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An ancestral SARS-CoV-2 vaccine induces anti-Omicron variants antibodies by hypermutation
Repeat vaccination with COVID-19 mRNA vaccines has been shown to increase breadth of the antibody response. Here the authors demonstrate that B cell clones induced by the ancestral COVID-19 vaccine develop into daughter clones with different reactivity to individual SARS-CoV-2 variants through the accumulation of somatic hypermutations.
- Seoryeong Park
- , Jaewon Choi
- & Junho Chung
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Article
| Open Access
Impact of PEG sensitization on the efficacy of PEG hydrogel-mediated tissue engineering
Concerns over the immunogenicity of poly(ethylene glycol) (PEG) are growing, and the implications for tissue engineering are unknown. Here the authors evaluate the impact of anti-PEG antibodies and PEG immunogenicity on the efficacy of a PEG hydrogel-based tissue engineering therapy.
- Alisa H. Isaac
- , Sarea Y. Recalde Phillips
- & Daniel L. Alge
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| Open Access
Emerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection
Many emerging SARS-CoV-2 variants partially escape the humoral immune response. Here, Liu et al. characterize 28 antibodies from BA.4/5 breakthrough infections and find attrition of neutralization and complete loss of function for variants with Spike mutations at positions 455 and 456.
- Chang Liu
- , Raksha Das
- & Gavin R. Screaton
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| Open Access
Influenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children
In this study, the authors assessed influenza-specific antibody responses in a cohort of seasonally vaccinated children and report that seasonal vaccination is beneficial by enhancing pandemic influenza virus-specific antibodies and cross-reactive effector functions.
- Janice Z. Jia
- , Carolyn A. Cohen
- & Sophie A. Valkenburg
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| Open Access
Deep learning predictions of TCR-epitope interactions reveal epitope-specific chains in dual alpha T cells
Prediction of the specificity of a T cell receptor from amino acid sequence has been performed using different methods and approaches. Here the authors use TCRab sequences with known specificity to develop a deep learning TCR-epitope interaction predictor and use this method to predict specificity of dual alpha chain TCRs and TCRs specific for different antigens.
- Giancarlo Croce
- , Sara Bobisse
- & David Gfeller
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Semaphorin 3A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells
Interactions between Semaphorin-3A (SEMA3A) and Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 have been shown to affect T cell development. Here the authors investigate how these interactions affect CD8+ T cells in tumour immunity, showing that NRP-1, Plexin-A1 and Plexin-A4 are upregulated on T cells allowing tumour derived SEMA3A to inhibit CD8+ T cell migration and function.
- Mike B. Barnkob
- , Yale S. Michaels
- & Vincenzo Cerundolo
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| Open Access
CoPoP liposomes displaying stabilized clade C HIV-1 Env elicit tier 2 multiclade neutralization in rabbits
HIV vaccine candidates often have limited capacity to induce broadly neutralizing antibodies (nAbs). In this study, the authors show that stabilized Clade C HIV-1 Env protein trimers decorated on CoPoP liposomes induce nAbs against 18 of 20 multiclade tier 2 HIV-1 strains in immunized rabbits.
- Annemart Koornneef
- , Kanika Vanshylla
- & Frank Wegmann
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| Open Access
Vaccination impairs de novo immune response to omicron breakthrough infection, a precondition for the original antigenic sin
Immune imprinting can affect the response to future infection with pathogen variants. Here, Pušnik et. al. demonstrate that previous vaccination with wild-type SARS-CoV-2 vaccine hampers the formation of an immune response to mutated regions of omicron surface proteins following omicron breakthrough infection.
- Jernej Pušnik
- , Jasmin Zorn
- & Hendrik Streeck
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Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection
In this study, Giron et al. find that people living with chronic HIV experience accelerated aging-associated alterations in antibody glycans. These alterations, attributed to senescence enzymes, predict comorbidities and reduce the antiviral function of antibodies.
- Leila B. Giron
- , Qin Liu
- & Mohamed Abdel-Mohsen
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| Open Access
SARS-CoV-2-specific cellular and humoral immunity after bivalent BA.4/5 COVID-19-vaccination in previously infected and non-infected individuals
Prior infection or exposure to SARS-CoV-2 may influence immunogenicity and effectiveness of subsequent vaccination to new strains of virus. Here the authors show that immunogenicity of a BA.4/5 mRNA vaccine differed in recipients depending on whether they had been exposed to or infected with an earlier strain of virus.
- Rebecca Urschel
- , Saskia Bronder
- & Martina Sester
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Article
| Open Access
Developmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8+ T cells in murine models of inflammation
The heterogeneity in naive CD8+ T cells is essential for diverse immune responses. Here the authors show that variations in developmental self-reactivity of CD8+ T cells influence their differentiation into Tc17 cells in inflammatory conditions.
- Gil-Woo Lee
- , Young Ju Kim
- & Jae-Ho Cho
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Article
| Open Access
Monoclonal antibodies targeting sites in respiratory syncytial virus attachment G protein provide protection against RSV-A and RSV-B in mice
Effective antibodies targeting various respiratory syncytial virus (RSV) proteins are needed to address public health burden of RSV. Here the authors shows that in addition to the currently approved F-targeting monoclonal antibodies, anti-G cross-reactive monoclonal antibodies to RSV-A and RSV-B strains can provide cross-protection and prevent from RSV disease.
- Youri Lee
- , Laura Klenow
- & Surender Khurana
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| Open Access
Dupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells
Dupilumab-associated head and neck dermatitis has been described in a subset of patients treated with the IL4R-blocker dupilumab. Here the authors characterise the immune cell composition and single-cell transcriptome in comparison with untreated forms of atopic dermatitis in a small cohort showing increases in IL-22-associated genes.
- Christine Bangert
- , Natalia Alkon
- & Patrick M. Brunner
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| Open Access
Immunosenescence and vaccine efficacy revealed by immunometabolic analysis of SARS-CoV-2-specific cells in multiple sclerosis patients
SARS-CoV-2 immune responses after vaccination in individuals with multiple sclerosis (MS) remain poorly understood. Here, using mass cytometry, the authors demonstrate that, following three doses of mRNA vaccine, patients with MS have distinct metabolic profiles in antigen-specific B and T cells.
- Sara De Biasi
- , Domenico Lo Tartaro
- & Andrea Cossarizza
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| Open Access
Autophagy-enhancing ATG16L1 polymorphism is associated with improved clinical outcome and T-cell immunity in chronic HIV-1 infection
T cell dysregulation is a hallmark of chronic HIV-1 infection that is partially restored by antiretroviral therapy. Here the authors show that ATG16L1 rs6861 polymorphism is associated clinically with prolonged control of disease pathogenesis, and functionally with enhanced autophagy and T-cell immunity in chronically HIV-1 infected individuals.
- Renée R. C. E. Schreurs
- , Athanasios Koulis
- & Carla M. S. Ribeiro
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| Open Access
IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model
Loss of function mutation studies has provided insights into regulatory T-cell biology. Here Cardinez et al explore the effects of a murine Ikbkb (IKK2) gain of function model and show IKK2 activity results in the expansion of regulatory T cells with partial effector function and suggest an IKK2 dose-dependent relation between psoriatic immunopathology and psoriatic arthritis.
- Chelisa Cardinez
- , Yuwei Hao
- & Matthew C. Cook
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Article
| Open Access
Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease
IgG4-related disease is a fibro-inflammatory disorder, characterized by infiltration of IgG4 producing plasma cells in the target organs. Here authors show that the affected B cells express less ubiquitin-specific protease 25 (USP25), and this results in activation of multiple pathways involved in cytoskeleton reorganization, inflammation and energy metabolism, which might govern disease pathogenesis.
- Panpan Jiang
- , Yukai Jing
- & Chaohong Liu
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| Open Access
Prior infection with unrelated neurotropic virus exacerbates influenza disease and impairs lung T cell responses
Co-infections are much less studied than single pathogen infections. Here, the authors show that co-infection with two unrelated viruses, neurotropic Semliki Forest virus and influenza A virus, exacerbates influenza-related lung pathology and prolongs lung virus replication in a mouse model.
- Isabelle Jia-Hui Foo
- , Brendon Y. Chua
- & Lukasz Kedzierski
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| Open Access
Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation
Activation of the mechanistic target of rapamycin (mTOR) is important in the metabolic function of proinflammatory T cells in autoimmunity. Here the authors characterise how Rab4A is involved with CD98 and endosome recycling which subsequently affects mTOR activation, autoimmunity and T cell expansion.
- Nick Huang
- , Thomas Winans
- & Andras Perl
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Article
| Open Access
Defective mitochondria remodelling in B cells leads to an aged immune response
B cell activation in the germinal centre (GC) is accompanied by metabolic adaptation, but the functions of mitochondria remodelling during this process is unclear. Here the authors find that B cell-specific deficiency of Tfam, a transcription factor modulating mitochondria remodelling, impacts GC responses and induces aged immune features in B cells.
- Marta Iborra-Pernichi
- , Jonathan Ruiz García
- & Nuria Martínez-Martín
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| Open Access
Clearance of persistent SARS-CoV-2 associates with increased neutralizing antibodies in advanced HIV disease post-ART initiation
There is limited data on immune factors contributing to SARS-CoV-2 viral clearance in people living with HIV. Here, the authors show that re-emergence of the neutralizing antibody response may be key to clearing persistent SARS-CoV-2 infection in ART-mediated recovery from immunosuppression in advanced HIV disease.
- Farina Karim
- , Catherine Riou
- & Alex Sigal
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| Open Access
Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion
SARS-CoV-2 evolved into several sublineages harboring different mutations in spike. Here, the authors isolate and characterize nine SARS-CoV-2 variants and show that EG.5.1.3 has highest fitness in nasal epithelial cells, while JN.1 shows lower affinity to ACE2 and higher immune evasion compared to BA.2.86.1.
- Delphine Planas
- , Isabelle Staropoli
- & Olivier Schwartz
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Article
| Open Access
The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression
Regulation of thymocyte development by RNA-binding proteins is not fully characterized. Here the authors show the RBP ARPP21 interacting with the Rag1 3’-UTR to promote Rag1 expression, TCR rearrangement and an increased diversity of the TCR repertoire and that ARPP21 is down regulated by TCR stimulation.
- Meng Xu
- , Taku Ito-Kureha
- & Vigo Heissmeyer
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| Open Access
Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors
The migration of T cells into tumours and how this is regulated by metabolic pathways is not completely understood. Here the authors use human and xenograft mouse models to explore the functional changes in T cells during migration in tumours and how glycolytic and TCA cycle metabolism is involved.
- Luca Simula
- , Mattia Fumagalli
- & Emmanuel Donnadieu
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Article
| Open Access
Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria
Antibody based biologics are a rapidly growing class of therapeutics with interest to enhance their performance, distribution, longevity and effectivity. Here, authors report the engineering of human IgG Fc to enhance plasma half-life, mucosal distribution and killing of cancer cells and bacteria.
- Stian Foss
- , Siri A. Sakya
- & Jan Terje Andersen
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Notch2 controls developmental fate choices between germinal center and marginal zone B cells upon immunization
Sustained exogenous Notch2 signaling prompts Follicular B cells to trans-differentiate into Marginal Zone B cells. This study reveals that under physiological conditions, Notch2 signalling regulates a fate choice in antigen activated Follicular B cells, dictating whether they develop into Germinal Center B cells or Marginal Zone B cells.
- Tea Babushku
- , Markus Lechner
- & Lothar J. Strobl
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CD8+ T cell priming that is required for curative intratumorally anchored anti-4-1BB immunotherapy is constrained by Tregs
Antibodies stimulating the T cell co-activator 4-1BB (CD137) do enhance anti-tumour T cell function, but their utility is hampered by on target, off tumor toxicity. Here authors show that anchoring anti-4-1BB to tumours via fusion with the collagen binding protein LAIR diminishes systemic dissemination of the drug, and they demonstrate a curative effect in a triple-combination-therapy that relieves regulatory T cell immunosuppression in a mouse model of cancer.
- Joseph R. Palmeri
- , Brianna M. Lax
- & K. Dane Wittrup
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| Open Access
Altered receptor binding, antibody evasion and retention of T cell recognition by the SARS-CoV-2 XBB.1.5 spike protein
New variants of SARS-CoV-2 virus can evolve such that antibodies that recognised previous versions are not able to recognise newer versions. Here the authors characterise antibody binding to the XBB.1.5 variant and how antibodies and T cells from persons infected with earlier versions of SARS-CoV-2 are able to recognise and/or bind to the XBB.1.5 spike protein.
- Dhiraj Mannar
- , James W. Saville
- & Sriram Subramaniam
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Article
| Open Access
BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion
Acute-on-chronic liver failure (ACLF) is characterized by rapid deterioration of liver function in patients with chronic liver disease. Here, the authors show that BTLA expression in CD4+ T cells is associated with disease severity and inflammation in hepatitis B virus-related ACLF.
- Xueping Yu
- , Feifei Yang
- & Jiming Zhang
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Article
| Open Access
Type 1 interferons and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice
Although continuous activity of Foxo transcription factors substantially increase the life span of species such as Hydra vulgaris, these proteins have never been implicated in mammalian aging. In this study, the authors demonstrate that, with age, Foxo1 is down-regulated in mouse T lymphocytes and associated with exhaustion.
- Aurélie Durand
- , Nelly Bonilla
- & Bruno Lucas
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Article
| Open Access
Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection
Flavivirus infection or vaccination can induce cross-reactive immune responses. Here, the authors show how previous immunization with the tick-borne encephalitis virus vaccine affects the immune response to the yellow fever vaccine, suggesting that the yellow fever vaccine virus conceals epitopes shared with other flaviviruses in flavivirus-naive but not flavivirus-pre-exposed individuals.
- Antonio Santos-Peral
- , Fabian Luppa
- & Simon Rothenfusser
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| Open Access
Efficient encoding of large antigenic spaces by epitope prioritization with Dolphyn
Profiling antibody responses to vast antigenic spaces has been challenging using programmable phage display (PhIP-Seq). Here, authors develop a methodology for compressing large proteomic spaces and have discovered human antibodies targeting gut bacteria-infecting phages.
- Anna-Maria Liebhoff
- , Thiagarajan Venkataraman
- & H. Benjamin Larman
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| Open Access
Demographic 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 Access
Cell 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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Article
| Open Access
TYK2 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 Access
A 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 Access
T-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 Access
A 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 Access
A 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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Article
| Open Access
Enhancing 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 Access
Humoral 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 Access
CaMK4 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 Access
Identification 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 Access
Identification 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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Article
| Open Access
Human 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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Article
| Open Access
MARS 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 Access
i-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 Access
The 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 Access
HLA 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
PD-L1- and IL-4-expressing basophils promote pathogenic accumulation of T follicular helper cells in lupus