effector functions of their soluble form, such as complement activation and binding to Fcɣ receptors. Here authors show that in a model B-cell line, neither the expression nor the function of the membrane-bound form of IgG depend on glycosylation.
- Theresa Kissel
- , Veerle F. A. M. Derksen
- & René E. M. Toes
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Article
| Open AccessProtection against symptomatic dengue infection by neutralizing antibodies varies by infection history and infecting serotype
There is still a need to improve understanding of dengue-specific immunity. Here, by analyzing the antibody response in a pediatric cohort the authors show that the protective capacity of neutralizing antibodies depends on infection history and serotype, but its estimation varies by assay condition and virion maturation.
- Sandra Bos
- , Aaron L. Graber
- & Eva Harris
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Article
| Open AccessIgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition
The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.
- Benjamin S. Haslund-Gourley
- , Kyra Woloszczuk
- & Mary Ann Comunale
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Article
| Open AccessIdentifying immune signatures of sepsis to increase diagnostic accuracy in very preterm babies
Bacterial infections and sepsis are a major cause of mortality in preterm babies. Here Das and colleagues assess the paediatric immune response to bacterial infection in very preterm babies and identify blood immune markers that could improve accuracy of diagnostics to rule-out sepsis and guide antibiotic treatment.
- A. Das
- , G. Ariyakumar
- & D. L. Gibbons
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Article
| Open AccessSecreted IgM modulates IL-10 expression in B cells
Il-10-expressing B cells play a pivotal role in immune homeostasis, but little is known about the factors and pathways that affect the development of this heterologous population of regulatory B cells. Here authors show in a mouse model that in embryonic life, soluble IgM restrains the expansion of Il-10-positive B cells, via utilizing FcµR and other putative receptors.
- Shannon Eileen McGettigan
- , Lazaro Emilio Aira
- & Gudrun F. Debes
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Article
| Open AccessSystems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis
Systemic sclerosis (SSc) is an autoimmune disease causing skin fibrosis and organ inflammation. Here the authors generate and analyze SSc skin single cell RNA sequencing data to propose contributions from both myofibroblasts and endothelial-to-mesenchymal -transitioning cells (EndoMT) to skin fibrosis, and to implicate the involvement of Hippo signaling pathways.
- Feiyang Ma
- , Pei-Suen Tsou
- & Johann E. Gudjonsson
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Article
| Open AccessPharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1
PD-L1 expression on the surface of cancer cells is believed to contribute to tumor immune evasion via triggering the inhibitory T cell co-receptor, PD-1, resulting in decreased T cell cytotoxicity. Here authors show that OTUB2 regulates PD-L1 expression via inhibition of its ubiquitin-mediated degradation, and that OTUB2 inhibition increases T cell cytotoxicity directed against tumors.
- Wenfeng Ren
- , Zilong Xu
- & Ningshao Xia
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Article
| Open AccessIntegrative genotyping of cancer and immune phenotypes by long-read sequencing
Single-cell transcriptomics excel in cell subset classification and can be augmented by suitable genotype information. Here the authors devise a long-read sequencing workflow, termed nanoranger, for detection of molecular barcodes from single-cell cDNA and apply this to clonal tracking of acute myeloid leukemia and identification of complex immune phenotypes.
- Livius Penter
- , Mehdi Borji
- & Catherine J. Wu
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Article
| Open AccessMCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation
B cell activation and differentiation entails metabolic remodelling, involving differential utilisation of monocarboxylates such as L-lactate and pyruvate. Here authors show by B-cell-specific genomic deletion of monocarboxylate transporter 1 (MCT1) that the consequential scarcity of pyruvate results in decreased acetylation of Histone H3 at K27, leading to decreased AID transcription and deficient class switching to IgG.
- Wenna Chi
- , Na Kang
- & Ligong Chen
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Article
| Open AccessRecently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy
Marking of recently activated T cells may help further our understanding of immunity against Mycobacterium tuberculosis (Mtb). Here the authors use Nur77-GFP reporter mice infected with Mtb and systems data approaches to implicate OX40 as a marker for recently activated, functionally and transcriptome-wise distinct CD4 T cells, and as a potential target for immunotherapy.
- Abigail R. Gress
- , Christine E. Ronayne
- & Tyler D. Bold
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Article
| Open AccessHigh monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials
Antibody Mediated Prevention (AMP) trials showed that the broadly neutralizing antibody VRC01 could prevent some HIV-1 acquisitions. Here the authors use VRC01 levels and the sensitivity of each acquired HIV virus to predict viral loads in the AMP studies and show that VRC01 influenced viral loads, though potency was lower in vivo than expected.
- Daniel B. Reeves
- , Bryan T. Mayer
- & Srilatha Edupuganti
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Article
| Open AccessEarly mucosal events promote distinct mucosal and systemic antibody responses to live attenuated influenza vaccine
Nasally delivered live attenuated influenza vaccines (LAIV) have been shown to be effective in vaccine trials yet immune responses are mostly measured in blood. Here the authors report a clinical trial in young adults and measure immune responses in the mucosa and blood to identify compartmentalised responses.
- Ryan S. Thwaites
- , Ashley S. S. Uruchurtu
- & Peter J. M. Openshaw
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| Open AccessA lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection
The authors use lipid nanoparticles (LNPs) that predominantly accumulate in the lung to deliver mRNA encoding for the broadly neutralizing antibody 8-9D, and achieve superior inhibition of SARS-CoV-2 infection in mice compared to control LNPs.
- Wanbo Tai
- , Kai Yang
- & Gong Cheng
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Article
| Open AccessInteraction dynamics between innate and adaptive immune cells responding to SARS-CoV-2 vaccination in non-human primates
Innate immune responses to mRNA vaccines are less well understood than adaptive immunity. Here, the authors comprehensively characterize the innate and adaptive immune responses to mRNA-1273 vaccinations in rhesus macaques and show how the vaccine activates interactions among components of the two systems.
- Chaim A. Schramm
- , Damee Moon
- & Daniel C. Douek
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| Open AccessNeutralization of SARS-CoV-2 Omicron BQ.1, BQ.1.1 and XBB.1 variants following SARS-CoV-2 infection or vaccination in children
In this work, authors investigate the virus-neutralizing capacity in children against circulating BQ.1, BQ.1.1 and XBB.1 SARS-CoV-2 variants. Vaccination induced more neutralizing antibodies against BQ.1.1 and XBB.1 in youngest children ( < 5 years) compared with >5 years children.
- Lorenza Bellusci
- , Gabrielle Grubbs
- & Surender Khurana
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Article
| Open AccessAdults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01
Small molecule drugs can affect clearance of monoclonal antibodies, but this hasn’t been assessed for oral HIV-1 pre-exposure prophylaxis. Here, the authors find that faster serum clearance of an experimental IgG1 monoclonal antibody, VRC01, is associated with use of tenofovir-emtricitabine, possibly explained by increased epithelial intestinal permeability.
- Yunda Huang
- , Lily Zhang
- & Maria P. Lemos
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Article
| Open AccessCAR+ and CAR− T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies
Phenotype of cells in the infusion product as well at specific post-infusion time points has been associated with clinical response to CD19 CAR T cells. Here the authors present a single-cell multi-omics analysis of pre- and post-infusion CAR+ and CAR- T cells from patients with relapsed or refractory B-ALL or LBCL who received CD19 CAR T therapy.
- Raymond Hall Yip Louie
- , Curtis Cai
- & Fabio Luciani
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Article
| Open AccessSequential vaccinations with divergent H1N1 influenza virus strains induce multi-H1 clade neutralizing antibodies in swine
Seasonal influenza vaccines typically fail to induce cross-protective antibody responses. Here, Van Reeth et al. sequentially vaccinate pigs with diverse H1N1 viruses and show that this strategy induces antibodies against a panel of H1N1 strains from swine and humans and protects against antigenically mismatched strains.
- Kristien Van Reeth
- , Anna Parys
- & Elien Vandoorn
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Article
| Open AccessCytolytic circumsporozoite-specific memory CD4+ T cell clones are expanded during Plasmodium falciparum infection
It is important to understand why some individuals in endemic regions acquire natural immunity against malaria while others remain susceptible. Here authors show that during episodes of Plasmodium falciparum malaria, circumsporozoite-specific cytolytic memory CD4+ T cells are clonally expanded in patients, and those with clinical immunity demonstrate reduction in the chemotactic and inhibitory receptor expression in ZEB2+ memory CD4+ T cells.
- Raquel Furtado
- , Mahinder Paul
- & Grégoire Lauvau
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Article
| Open AccessStepwise differentiation of follicular helper T cells reveals distinct developmental and functional states
Follicular helper T cells play critical roles in the formation of high affinity antibody responses, but the signals involved in the development of these cells after initial differentiation are poorly understood. Here Podestà, Cavazzoni and colleagues characterise transitionary phases of follicular helper T cell development and how progression through these stages is linked to humoral immunity.
- Manuel A. Podestà
- , Cecilia B. Cavazzoni
- & Peter T. Sage
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Article
| Open AccessThe extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome
Although B cell-targeting therapies can provide clinical benefits to children with idiopathic nephrotic syndrome (INS), B lymphocyte subsets have not been extensively studied in this disease. Here, using single-cell RNA sequencing, the authors identify an extrafollicular B cell signature in children with INS.
- Tho-Alfakar Al-Aubodah
- , Lamine Aoudjit
- & Tomoko Takano
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Article
| Open AccessMultifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis
The presence of antibodies to citrullinated protein antigens (ACPA) in peripheral blood represents a risk a state that is ‘at-risk’ for subsequent development of rheumatoid arthritis (RA). Here authors compare multiple molecular and immunological parameters in individuals who are ACPA positive without inflammatory arthritis, ACPA negative controls and patients diagnosed with ACPA positive early-stage RA to conclude that complex immunopathological processes are present in an ACPA positive state which may be targeted by future preventive approaches for RA.
- Eddie A. James
- , V. Michael Holers
- & Kevin D. Deane
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Article
| Open AccessThe structure of the teleost Immunoglobulin M core provides insights on polymeric antibody evolution, assembly, and function
The formation of polymeric Ig complexes is important for the function of IgM and can vary between species. Here the authors structurally analyse IgM from a teleost species that doesn’t encode a joining chain, which results in a different 3D structure compared to mammalian IgM where other parts of the protein associate to form polymeric complexes.
- Mengfan Lyu
- , Andrey G. Malyutin
- & Beth M. Stadtmueller
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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 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 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 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 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