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Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF‐β and IL‐35, a recently identified heterodimeric cytokine that belongs to the IL‐12 cytokine family. However, the effect of regulatory IL‐35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL‐35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL‐35 and different profibrotic cytokines in fibrotic (F‐ILD) and non‐fibrotic (NF‐ILD) patients by ELISA were compared to that of intracellular IL‐35 and IL‐17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL‐35 (rIL‐35) and TGF‐β (rTGF‐β), which were evaluated by flow cytometry. We observed that BAL concentration of IL‐35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF‐β (p < 0.001) and IL‐17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL‐35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL‐17 + CD4+ T cells (p < 0.001). The percentage of IL‐35 + CD4+ T cells correlated positively with BAL concentration of IL‐35 (p = 0.02), but correlated negatively with BAL concentrations of IL‐17 (p = 0.007) and TGF‐β (p = 0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF‐β: IL‐35 ratio of 1:4, an enhanced percentage of IL‐35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL‐17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL‐35 to the BAL from F patients until a 1:4 ratio of TGF‐β: IL‐35 was reached, a significantly increased percentage of IL‐35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL‐17 + CD4+ T cells (p = 0.003) was found. These results suggest that IL‐35 may induce an anti‐fibrotic response, regulating the effect of TGF‐β and the inflammatory response on CD4+ T cells. In addition, the TGF‐β: IL‐35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD. [ABSTRACT FROM AUTHOR]

Summary: The Immune Epitope Database and Analysis Resource (IEDB) provides the scientific community with open access to epitope data, as well as epitope prediction and analysis tools. The IEDB houses the most extensive collection of experimentally validated B‐cell and T‐cell epitope data, sourced primarily from published literature by expert curation. The data procurement requires systematic identification, categorization, curation and quality‐checking processes. Here, we provide insights into these processes, with particular focus on the dividends they have paid in terms of attaining project milestones, as well as how objective analyses of our processes have identified opportunities for process optimization. These experiences are shared as a case study of the benefits of process implementation and review in biomedical big data, as well as to encourage idea‐sharing among players in this ever‐growing space. [ABSTRACT FROM AUTHOR]

In the past few years, the evolution of immunotherapy has resulted in a shift in cancer treatment models. However, with immunosuppressive effects of the tumour microenvironment continues to limit advances in tumour immunotherapy. The tumour microenvironment induces metabolic reprogramming in cancer cells, which results in competition for nutrients between tumour cells and host immunocytes. Metabolic and waste products originating in tumour cells can influence the activation and effector properties of immunocytes in numerous ways and ultimately promote the survival and propagation of tumour cells. In this paper, we discuss metabolic reprogramming in tumour cells and the influence of metabolite by‐products on the immune microenvironment, providing novel insights into tumour immunotherapy. [ABSTRACT FROM AUTHOR]

Citrullination and homocitrullination are stress induced post‐translational modifications (siPTMs) which can be recognized by T cells. Peripheral blood mononuclear cells isolated from healthy donors and rheumatoid arthritis (RA) patients were stimulated with nine siPTM‐peptides. CD45RA/CD45RO depletion was employed to determine if peptide‐specific responses are naïve or memory. Human leucocyte antigen (HLA)‐DP4 and HLA‐DR4 transgenic mice were immunized with siPTM‐peptides and immune responses were determined with ex vivo ELISpot assays. The majority (24 out of 25) of healthy donors showed CD4 T cell‐specific proliferation to at least 1 siPTM‐peptide, 19 to 2 siPTM‐peptides, 14 to 3 siPTM‐peptides, 9 to 4 siPTM‐peptides, 6 to 5 siPTM‐peptides and 4 to 6 siPTM‐peptides. More donors responded to Vim28‐49cit (68%) and Bip189‐208cit (75%) compared with Vim415‐433cit (33%). In RA patients, the presentation of citrullinated epitopes is associated with HLA‐SE alleles; however, we witnessed responses in healthy donors who did not express the SE allele. The majority of responding T cells were effector memory cells with a Th1/cytotoxic phenotype. Responses to Vim28‐49cit and Eno241‐260cit originated in the memory pool, while the response to Vim415‐433cit was naïve. In the HLA‐DP4 and HLA‐DR4 transgenic models, Vim28cit generated a memory response. Peptide‐specific T cells were capable of Epstein–Barr virus transformed lymphoblastoid cell line recognition suggesting a link with stress due to infection. These results suggest siPTM‐peptides are presented under conditions of cellular stress and inflammation and drive cytotoxic CD4 T cell responses that aid in the removal of stressed cells. The presentation of such siPTM‐peptides is not restricted to HLA‐SE in both humans and animal models. [ABSTRACT FROM AUTHOR]

Vaccines based on tumour‐specific antigens are a promising approach for immunotherapy. However, the clinical efficacy of tumour‐specific antigens is still challenging. Twelve conjugates with self‐assembly properties were designed and synthesized using MAGE‐A1 peptide and TLR2 agonist, combined with different covalent bonds. All the developed conjugates formed spherical nanoparticles with a diameter of approximately 150 nm, and enhanced the efficacy of the peptide vaccines with the better targeting of lymph nodes. All the conjugates could well bind to serum albumin and improve the plasma stability of the individual antigenic peptides. In particular, conjugate 6 (N‐Ac PamCS‐M‐6) had a more significant ability to promote dendritic cell maturation, CD8+ T cell activation, and subsequent killing of tumour cells, with an in vivo tumour inhibition rate of 70 ± 2.9%. The interaction between specific response and the different conjugation modes was further explored, thereby providing a fundamental basis for novel immune anti‐tumour molecular platforms. [ABSTRACT FROM AUTHOR]

Keywords: antibodies; mucosal immunology; vaccination; viral EN antibodies mucosal immunology vaccination viral 384 387 4 06/19/23 20230701 NES 230701 Abbreviations 95% CI 95% confidence intervals BAU/mL binding antibody units per mL GMC geometric mean concentrations Vaccination against COVID-19 has mitigated the impact of SARS-CoV-2 infection, decreasing the probability of progression to severe disease and death in vaccinated people. In this study, we observed a high salivary antibody prevalence (81%), detecting antibodies even in children whose last contact with SARS-CoV-2 antigens had been 270 days before sample collection. Antibody concentrations in binding antibody units (BAU) per mL (BAU/mL) were obtained interpolating the OD 450 nm values of samples into a calibration curve constructed with the provided standard (400 BAU/mL). [Extracted from the article]

In severe respiratory virus infections, including influenza, an exaggerated host immune response has been linked to the severe disease and death. Control of the overwhelming immune response is thus essential. Efforts with broad‐spectrum immunosuppressive agents such as steroids are disappointing. A better understanding of host immune response using animal experimental system is required to avoid undesired outcome of experimental manipulation. Following severe influenza virus infection in influenza hemagglutinin antigen‐specific transgenic mouse experimental model, step‐wise evolving cells from a pool of naïve hemagglutinin‐specific CD4+ T cells were studied for phenotypic, genomic, and functional characterization in vivo. Naïve CD4+ T cells respond with Th1 commitment in the absolute majority. They first develop into LAG‐3MedIFN‐γ‐secreting Th1 effectors and then evolve into LAG‐3HighIFN‐γ‐not‐secreting regulators with increasing LAG‐3 expression upon continuous activation and cell division. The LAG‐3MedIFN‐γ‐secreting effectors contribute to inflammation, boost inflammatory response of cognate antigen‐specific CD8+ T cells, and aggravate the disease despite facilitated virus clearance. In contrast, LAG‐3High regulators do not contribute to inflammation, suppress CD8+ T cell inflammatory response, alleviate lung pathology, and ameliorate the disease with preserved virus clearance. Moderated CD8+ T cells retain proliferative capacity, and persist beyond virus clearance. Such moderation is distinct from Foxp‐3+ regulator‐mediated suppression, which suppresses proliferative and inflammatory responses of the CD8+ T cells and impairs virus clearance with inflammation alleviation. Origin of regulatory from the effector cells of LAG‐3‐marked Th1 immunity alleviates lung inflammation without impairment of virus eradication. [ABSTRACT FROM AUTHOR]

Taurine (Tau) is a special sulphur‐containing amino acid and has been widely used as a dietary supplement. Although Tau exists in lymphocytes in large quantities, the physiological significance of Tau to modulate human immunity is unknown. In the present study, we first found that Tau regulates the B‐cell receptor (BCR)‐mediated signal transduction and induces the B cells activation. The IgG production of mice after ovalbumin immunization was also increased by Tau administration. Moreover, the isothermal titration calorimetry and surface plasmon resonance analysis have shown that Tau specifically bound to the IgG2a‐BCR. The Tau could bind to IgG F(ab′)2 regions via fluorescence spectroscopy analysis. In the molecular docking analysis, Tau bound to the framework regions (FRs) of variable region of the heavy chains (VH) and in the light chains (VL) of IgG2a‐BCR. Our results suggested that Tau could improve the activation of B cells by interaction with the VH/VL FRs of BCR. [ABSTRACT FROM AUTHOR]

Oncogene SET Domain Bifurcated 1 (SETDB1)/ESET, an H3K9 methyltransferase, was originally discovered over two decades ago; however, its function in the immune response was not first reported until 2011. SETDB1 immune functions include B cell maturation, T cell activity regulation, and immune escape in cancer cells. In B lymphocytes, SETDB1 mediates the transition from pro‐B to pre‐B cells and represses endogenous retroviruses (ERV) to encourage B cell lineage differentiation and maturation. SETDB1 alters T cell function by methylating IL‐2 and IL‐17 promoters and mediating T cell lineage commitment and development. In addition, SETDB1 plays a critical role in ERV silencing within a variety of immune cells, which can indirectly weaken the immune response. Although SETDB1 is critical for normal immune cell function, overexpression in cancer cells negatively impacts immune cell fights against cancer through decreased tumour immunogenicity. Within cancer cells, SETDB1 overexpression represses production and infiltration of antitumour immune cells, mediates immune escape through TE and ERV silencing, represses the type I interferon pathway, and interferes in immune checkpoint blockade (ICB) outcomes by regulation of PD‐L1 expression and IFN signalling. In this review, we further discuss the immunological mechanisms of SETDB1 in normal and cancerous cells and its implications in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Sjӧgren's syndrome (SS) is an autoimmune inflammatory disease characterized by chronic inflammation and dysfunction of exocrine glands and causes dry mouth, dry eyes and various systemic health problems. The objective of this study is to define the in vivo actions of the endogenous NLRP3 inflammasome, a key initiator and mediator of various immune and inflammatory conditions, in newly established SS disease. MCC950, a highly specific small‐molecule inhibitor of NLRP3 inflammasome formation and activation, was intraperitoneally administered to the female non‐obese diabetic (NOD) mice aged 11 weeks, which have newly established SS‐like hyposalivation and pathologies. The injection was conducted three times weekly for three consecutive weeks and mice were analysed for characteristic SS pathologies at the end of the treatments. MCC950 treatment resulted in a marked reduction in salivary secretion and an exacerbation of leukocyte infiltration of submandibular glands. The disease‐worsening effect of MCC950 treatment was accompanied by increased T and B cell numbers, enhanced T helper 1 response and reduced aquaporin 5 expression in submandibular glands. Hence, ablation of endogenous NLRP3 inflammasome activity by MCC950 with established autoimmune exocrinopathy exacerbates salivary gland dysfunction and inflammation, indicating a disease‐alleviating and inflammation‐dampening action of the endogenous NLRP3 inflammasome activity during established SS disease in the non‐obese diabetic mouse model. [ABSTRACT FROM AUTHOR]

Autoimmune and autoinflammatory diseases (AIIDs) involve a deficit in an individual's immune system function, whereby the immune reaction is directed against self‐antigens. Many AIIDs have a strong genetic component, but they can also be triggered by environmental factors. AIIDs often have a highly negative impact on the individual's physical and mental wellbeing. Understanding the genetic underpinning of AIIDs is thus crucial both for diagnosis and for identifying individuals at high risk of an AIID and mental illness as a result thereof. The aim of the present study was to perform systematic statistical and genetic analyses to assess the role of human leukocyte antigen (HLA) alleles in 30 AIIDs and to study the links between AIIDs and psychiatric disorders. We leveraged the Danish iPSYCH Consortium sample comprising 65 534 individuals diagnosed with psychiatric disorders or selected as part of a random population sample, for whom we also had genetic data and diagnoses of AIIDs. We employed regression analysis to examine comorbidities between AIIDs and psychiatric disorders and associations between AIIDs and HLA alleles across seven HLA genes. Our comorbidity analyses showed that overall AIID and five specific AIIDs were associated with having a psychiatric diagnosis. Our genetic analyses found 81 significant associations between HLA alleles and AIIDs. Lastly, we show connections across AIIDs, psychiatric disorders and infection susceptibility through network analysis of significant HLA associations in these disease classes. Combined, our results include both novel associations as well as replications of previously reported associations in a large sample, and highlight the genetic and epidemiological links between AIIDs and psychiatric disorders. [ABSTRACT FROM AUTHOR]

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an essential component of the innate immune system and is central to the identification of abnormal DNA leakage caused by ionising radiation (IR) damage. Cell‐intrinsic cGAS–STING initiation has been revealed to have tremendous potential for facilitating interferon synthesis and T‐cell priming. Targeting the cGAS–STING axis has been proposed as a strategy to improve radiosensitivity or enhance immunosurveillance. However, due to the complex biology of the irradiated tumour microenvironment and the extensive involvement of the cGAS–STING pathway in various physiological and pathological processes, many defects in this strategy limit the therapeutic effect. Here, we outline the molecular mechanisms by which IR activates the cGAS–STING pathway and analyse the dichotomous roles of the cGAS–STING pathway in modulating cancer immunity after radiotherapy (RT). Then, based on the crosstalk between the cGAS–STING pathway and other signalling events induced by IR, such as necroptosis, autophagy and other cellular effects, we discuss the immunomodulatory actions of the broad cGAS–STING signalling network in RT and their potential therapeutic applications. Finally, recent advances in combination therapeutic strategies targeting cGAS–STING in RT are explored. [ABSTRACT FROM AUTHOR]

Oesophageal adenocarcinoma (OAC) has a relatively poor long‐term survival and limited treatment options. Promising targets for immunotherapy are short peptide neoantigens containing tumour mutations, presented to cytotoxic T‐cells by human leucocyte antigen (HLA) molecules. Despite an association between putative neoantigen abundance and therapeutic response across cancers, immunogenic neoantigens are challenging to identify. Here we characterized the mutational and immunopeptidomic landscapes of tumours from a cohort of seven patients with OAC. We directly identified one HLA‐I presented neoantigen from one patient, and report functional T‐cell responses from a predicted HLA‐II neoantigen in a second patient. The predicted class II neoantigen contains both HLA I and II binding motifs. Our exploratory observations are consistent with previous neoantigen studies in finding that neoantigens are rarely directly observed, and an identification success rate following prediction in the order of 10%. However, our identified putative neoantigen is capable of eliciting strong T‐cell responses, emphasizing the need for improved strategies for neoantigen identification. [ABSTRACT FROM AUTHOR]

Arthralgia is a hallmark of chikungunya virus (CHIKV) infection and can be very debilitating and associated with a robust local inflammatory response. Many pathophysiological aspects associated with the disease remain to be elucidated. Here, we describe a novel model of CHIKV infection in immunocompetent mice and evaluate the role of tumour necrosis factor in the pathogenesis of the disease. C57BL/6 wild type (WT) or TNF receptor 1 deficient (TNFR1−/−) mice were inoculated with 1 × 106 PFU of CHIKV in the paw. Alternatively, etanercept was used to inhibit TNF in infected WT mice. Hypernociception, inflammatory and virological analysis were performed. Inoculation of CHIKV into WT mice induced persistent hypernociception. There was significant viral replication in target organs and local production of inflammatory mediators in early time‐points after infection. CHIKV infection was associated with specific humoral IgM and IgG responses. In TNFR1−/− mice, there was a decrease in the hypernociception threshold, which was associated with a milder local inflammatory response in the paw but delayed viral clearance. Local or systemic treatment with etanercept reduced CHIKV‐induced hypernociception. This is the first study to describe hypernociception, a clinical correlation of arthralgia, in immunocompetent mice infected with CHIKV. It also demonstrates the dual role of TNF in contributing to viral clearance but driving tissue damage and hypernociception. Inhibition of TNF may have therapeutic benefits but its role in viral clearance suggests that viral levels must be monitored in CHIKV‐infected patients and that TNF inhibitors should ideally be used in combination with anti‐viral drugs. [ABSTRACT FROM AUTHOR]

Tumour‐associated macrophages (TAMs) are one of the primary sources of PD‐L1 expression in the tumour microenvironment (TME). Ionizing radiation (IR) promotes PD‐L1 expression in tumour cells. However, the effect of IR on macrophage PD‐L1 expression and the underlying mechanisms remain unclear. ATM kinase, as the key kinase for initiating DNA damage repair (DDR) process, is associated with innate immune STING axis activation. Here, we explored the molecular mechanism implicated in macrophage PD‐L1 expression regulated by IR as well as the role of ATM kinase in this process. IR‐regulated PD‐L1 expression in macrophages and associated signalling pathways were explored by in vitro studies using murine and human macrophage cell lines. A colorectal xenograft murine model was employed to demonstrate the impact of targeting ATM and PD‐L1 expression in TAMs following IR on growth of tumour in vivo. IR up‐regulated PD‐L1 expression in macrophages, which was further augmented by ATM kinase inhibition. ATM inhibition increased IR‐induced DNA damage, which activated STING/interferon regulatory factor 3 (IRF3) signalling pathway and up‐regulated type I interferon (IFN‐I) expression in macrophages. IFN‐I bound to the IFN α receptor 1 on macrophages, activated the downstream JAK1 and STAT1/3 signalling and eventually led to PD‐L1 up‐expression. ATM inhibition augmented IR‐induced PD‐L1 expression in macrophages and CD8+ T cell infiltration, and promoted anti‐tumour efficacy in vivo. These results suggested that ATM inhibition promoted IR‐induced PD‐L1 expression through the activation of innate immunity in TAMs, which provided a novel approach to enhance the anti‐tumour efficacy of RT. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSC) induced cellular immune deficiency and bone marrow inflammatory microenvironment play an important role in the pathogenesis and progression of myelodysplastic syndrome (MDS), but the underlying mechanism remains unclear. Here, we revealed that immune checkpoint protein TIM3 and CEACAM1 were highly demonstrated on MDSC and CD8+ T cells in MDS patients. CD8+ T cells were reduced in number and function and presented a exhaustion state. The levels of pro‐inflammatory cytokines (IL‐1β, IL‐18) and CEACAM1 were raised in bone marrow supernatants and MDSC culture supernatants. Blocking or neutralizing TIM3/CEACAM1 and IL‐1β/IL‐18 partially reversed exhaustion of CD8+ T cells. Moreover, TIM3 correlated with NF‐κB /NLRP3 inflammatory pathway. The levels of NF‐κB/NLRP3/Caspase‐1/IL‐1β and IL‐18 were all increased in MDSC of MDS. Co‐culturing MDSC from MDS patients with rhCEACAM1 enhanced NF‐κB/NLRP3/Caspase‐1/IL‐1β and IL‐18 levels, whereas blocking TIM3 could partially reverse the above manifestations. These results indicated that TIM3/CEACAM1 pathway involved in CD8+ T cells exhaustion and might activate the NF‐κB/NLRP3/Caspase‐1 pathway in MDSC, increasing pro‐inflammatory cytokines secretion in MDS bone marrow microenvironment. This study provided a basis for applying immune checkpoint inhibitors that could simultaneously modulate pro‐inflammatory cytokine secretion and enhance anti‐tumour immune function in the treatment of MDS. [ABSTRACT FROM AUTHOR]

Two human natural anti‐carbohydrate antibodies appeared in critical evolutionary events that brought primates and hominins to brink of extinction. The first is the anti‐Gal antibody, produced in Old‐World monkeys (OWM), apes and humans. It binds the carbohydrate‐antigen 'α‐gal epitope' (Galα1‐3Galβ1‐4GlcNAc‐R) on carbohydrate‐chains (glycans) synthesized by non‐primate mammals, lemurs and New‐World monkeys (NWM). The second is anti‐N‐glycolylneuraminic‐acid (anti‐Neu5Gc) antibody binding Neu5Gc on glycans synthesized by OWM, apes and most non‐primate mammals. Ancestral OWM and apes synthesized α‐gal epitopes and were eliminated ~20–30 million‐years‐ago (mya). Only few accidentally mutated offspring lacking α‐gal epitopes, produced anti‐Gal and survived. Hominin‐populations living ~3 mya synthesized Neu5Gc and were eliminated, but few mutated offspring that accidently lost their ability to synthesize Neu5Gc, produced natural anti‐Neu5Gc antibody. These hominins survived and ultimately evolved into present‐day humans. It is argued that these two near‐extinction events were likely to be the result of epidemics caused by highly virulent and lethal enveloped viruses that killed parental‐populations. These viruses presented α‐gal epitopes or Neu5Gc synthesized in host‐cells of the parental‐populations. Mutated offspring survived the epidemics because they were protected from the lethal virus by the natural anti‐Gal or anti‐Neu5Gc antibodies they produced due to loss of immune‐tolerance to α‐gal epitopes or to Neu5Gc, respectively. [ABSTRACT FROM AUTHOR]

Exosomes are extracellular vesicles released by all cell types; perform several important functions such as cell‐to‐cell communication, growth, differentiation and so on. Exosomes elicit several signalling mechanisms as they carry information in the form of DNA, RNA or protein docked on them. We show that exosomes released from Mycobacterium tuberculosis (Mtb)‐infected macrophages not only induce differentiation of naïve monocytes but also generate functionally active macrophages via MAPK‐dependent signalling mechanism through MK‐2 and NF‐κβ activation which is completely different from the differentiation induced by exosomes from uninfected macrophages. Further, we elucidate unequivocally the signalling mechanism behind the enhanced release of exosome generation from infected macrophages driven by AKT phosphorylation involving Rab7a and Rab11a. Genes of both ESCRT‐dependent and ‐independent pathways are found to be involved in enhanced exosomes release and are modulated by AKT. However, interestingly, the genes of the ESCRT‐independent pathway are dependent on NF‐κβ activation while the genes of the dependent pathway are not, suggesting two parallel signalling cascades operating in tandem. [ABSTRACT FROM AUTHOR]

Obesity is generally associated with low‐grade inflammation. Adipose tissue macrophages (ATMs) orchestrate metabolic inflammation. The classical (M1‐like) or alternative (M2‐like) activation of ATMs is functionally coupled with the metabolic status of fat tissues. It has been found that T‐cell immunoglobulin‐ and mucin‐domain‐containing molecule‐4 (Tim‐4) inhibits inflammation by regulating macrophages. However, the exact role of Tim‐4 in macrophage polarization and obesity remains unknown. Here, we identified Tim‐4 as a critical switch governing macrophage M1/M2 polarization and energy homeostasis. Tim‐4 deletion led to spontaneous obesity in elder mice and promoted obesity severity of db/db mice. Obesity microenvironment enhanced the expression of Tim‐4 in white adipose tissue and ATMs. In vitro, we detected an increase in M1‐like cells and decrease in M2‐like cells in both peritoneal macrophages and bone marrow‐derived macrophages from Tim‐4 knockout mice. Mechanistically, we demonstrated that Tim‐4 promoted M2‐like macrophages polarization via suppressing nuclear factor kappa B (NF‐κB) signaling pathway. In addition, we found that Tim‐4 promoted TLR4 internalization, which might contribute to regulation of NF‐κB signaling. Collectively, these results indicated that Tim‐4 maintained adipose tissue homeostasis by regulating macrophage polarization via NF‐κB pathway, which would provide a new target for obesity intervention. [ABSTRACT FROM AUTHOR]

Summary: Some human antibodies may paradoxically inhibit complement activation on bacteria and enhance pathogen survival in humans. This property was also claimed for IgG antibodies reacting with terminal galactose‐α‐1,3‐galactose (Galα3Gal; IgG anti‐αGal), a naturally occurring and abundant antibody in human plasma that targets numerous different pathogens. To reinvestigate these effects, we used IgG anti‐αGal affinity isolated from a pool of normal human IgG and human hypogammaglobulinaemia serum as a complement source. Flow cytometry was performed to examine antibody binding and complement deposition on pig erythrocytes, Escherichia coli O86 and Streptococcus pneumoniae serotype 9V. Specific nanobodies were used to block the effect of single complement factors and to delineate the complement pathways involved. IgG anti‐αGal was capable of activating the classical complement pathway on all the tested target cells. The degree of activation was exponentially related to the density of bound antibody on E. coli O86 and pig erythrocytes, but more linearly on S. pneumoniae 9V. The alternative pathway of complement amplified complement deposition. Deposited C3 fragments covered the activating IgG anti‐αGal, obstructing its detection and highlighting this as a likely general caveat in studies of antibody density and complement deposition. The inherent capacity for complement activation by the purified carbohydrate reactive IgG anti‐αGal was similar to that of normal human IgG. We propose that the previously reported complement inhibition by IgG anti‐αGal relates to suboptimal assay configurations, in contrast to the complement activating property of the antibodies demonstrated in this paper. [ABSTRACT FROM AUTHOR]

Grass pollen allergens are shown to remain associated with protein material and a yellow pigment during paper chromatography and during dialyses and ultrafiltrations of various types. Dialysable* allergens comprise only a fraction of I per cent of the total activity and the amount of activity extractable by diethylene glycol (DEG) and similar solvents is of the same order. Besides the allergens, the DEG and aqueous extracts contain large amounts of inositol, glucose and fructose, also some yellow pigments and phosphates. Larger amounts of free and combined amino acids are found in the aqueous than in the DEG extracts, but the reverse is true for sucrose. In addition the DEG extracts contain a yellow glucoside different from the dactylen of the aqueous extracts, a glucosan and an arabinose-galactose-pigment complex, only the latter being associated with any activity. The spontaneous release of the crystalline dactylen from originally clear aqueous pollen extracts is found not to be caused by enzymes. The washed crystals are found to be chromatographically and electrophoretically homogeneous and devoid of allergenic activity. [ABSTRACT FROM AUTHOR]

The antigenic components of adrenal extract were fractionated by chromatography on DEAE-cellulose. Using a stepwise elution procedure, it was found that a component of major interest, termed Pk3b, was eluted by a buffer of pH 6.70 and 0.09 M in phosphate-chloride. This antigenic preparation reacted with several rabbit antisera that had been prepared by isoimmunization with rabbit adrenal homogenate, in contrast to several other fractions, which reacted with only one (or two) of the antisera. Pk3b also showed a high degree of homogeneity, as shown by immunodiffusion, paper electrophoresis, and analytical ultracentrifugation. By the latter technique, an extrapolated sedimentation coefficient of 4.45S was determined. The further comparison of this antigen in immunodiffusion, along with an antiserum and the adrenal extract from the antiserum-providing animal, confirmed again that this is an autoantigen, and that it is one of five autoantigens of the adrenal gland. [ABSTRACT FROM AUTHOR]

The immune checkpoint programmed death receptor 1 (PD‐1) and programmed death ligand 1 (PD‐L1) are biologically important immunosuppressive molecules, and the PD‐L1/PD‐1‐mediated signalling pathway is currently considered one of the main mechanisms of tumour escape immune surveillance. PD‐L1 is highly expressed on the cytomembrane of tumour cell and binds to PD‐1 receptor of activated T cells. This interaction activates PD‐L1/PD‐1 downstream signal transduction, inhibiting T cells anti‐tumour activity. Therefore, inhibitors of PD‐L1/PD‐1 activation, showing significant efficacy in some types of tumours, have been widely approved in clinical tumour therapy. Recent research on PD‐L1/PD‐1 signalling pathway regulation has shown post‐translational modifications (PTMs) form of PD‐L1 or PD‐1, including glycosylation, ubiquitination, phosphorylation, and acetylation, which may play an important role in PD‐L1/PD‐1 signalling pathway regulation and anti‐tumour function of T cells. In this review, we focused on PTMs of PD‐L1/PD‐1 research and potential applications in tumour immunotherapy. [ABSTRACT FROM AUTHOR]

Mast cells (MCs), central players in allergy and parasitic infections, play key roles in inflammation and fibrosis. Here, the impact of MCs on the progression of Coxsackievirus B3 (CVB3)‐induced viral myocarditis (VMC) and fibrosis was investigated using MC‐deficient KitW‐sh mice. Viral titres, cellular infiltrates and heart pathologies were evaluated and compared with wild‐type (WT) mice during acute CVB3 infection of C57BL/6 mice. CVB3 infection induced an increased accumulation and degranulation of MCs in the hearts of mice during acute infection. MC‐deficient KitW‐sh mice had slightly higher viral titres, decreased VMC and cardiac fibrosis and improved cardiac dysfunction compared to WT mice via decreasing cardiac influx of Ly6Chigh monocytes/macrophages (Mo/Mφ). While bone marrow‐derived MC reconstitution decreased viral titre and worsened improved survival and VMC severity in Wsh mice. MC‐fibroblasts co‐culture revealed a cardiac MC‐fibroblasts crosstalk during early infection: fibroblasts trigger MC degranulation and secretion of CCL2 and tumour necrosis factor alpha (TNF‐α) via producing early stem cell factor (SCF); while MCs‐fibrogenic mediators (TNF‐α) stimulate fibroblasts to increase CCL2, α‐smooth muscle actin (SMA), collagen and transforming growth factor beta（TGFβ) expression, thus aggravating cardiac fibrosis. MCs and fibroblast‐derived CCL2s are both essential for cardiac Ly6Chigh Mo/Mφ influx. Administration of recombinant mouse SCF to CVB3‐infected mice aggravates VMC via accelerating MCs accumulation and cardiac influx of Ly6Chi Mo/Mφ. Collectively, our data highlight an early MC‐fibroblast crosstalk and SCF/MC/CCL2/Mo/Mφ axis as important mechanisms required for triggering VMC and myocardial fibrosis. This finding indicates critical roles of MCs in initiating and modulating cardiac innate response to CVB3 and has an implication in developing new and more effective treatments for VMC. [ABSTRACT FROM AUTHOR]

The relative abundance of myeloid‐derived suppressor cells (MDSCs) compared to cytotoxic T cells determines the outcomes of diseases and the efficacy of immunotherapy. Ubiquitin‐specific peptidase 12 (USP12), a member of the USP family of deubiquitinases, targets multiple signalling pathways and regulates diverse biological processes, including cell proliferation and survival. It is well known that ubiquitylation is an important mechanism for regulating the immune response. However, it is unclear whether USP12 regulates tumour growth by influencing MDSCs. In the present study, we reported that USP12 deficiency decreased infiltration and impaired the suppressor function of monocytic (M)‐MDSCs, resulting in increased CD8+ T‐cell response and decelerated tumour growth. USP12‐knockout M‐MDSCs were less potent in inhibiting the proliferation of CD8+ T cells and their ability to secrete IFN‐γ. Furthermore, USP12 deficiency inhibited the suppressor function of M‐MDSCs by downregulating the negative regulatory molecules inducible nitric oxide synthase and PD‐L1, through deubiquitinating and stabilizing p65. Our results suggest that USP12 is a positive regulator of M‐MDSCs and may serve as a potential target for antitumor therapy. [ABSTRACT FROM AUTHOR]

Published data for the Streptococcus pneumoniae virulence factor Pneumolysin (Ply) show contradictory effects on the host inflammatory response to infection. Ply has been shown to activate the inflammasome, but also can bind to MRC‐1 resulting in suppression of dendritic cell inflammatory responses. We have used an in vitro infection model of human monocyte‐derived macrophages (MDM), and a mouse model of pneumonia to clarify whether pro‐ or anti‐inflammatory effects dominate the effects of Ply on the initial macrophage inflammatory response to S. pneumoniae, and the consequences during early lung infection. We found that infection with S. pneumoniae expressing Ply suppressed tumour necrosis factor (TNF) and interleukin‐6 production by MDMs compared to cells infected with ply‐deficient S. pneumoniae. This effect was independent of bacterial effects on cell death. Transcriptional analysis demonstrated S. pneumoniae expressing Ply caused a qualitatively similar but quantitatively lower MDM transcriptional response to S. pneumoniae compared to ply‐deficient S. pneumoniae, with reduced expression of TNF and type I IFN inducible genes. Reduction of the MDM inflammatory response was prevented by inhibition of SOCS1. In the early lung infection mouse model, the TNF response to ply‐deficient S. pneumoniae was enhanced and bacterial clearance increased compared to infection with wild‐type S. pneumoniae. Overall, these data show Ply inhibits the initial macrophage inflammatory response to S. pneumoniae, probably mediated through SOCS1, and this was associated with improved immune evasion during early lung infection. [ABSTRACT FROM AUTHOR]

Autoreactive T cells with the phenotype and function of different memory subsets are present in patients who developed type 1 diabetes (TID). According to the progressive differentiation model, memory subsets generate from naïve precursors in a linear and unidirectional path depending on the strength and quality of stimulatory signals. By observing human naïve T cells in contact with GAD65 loaded autologous dendritic cells, we observed that approximately 10% of cells divided with the plane of cell division parallel to the one of the immune synapse, causing phenotypic asymmetries in the proximal and distal daughter T cells. After the first T cell division, proximal and distal daughter T cells showed different phenotype, metabolic signature and commitment to differentiate towards long‐lived memory T cells or T cells with effector function. Subjects with or without T1D showed a similar frequency of asymmetric T cell division (ATCD) for autoantigens and recall antigens specific T cells, however the frequency of ATCD is significantly increased in autoreactive T cells in patients with T1D when IL‐7 was added to the culture. An increased upregulation of GLUT1 in response to IL‐7 in patients with T1D was related to the rate of ATCD. Our results showed that ATCD is associated with an early divergence in the differentiation fate of naïve T cells specific for GAD65 during first antigen encounter. [ABSTRACT FROM AUTHOR]

Immunodisruptive homeostasis is recognized in allergic disorders. The mechanism of restoration of immunologic homeostasis in the body is not fully understood. Galectin‐9 (Gal9) and CD22 have immune regulatory functions. The goal of this study is to test the role of CD22+ CD9+ B regulatory cells in immune homeostasis the body. A much smaller amount of IL‐10 in B10 cells was detected in patients with allergic rhinitis (AR) in contrast to healthy subjects. The IL‐10 expression levels in B10 cells were positively correlated with the CD22 expression. CD22 mediated the effects of Gal9 on the enhanced expression of IL‐10 in AR B10 cells. Gal9 overcame the refractory induction of IL‐10 in B‐cells of AR subjects. The immune regulatory ability of AR B10 cells could be restored by Gal9. Combination of Gal9 and SIT induced and activated antigen‐specific B10 cells. The B10 cells of Gal9/specific immunotherapy‐treated AR mice showed immunosuppressive functions on T‐cell activities and induction of type 1 regulatory T cells in an antigen‐specific manner. Administration of Gal9 potentiated the effects of specific immunotherapy in mice with AR. In summary, a fraction of regulatory B cells, the CD19+ CD22+ CD9+ B cells, was characterized in the present study. CD22 mediates the effects of Gal9 to promote immunotherapy for allergic diseases by inducing B10 cells. In an antigen‐specific manner, the B10 cells suppressed CD4+ T cell activities, and alleviated experimental AR. [ABSTRACT FROM AUTHOR]

Trained immunity (TRAIM) may be defined as a form of memory where innate immune cells such as monocytes, macrophages, dendritic and natural killer (NK) cells undergo an epigenetic reprogramming that enhances their primary defensive capabilities. Cross‐pathogen protective TRAIM can be triggered in different hosts by exposure to live microbes or microbe‐derived products such as heat‐inactivated Mycobacterium bovis or with the glycan α‐Gal to elicit protective responses against several pathogens. We review the TRAIM paradigm using two models representing distinct scales of immune sensitization: the whole bacterial cell and one of its building blocks, the polysaccharides or glycans. Observations point out to macrophage lytic capabilities and cytokine regulation as two key components in non‐specific innate immune responses against infections. The study of the TRAIM response deserves attention to better characterize the evolution of host–pathogen cooperation both for identifying the aetiology of some diseases and for finding new therapeutic strategies. In this field, the zebrafish provides a convenient and complete biological system that could help to deepen in the knowledge of TRAIM‐mediated mechanisms in pathogen–host interactions. [ABSTRACT FROM AUTHOR]

Cells must control genes that are induced by virus infection to mitigate deleterious consequences of inflammation. We investigated the mechanisms whereby Keap1 moderates the transcription of genes that are induced by Sendai virus infection in mouse embryo fibroblasts (MEFs). Keap1−/− deletions increased the transcription of virus induced genes independently of Nrf2. Keap1 moderated early virus induced gene transcription. Virus infection induced Keap1 to bind Ifnb1, Tnf and Il6, and reduced Keap1 binding at Cdkn1a and Ccng1. Virus infection induced G9a‐GLP and NFκB p50 recruitment, and H3K9me2 deposition. Keap1−/− deletions eliminated G9a‐GLP and NFκB p50 recruitment, and H3K9me2 deposition, but they did not affect NFκB p65, IRF3 or cJun recruitment. G9a‐GLP inhibitors (BIX01294, MS012, BRD4770) enhanced virus induced gene transcription in MEFs with intact Keap1, but not in MEFs with Keap1−/− deletions. G9a‐GLP inhibitors augmented Keap1 binding to virus induced genes in infected MEFs, and to cell cycle genes in uninfected MEFs. G9a‐GLP inhibitors augmented NFκB subunit recruitment in MEFs with intact Keap1. G9a‐GLP inhibitors stabilized Keap1 retention in permeabilized MEFs. G9a‐GLP lysine methyltransferase activity was required for Keap1 to moderate transcription, and it moderated Keap1 binding to chromatin. The interdependent effects of Keap1 and G9a‐GLP on the recruitment of each other and on the moderation of virus induced gene transcription constitute a feedback circuit. Keap1 and the electrophile tBHQ reduced virus induced gene transcription through different mechanisms, and they regulated the recruitment of different NFκB subunits. Characterization of the mechanisms whereby Keap1, G9a‐GLP and NFκB p50 moderate virus induced gene transcription can facilitate the development of immunomodulatory agents. [ABSTRACT FROM AUTHOR]

The source of macrophages that contribute to human liver disease remains poorly understood. The purpose of this study is to investigate the functional mechanism of peritoneal macrophages in the development of hepatic immunopathology. By performing the natural infection with the blood fluke Schistosoma japonicum (S. japonicum) and the chemically carbon tetrachloride (CCl4)‐induced liver injured mouse model, we identified the peritoneal cavity as an essential source of hepatic macrophages. Here, we show that a large number of F4/80+ macrophages was accumulated in the peritoneal cavity during liver injury. An unknown source population of macrophages, which highly expressed GATA6 that is specific to peritoneal macrophages, was found to exist in the injured livers. Peritoneal macrophage deletion by injection with clodronate‐containing liposomes led to an attenuated hepatic pathology and the inflammatory microenvironment, while adoptive transfer of macrophages into the abdominal cavity, by contrast, results in restoring liver pathology. Importantly, there are set genes of monocyte chemoattractant protein (MCP)‐1, ‐2, and ‐3 that are highly related to recruit GATA6+ macrophages during S. japonicum infection, while administration of bindarit, a selective inhibitor of MCPs synthesis, dramatically decreased the hepatic expression of GATA6+ macrophages and thus attenuated hepatic pathology. Furthermore, in vivo study showed that peritoneal macrophages promote hepatic immunopathology is dependent on the accumulation of regulatory T cells (Tregs) in the liver. Altogether, these data provide the first clear evidence that GATA6+ peritoneal macrophages play critical roles in both the formation of hepatic immunopathology and the accumulation of Tregs cells. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized cancer therapy by reactivating tumour‐resident cytotoxic lymphocytes. More recently, immunotherapy has emerged to restore immunity against infectious agents, including bacterial infections. Immunotherapy primarily targets inhibitory pathways in T cells, however interest in other effector populations, such as natural killer (NK) cells, is growing. We have previously discovered that NK cell metabolism, proliferation and activation can be neutralized through the immunosuppressive transforming growth factor (TGF)‐β pathway by inducing plasticity of NK cells and differentiation into innate lymphoid cell (ILC)1‐like subsets. NK cells are also regulated through cytokine‐inducible SH2‐containing protein (CIS), which is induced by interleukin (IL)‐15 and is a potent intracellular checkpoint suppressing NK cell survival and function. Targeting these two distinct pathways to restore NK cell function has shown promise in cancer models, but their application in bacterial infection remains unknown. Here, we investigate whether enhancement of NK cell function can improve anti‐bacterial immunity, using Salmonella Typhimurium as a model. We identified conversion of NK cells to ILC1‐like for the first time in the context of bacterial infection, where TGF‐β signalling contributed to this plasticity. Future study should focus on identifying further drivers of ILC1 plasticity and its functional implication in bacterial infection model. We further describe that CIS‐deficient mice displayed enhanced pro‐inflammatory function and dramatically enhanced anti‐bacterial immunity. Inhibition of CIS may present as a viable therapeutic option to enhance immunity towards bacterial infection. [ABSTRACT FROM AUTHOR]

I "And, one last thing, I'm recruiting postdocs to the lab." i At this year's Annual Meeting for the American Association of Immunologists, this phrase was easily the most common final line of any talk by a principal investigator (PI). Several institutions have experimented with supplementing postdoc salaries, providing increases over the mandated NIH stipend as well as access to better benefits and retirement savings. We are going to have to work to actively change our expectations, or risk having empty labs, continually shouting into the void, 'and, like everyone else, I'll just add that I'm recruiting postdocs to the lab'. In years past, the postdoc was considered to be a time of "sacrifice": a few years of your life on your way to your faculty job, so you could accept an undercut salary. [Extracted from the article]

B lymphocyte‐mediated humoral immune response is essential for protection against infectious diseases. Deeper research in B cell biology, particularly metabolism is required for the better understanding of its properties in homeostasis and in diseases. Emerging immunometabolism, including anabolism and catabolism, has tremendously impacts on immune cells from development to function and markedly advances our view on immunoregulation. Growing evidence suggests that the ultimate effect of intracellular metabolism on immune cell functions is not only influenced by the external stimuli but also by the balance of the different metabolic pathways. However, B cell immunometabolism is not deeply investigated like T cells. The complex development and differentiation processes of B cell subsets have left many untouched, but fundamental aspects in B cell metabolism. Available evidence demonstrated that the intracellular metabolism has the ubiquitous impact on B cell fate and function decisions at the transcriptional regulation and signal transduction processes. In this review, we update the recent development in the immunometabolism of B cells with the latest findings including the immune‐metabolic steering on B cell development, differentiation, and function skewing, and emphasis on how immunometabolism landscape may shape B cell functions in metabolic, autoimmune, and inflammatory disorders. The metabolic interaction of B cells with other immune cells in disease context will also be discussed. [ABSTRACT FROM AUTHOR]

Our previous studies have demonstrated that tetrandrine can induce the generation of regulatory T (Treg) cells in vitro and in vivo. But, the underlying mechanism of tetrandrine remains obscure. Naïve CD4+ T cells are isolated from the mesenteric lymph nodes of mice for the differentiation of Treg cells. Flow cytometry is used to detect the frequencies of Treg cells. Non‐targeted metabolomics analysis based on UHPLC‐QTOF/MS is performed to assess the intracellular metabolic profiles. ChIP‐PCR analysis is conducted to detect the level of H3K27ac at Foxp3 promoter and CNS regions. Tetrandrine treatment alters the metabolic profile of Treg cells, and pathway enrichment of differential metabolites mainly involves fatty acid oxidation (FAO). Tetrandrine promotes the mRNA expression of carnitine palmitoyl transferase‐1, and increases the level of acetyl coenzyme A (acetyl‐CoA) and the intracellular oxygen consumption rate. Either CPT1 inhibitor (etomoxir) or siRNA markedly diminishes the promotion of tetrandrine on Treg cell differentiation. Furthermore, tetrandrine enhances the acetylation of H3K27 in the promoter and CNS1 regions of Foxp3 through the acetyl‐CoA derived from FAO. In the mice with collagen‐induced arthritis, tetrandrine also induces Treg cell generation through FAO pathway. In addition, tetrandrine enhances the immunosuppressive function of Treg cells both in vitro and in vivo. The findings indicate that tetrandrine promotes Treg cell differentiation by enhancing FAO‐mediated Foxp3 acetylation, and the CPT1‐mediated FAO can serve as the target for the discovery of novel inducers of Treg cell generation. [ABSTRACT FROM AUTHOR]

Conventional dendritic cells (cDCs) arise from committed precursor dendritic cells (pre‐DCs) in the bone marrow that continuously seed the periphery. Pre‐DCs and other upstream progenitors proliferate and mature in response to Fms‐related receptor tyrosine kinase 3 ligand, which is considered the key cytokine for cDC development. However, other cytokines such as stem cell factor and colony‐stimulating factor 1 (CSF1) were also shown to induce pre‐DC maturation into DC‐like cells. Yet, it is still only incompletely understood which cells contribute to cDC development once pre‐DCs arrive in peripheral tissues. Here, we analysed the impact of lymph node (LN) fibroblastic stromal cells (FSCs) on the maturation of pre‐DCs into cDC‐like cells. We could demonstrate that ex vivo isolated LN FSCs co‐cultured with pre‐DCs induce precursor maturation into DC‐like cells, which were capable of efficiently promoting the proliferation of naïve CD4+ T cells. Interestingly, FSCs isolated from distinct LNs induced DC‐like cells with highly comparable transcriptomes, characterized by the expression of signature genes of both ex vivo isolated DCs and macrophages. Finally, by performing supplementation and receptor blocking studies, we could demonstrate that CSF1 is a driving factor for LN FSC‐mediated pre‐DC maturation into DC‐like cells. In summary, we could identify CSF1 as a stromal cell‐derived factor that has the potential to support the maturation of pre‐DCs into cDC‐like cells within secondary lymphoid organs. [ABSTRACT FROM AUTHOR]

Cyclic GMP‐AMP synthase (cGAS) is essential for fighting against viruses and bacteria, but how cGAS is involved in host immune response remains largely elusive. Here, we uncover the crucial role of cGAS in host immunity based on a Pseudomonas aeruginosa pulmonary infection model. cGAS−/− mice showed more heavy bacterial burdens and serious lung injury accompanied with exorbitant proinflammatory cytokines than wild‐type mice. cGAS deficiency caused an accumulation of mitochondrial DNA in the cytoplasm, which, in turn, induced excessive secretion of proinflammatory factors by activating inflammasome and TLR9 signalling. Mechanistically, cGAS deficiency inhibited the recruitment of LC3 by reducing the binding capacity of TBK‐1 to p62, leading to impaired mitophagy and augmented release of mitochondrial DNA. Importantly, cytoplasmic mitochondrial DNA also acted as a feedback signal that induced the activation of cGAS. Altogether, these findings identify protective and homeostasis functions of cGAS against Pseudomonas aeruginosa infection, adding significant insight into the pathogenesis of bacterial infectious diseases. [ABSTRACT FROM AUTHOR]

In this study we show that glycosylation is relevant for immune recognition of therapeutic antibodies, and that defined glycan structures can modulate immunogenicity. Concerns regarding immunogenicity arise from the high heterogeneity in glycosylation that is difficult to control and can deviate from human glycosylation if produced in non‐human cell lines. While non‐human glycosylation is thought to cause hypersensitivity reactions and immunogenicity, less is known about effects of Fc‐associated glycan structures on immune cell responses. We postulated that glycosylation influences antigen recognition and subsequently humoral responses to therapeutic antibodies by modulating 1) recognition and uptake by dendritic cells (DCs), and 2) antigen routing, processing and presentation. Here, we compared different glycosylation variants of the antibody rituximab (RTX) in in vitro assays using human DCs and T cells as well as in in vivo studies. We found that human DCs bind and internalize unmodified RTX stronger compared to its aglycosylated form suggesting that glycosylation mediates uptake after recognition by glycan‐specific receptors. Furthermore, we show that DC‐uptake of RTX increases or decreases if glycosylation is selectively modified to recognize activating (by mannosylation) or inhibitory lectin receptors (by sialylation). Moreover, glycosylation seems to influence antigen presentation by DCs because specific glycovariants tend to induce either stronger or weaker T cell activation. Finally, we demonstrate that antibody glycosylation impacts anti‐drug antibody (ADA) responses to RTX in vivo. Hence, defined glycan structures can modulate immune recognition and alter ADA responses. Glyco‐engineering may help to decrease clinical immunogenicity and ADA‐associated adverse events such as hypersensitivity reactions. [ABSTRACT FROM AUTHOR]

‘Natural’ opsonins to Salmonella typhimurium in serum from foetal and natal rats have been shown to be in part macroglobulins. The titre of these opsonins was shown to increase in the young natal animals. [ABSTRACT FROM AUTHOR]

T cell inhibitory receptors can regulate the proliferation or function of T cells by binding to their ligands and present a unique opportunity to manage destructive immune responses during porcine islet xenotransplantation. We applied ex vivo porcine islet xenotransplantation and in vitro mixed lymphocyte‐islet reaction models to assess immune checkpoint receptor expression profiles in recipient T cells, investigated whether CTLA4 or VISTA immunoglobulin (Ig) combination therapy alone could suppress porcine islet xenograft rejection and further analyzed its potential immune tolerance mechanism. Recipient T cells expressed moderate to high levels of CTLA4, PD‐1, TIGIT and VISTA, and the frequency of CTLA4+CD4+, TIGIT+CD4+, VISTA+CD4+ and VISTA+CD8+ T cells was positively correlated with porcine islet xenograft survival time in xenotransplant recipients. Combined treatment with CTLA4Ig and VISTAIg selectively inhibited recipient CD4+ T cell hyper‐responsiveness and proinflammatory cytokine production and significantly delayed xenograft rejection. SOCS1 deficiency in CD4+ T cells stimulated by xenogeneic islets facilitated hyper‐responsiveness and abolished the suppressive effect of combination therapy on recipient T cell‐mediated porcine islet damage in vivo and in vitro. Further mechanistic studies revealed that combined treatment significantly induced SOCS1 expression and inhibited the Jak‐STAT signalling pathway in wild‐type recipient CD4+ T cells stimulated by xenogeneic islets, whereas SOCS1 deficiency resulted in Jak‐STAT signalling pathway activation in recipient CD4+ T cells. We demonstrated a major role for CTLA4 and VISTA as key targets in CD4+ T cell hyper‐responsiveness and porcine islet xenograft rejection. The selective inhibition of CD4+ T cell immunity by CTLA4Ig/VISTAIg is based on SOCS1‐dependent signalling. [ABSTRACT FROM AUTHOR]

Chronic lung allograft dysfunction (CLAD) remains the major barrier to long‐term survival after lung transplantation and improved insight into its underlying immunological mechanisms is critical to better understand the disease and to identify treatment targets. We systematically searched the electronic databases of PubMed and EMBASE for original research publications, published between January 2000 and April 2021, to comprehensively assess current evidence on effector immune cells in lung tissue and bronchoalveolar lavage fluid from lung transplant recipients with CLAD. Literature search revealed 1351 articles, 76 of which met the criteria for inclusion in our analysis. Our results illustrate significant complexity in both innate and adaptive immune cell responses in CLAD, along with presence of numerous immune cell products, including cytokines, chemokines and proteases associated with tissue remodelling. A clear link between neutrophils and eosinophils and CLAD incidence has been seen, in which eosinophils more specifically predisposed to restrictive allograft syndrome. The presence of cytotoxic and T‐helper cells in CLAD pathogenesis is well‐documented, although it is challenging to draw conclusions about their role in tissue processes from predominantly bronchoalveolar lavage data. In restrictive allograft syndrome, a more prominent humoral immune involvement with increased B cells, immunoglobulins and complement deposition is seen. Our evaluation of published studies over the last 20 years summarizes the complex multifactorial immunopathology of CLAD onset and progression. It highlights the phenotype of several key effector immune cells involved in CLAD pathogenesis, as well as the paucity of single cell resolution spatial studies in lung tissue from patients with CLAD. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells protect against intracellular infection and cancer. These properties are exploited in oncolytic virus (OV) therapy, where antiviral responses enhance anti‐tumour immunity. We have analysed the mechanism by which reovirus, an oncolytic dsRNA virus, modulates human NK cell activity. Reovirus activates NK cells in a type I interferon (IFN‐I) dependent manner, inducing STAT1 and STAT4 signalling in both CD56dim and CD56bright NK cell subsets. Gene expression profiling revealed the dominance of IFN‐I responses and identified induction of genes associated with NK cell cytotoxicity and cell cycle progression, with distinct responses in the CD56dim and CD56bright subsets. However, reovirus treatment inhibited IL‐15 induced NK cell proliferation in an IFN‐I dependent manner and was associated with reduced AKT signalling. In vivo, human CD56dim and CD56bright NK cells responded with similar kinetics to reovirus treatment, but CD56bright NK cells were transiently lost from the peripheral circulation at the peak of the IFN‐I response, suggestive of their redistribution to secondary lymphoid tissue. Coupled with the direct, OV‐mediated killing of tumour cells, the activation of both CD56dim and CD56bright NK cells by antiviral pathways induces a spectrum of activity that includes the NK cell‐mediated killing of tumour cells and modulation of adaptive responses via the trafficking of IFN‐γ expressing CD56bright NK cells to lymph nodes. [ABSTRACT FROM AUTHOR]

SARS‐CoV‐2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID‐19, virus‐specific antibody and T‐cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS‐CoV‐2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T‐cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA‐DRB1*13:02 was associated with a 6·7‐fold increased risk of case definition symptomatic COVID‐19. In terms of immune responsiveness, HLA‐DRB1*15:02 was associated with lower nucleocapsid T‐cell responses. There was no association between DRB1 alleles and anti‐spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T‐cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies with nuclear antigen (nAg) specificity. Using (SWRxNZB)F1 (SNF1) mice, we showed higher levels of Immunoglobulin A (IgA) production in the intestine and the nAg reactivity of faecal IgA under lupus susceptibility. Here, we determined whether the faecal IgA abundance and nAg reactivity are higher in, different among, various lupus‐prone preclinical models (MRL/lpr, NZBxNZW‐F1, SNF1, NZM2410 and NZM2328). We also determined whether the faecal IgA nAg reactivity at preseropositive ages correlates with the eventual serum autoantibody levels in males and females of these mouse models. We show that age‐dependent increase in the abundance and nAg reactivity of faecal IgA can vary among different lupus‐prone mouse models. Importantly, faecal IgA in these mice show significant levels of nAg reactivity, starting as early as at juvenile age. Furthermore, the pre‐seropositive stage nAg reactivity of faecal IgA in most lupus‐prone strains correlates well with that of eventual, seropositive stage systemic autoantibody levels. Gender differences in serum autoantibody levels were preceded by similar differences in the faecal IgA abundance and nAg reactivity. These observations suggest that faecal IgA features, nAg reactivity particularly, could serve as a biomarker for early prediction of the eventual systemic autoimmunity in lupus‐prone subjects. [ABSTRACT FROM AUTHOR]

The NLRP3 inflammasome is a multiprotein complex that regulates caspase‐1 activation and subsequent interleukin (IL)‐1β and IL‐18 release from innate immune cells in response to infection or injury. Derivatives of the metabolites itaconate and fumarate, dimethyl itaconate (DMI), 4‐octyl itaconate (4OI) and dimethyl fumarate (DMF) limit both expression and release of IL‐1β following NLRP3 inflammasome activation. However, the direct effects of these metabolite derivatives on NLRP3 inflammasome responses require further investigation. Using murine bone marrow‐derived macrophages, mixed glia and organotypic hippocampal slice cultures (OHSCs), we demonstrate that DMI, 4OI and DMF pretreatments inhibit pro‐inflammatory cytokine production in response to lipopolysaccharide (LPS), as well as inhibit subsequent NLRP3 inflammasome activation induced by nigericin. DMI, 4OI, DMF and monomethyl fumarate (MMF), another fumarate derivative, also directly inhibited biochemical markers of NLRP3 activation in LPS‐primed macrophages, mixed glia, OHSCs and human macrophages in response to nigericin and imiquimod, including ASC speck formation, caspase‐1 activation, gasdermin D cleavage and IL‐1β release. DMF, an approved treatment of multiple sclerosis, as well as DMI, 4OI and MMF, inhibited NLRP3 activation in macrophages in response to lysophosphatidylcholine, which is used to induce demyelination, suggesting a possible mechanism for DMF in multiple sclerosis through NLRP3 inhibition. The derivatives also reduced pro‐IL‐1α cleavage in response to the calcium ionophore ionomycin. Together, these findings reveal the immunometabolic regulation of both the priming and activation steps of NLRP3 activation in macrophages. Furthermore, we highlight itaconate and fumarate derivatives as potential therapeutic options in NLRP3‐ and IL‐1α‐driven diseases, including in the brain. [ABSTRACT FROM AUTHOR]

Nutritional zinc deficiency induces thymic atrophy, but the underlying mechanisms remain unknown. In this study, we investigated the mechanism of thymic atrophy and fatty degeneration associated with zinc deficiency and its effect on T cell maturation. Building on previous research demonstrating the beneficial effect of IL‐4 administration or zinc supplementation on the spleen in zinc‐deficient rats, we further examined whether these supplements also improve thymic atrophy. Five‐week‐old male Sprague‐Dawley rats were fed a standard diet, zinc‐deficient diet (n = 16 each) with either saline or IL‐4, or a zinc‐deficient diet for 6 weeks followed by a standard diet for 4 weeks. Relative thymus weights, serum thymulin concentrations, and the number of cytokeratin‐8‐positive cells, AIRE‐positive cells, IL‐7‐positive cells, CD8+ T cells, CD4+ T cells, pre‐T cells, and CD25+ CD44+ (DN3) cells in the thymus of zinc‐deficient rats significantly decreased compared with those in all other groups. Conversely, PPAR‐γ–positive cells, oil red O‐positive areas, pro T cells, CD25− CD44+ cells, TUNEL‐positive cells, Viobility 405/452 Fixable Dye–positive cells, CD68‐, CD163‐ or CD169‐ macrophages, and IL‐1β concentrations were significantly increased in the thymus of zinc‐deficient rats as compared to those in the other groups. After IL‐4 administration or zinc supplementation for zinc deficiency, all the measurement indices were recovered to levels in standard rats. It was demonstrated that zinc deficiency caused thymic atrophy, accompanied by fatty degeneration in the cortical regions and affected T cell maturation. IL‐4 administration or zinc supplementation for zinc deficiency ameliorated thymic fatty degeneration. [ABSTRACT FROM AUTHOR]

Double‐negative (DN) T cells are present at relatively low frequencies in human peripheral blood, and are characterized as expressing the alpha‐beta or gamma‐delta T‐cell receptor (TCR), but not the CD4 nor the CD8 co‐receptors. Despite their low frequencies, these cells are potent producers of cytokines and, thus, are key orchestrators of immune responses. DN T cells were initially associated with induction of peripheral immunological tolerance and immunomodulatory activities related to disease prevention. However, other studies demonstrated that these cells can also display effector functions associated with pathology development. This apparent contradiction highlighted the heterogeneity of the DN T‐cell population. Here, we review phenotypic and functional characteristics of DN T cells, emphasizing their role in human diseases. The need for developing biomarkers to facilitate the translation of studies from animal models to humans will also be discussed. Finally, we will examine DN T cells as promising therapeutic targets to prevent or inhibit human disease development. [ABSTRACT FROM AUTHOR]

Summary: Hepatitis B virus (HBV) infection causes a self‐limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin‐like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA‐A‐Bw4 and HLA‐C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004–0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA‐A‐Bw4 and HLA‐C2 was highly sensitive to predict the outcome of HBV infection. [ABSTRACT FROM AUTHOR]