Asthma is a T helper 2 (Th2)-cell-mediated disease; however, recent findings implicate Th17 and innate lymphoid cells also in regulating airway inflammation. Herein, we have demonstrated profound ...interleukin-21 (IL-21) production after house dust mite (HDM)-driven asthma by using T cell receptor (TCR) transgenic mice reactive to Dermatophagoides pteronyssinus 1 and an IL-21GFP reporter mouse. IL-21-producing cells in the mediastinal lymph node (mLN) bore characteristics of T follicular helper (Tfh) cells, whereas IL-21+ cells in the lung did not express CXCR5 (a chemokine receptor expressed by Tfh cells) and were distinct from effector Th2 or Th17 cells. Il21r−/− mice developed reduced type 2 responses and the IL-21 receptor (IL-21R) enhanced Th2 cell function in a cell-intrinsic manner. Finally, administration of recombinant IL-21 and IL-25 synergistically promoted airway eosinophilia primarily via effects on CD4+ lymphocytes. This highlights an important Th2-cell-amplifying function of IL-21-producing CD4+ T cells in allergic airway inflammation.
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•House dust mites induce potent IL-21 production by Tfh cells in lymphoid organs•IL-21+ cells are distinct from Th2 cells and migrate to the lung tissue and airway•IL-21R provides cell-intrinsic cues for Th2 cell functions•IL-21 synergizes with innate signals to promote adaptive Th2 cell responses
Asthma is a well-described Th2-cell-mediated disease. Coquet, Lambrecht, and colleagues demonstrate that the allergen house dust mite induces pronounced IL-21 production in lymph nodes draining the lung, and also in lung tissue and in the airways. IL-21 and its receptor promote type 2 responses from adaptive CD4+ T cells.
Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the ...need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer-dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.
Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also ...generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.
Intestinal nematodes suppress immune responses in the context of allergy, gut inflammation, secondary infection and vaccination. Several mechanisms have been proposed for this suppression including ...alterations in Th2 cell differentiation and increased Treg cell suppressive function. In this study, we show that chronic nematode infection leads to reduced peripheral responses to vaccination because of a generalized reduction in the available responsive lymphocyte pool. We found that superficial skin-draining lymph nodes (LNs) in mice that are chronically infected with the intestinal nematode Heligmosomides polygyrus, do not reach the same cellularity as worm-free mice upon subsequent BCG infection in the skin. B cells and T cells, all declined in skin-draining LN of H. polygyrus-infected mice, resulting in LNs atrophy and altered lymphocyte composition. Importantly, anti-helminthic treatment improved lymphocyte numbers in skin-draining LN, indicating that time after de-worming is critical to regain full-scale LN cellularity. De-worming, and time for the skin LN to recover cellularity, also mended responses to Bacille Calmette-Guerin (BCG) in the LN draining the footpad injection site. Thus, our findings show that chronic nematode infection leads to a paucity of lymphocytes in peripheral lymph nodes, which acts to reduce the efficacy of immune responses at these sites.
Trends in scintillators that are used in many applications, such as medical imaging, security, oil-logging, high energy physics and non-destructive inspections are reviewed. First, we address ...traditional inorganic and organic scintillators with respect of limitation in the scintillation light yields and lifetimes. The combination of high–light yield and fast response can be found in Ce 3 + , Pr 3 + and Nd 3 + lanthanide-doped scintillators while the maximum light yield conversion of 100,000 photons/MeV can be found in Eu 3 + doped SrI 2 . However, the fabrication of those lanthanide-doped scintillators is inefficient and expensive as it requires high-temperature furnaces. A self-grown single crystal using solution processes is already introduced in perovskite photovoltaic technology and it can be the key for low-cost scintillators. A novel class of materials in scintillation includes lead halide perovskites. These materials were explored decades ago due to the large X-ray absorption cross section. However, lately lead halide perovskites have become a focus of interest due to recently reported very high photoluminescence quantum yield and light yield conversion at low temperatures. In principle, 150,000–300,000 photons/MeV light yields can be proportional to the small energy bandgap of these materials, which is below 2 eV. Finally, we discuss the extraction efficiency improvements through the fabrication of the nanostructure in scintillators, which can be implemented in perovskite materials. The recent technology involving quantum dots and nanocrystals may also improve light conversion in perovskite scintillators.
Naive CD4+ T cells differentiate into functionally diverse T helper (Th) cell subsets. Th2 cells play a pathogenic role in asthma, yet a clear picture of their transcriptional profile is lacking. We ...performed single-cell RNA sequencing (scRNA-seq) of T helper cells from lymph node, lung, and airways in the house dust mite (HDM) model of allergic airway disease. scRNA-seq resolved transcriptional profiles of naive CD4+ T, Th1, Th2, regulatory T (Treg) cells, and a CD4+ T cell population responsive to type I interferons. Th2 cells in the airways were enriched for transcription of many genes, including Cd200r1, Il6, Plac8, and Igfbp7, and their mRNA profile was supported by analysis of chromatin accessibility and flow cytometry. Pathways associated with lipid metabolism were enriched in Th2 cells, and experiments with inhibitors of key metabolic pathways supported roles for glucose and lipid metabolism. These findings provide insight into the differentiation of pathogenic Th2 cells in the context of allergy.
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•scRNA-seq resolves distinct subsets of T helper cells in response to HDM•Airway Th2 cells express over 100 distinct genes, including Il13, Plac8, and Igfbp7•ATAC-seq confirms scRNA-seq and identifies TF motifs enriched in Th2 cells•Airway Th2 cells are enriched for genes associated with lipid metabolism
Th2 cells play a pathogenic role in allergies such as asthma, yet a clear picture of their transcriptional profile in this setting is lacking. Tibbitt, Stark, et al. elucidate a distinct gene expression signature in Th2 cells responding to house dust mites and show that pathogenic airway Th2 cells are highly enriched for genes associated with lipid metabolism.
Several interconnected human, animal and environmental habitats can contribute to the emergence, evolution and spread of antibiotic resistance, and the health of these contiguous habitats (the focus ...of the One Health approach) may represent a risk to human health. Additionally, the expansion of resistant clones and antibiotic resistance determinants among human-associated, animal-associated and environmental microbiomes have the potential to alter bacterial population genetics at local and global levels, thereby modifying the structure, and eventually the productivity, of microbiomes where antibiotic-resistant bacteria can expand. Conversely, any change in these habitats (including pollution by antibiotics or by antibiotic-resistant organisms) may influence the structures of their associated bacterial populations, which might affect the spread of antibiotic resistance to, and among, the above-mentioned microbiomes. Besides local transmission among connected habitats-the focus of studies under the One Health concept-the transmission of resistant microorganisms might occur on a broader (even worldwide) scale, requiring coordinated Global Health actions. This Review provides updated information on the elements involved in the evolution and spread of antibiotic resistance at local and global levels, and proposes studies to be performed and strategies to be followed that may help reduce the burden of antibiotic resistance as well as its impact on human and planetary health.
Upon their activation, CD4 T cells can differentiate into distinct T helper cell subsets with specialised functions. Different T helper cell subsets produce specific cytokines that mediate beneficial ...and sometimes detrimental effects, depending on the infection or disease setting. CD4 T‐cell priming relies on signals delivered by the T‐cell antigen receptor, co‐stimulatory receptors and cytokine receptors on the CD4 T‐cell surface. Cytokine receptors are well known to deliver instructive signals that direct T helper cell differentiation. However, it is less appreciated that co‐stimulatory receptors also exert potent modulatory effects on this process. In this review, we outline the contribution of co‐stimulatory and co‐inhibitory receptors to the process of T helper cell differentiation, focusing on those pathways for which the underlying mechanisms are best known. Herein, we depict the physiological context of T‐cell priming and emphasise the impact of cell–cell communication on directing T helper cell differentiation.
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with resistance to neutralizing antibodies are threatening to undermine vaccine efficacy. Vaccination and ...infection have led to widespread humoral immunity against the pandemic founder (Wu-Hu-1). Against this background, it is critical to assess the outcomes of subsequent immunization with variant antigens. It is not yet clear whether heterotypic boosts would be compromised by original antigenic sin, where pre-existing responses to a prior variant dampen responses to a new one, or whether the memory B cell repertoire would bridge the gap between Wu-Hu-1 and VOCs. We show, in macaques immunized with Wu-Hu-1 spike, that a single dose of adjuvanted beta variant receptor binding domain (RBD) protein broadens neutralizing antibody responses to heterologous VOCs. Passive transfer of plasma sampled after Wu-Hu-1 spike immunization only partially protects K18-hACE2 mice from lethal challenge with a beta variant isolate, whereas plasma sampled following heterotypic RBD boost protects completely against disease.
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•Heterotypic RBD boost elicits cross-neutralizing antibody responses in macaques•No evidence that original antigenic sin hinders booster immunizations with beta RBD•Pre-boost plasma only partially protects K18-hACE2 mice from beta variant challenge•Post-boost plasma affords full protection from beta variant challenge
The emergence and spread of antibody-resistant SARS-CoV-2 variants of concern (VOCs) threatens to diminish vaccine efficacy. Sheward et al. show, in rhesus macaques and K18-hACE2 mice, that reduced vaccine protection against VOCs can be restored by broadening antibody responses with a third, heterotypic RBD booster immunization.
Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic ...inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe
mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.
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