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There are hundreds of prognostic models for ovarian cancer. These genes are based on different gene classes, and there are many ways to construct the models. Therefore, this paper aims to build the most stable prognostic evaluation system known to date through 101 machine learning strategies. We combined 101 algorithm combinations with 10 machine learning algorithms to create antigen presentation-associated genetic markers (AIDPS) with outstanding precision and steady performance. The inclusive set of algorithms comprises the elastic network (Enet), Ridge, stepwise Cox, Lasso, generalized enhanced regression model (GBM), random survival forest (RSF), supervised principal component (SuperPC), Cox partial least squares regression (plsRcox), survival support vector machine (Survival-SVM). Then, in the train cohort, the prediction model was fitted using a leave-one cross-validation (LOOCV) technique, which involved 101 different possible combinations of prognostic genes. Seven validation data sets (GSE26193, GSE26712, GSE30161, GSE63885, GSE9891, GSE140082 and ICGC&#95;OV&#95;AU) were compared and analysed, and the C-index was calculated. Finally, we collected 32 published ovarian cancer prognostic models (including mRNA and lncRNA). All data sets and prognostic models were subjected to a univariate Cox regression analysis, and the C-index was calculated to demonstrate that the antigen presentation process should be the core criterion for evaluating ovarian cancer prognosis. In a univariate Cox regression analysis, 22 prognostic genes were identified based on the expression profiles of 283 genes involved in antigen presentation and the intersection of genes (p < 0.05). AIDPS were developed by our machine learning-based integration method, which was applied to these 22 genes. One hundred and one prediction models are fitted using the LOOCV framework, and the C-index is calculated for each model across all validation sets. Interestingly, RSF + Lasso was the best model overall since it had the greatest average C-index and the highest C-index of any combination of models tested on the validated data sets. In comparing external cohorts, we found that the C-index correlated AIDPS method using the RSF + Lasso method in 101 prediction models was in contrast to other features. Notably, AIDPS outperformed the vast majority of models across all data sets. Antigen-presenting anti-tumour immune pathways can be used as a representative gene set of ovarian cancer to track the prognosis of patients with cancer. The antigen-presenting model obtained by the RSF + Lasso method has the best C-INDEX, which plays a key role in developing antigen-presenting targeted drugs in ovarian cancer and improving the treatment outcome of patients., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Introduction: The MHC‐peptide interaction has a subtle influence on host resistance to virus. This paper aims to study the relationship between MHC‐peptide interaction and MHC‐related virus‐resistance. Methods: By 3D homology modeling, the structure of chicken BF2 molecule BF2*0201 (PDB code: 4d0d) was studied and compared with the known structures of BF2 molecule BF2*0401 (PDB code: 4e0r) to elucidate the characteristics of BF2*0201‐binding antigenic peptides. Results: The results show that due to the amino acid difference between the two binding groove of 4e0r and 4d0d, the size of the binding groove of the two are 1130 ų and1380 ų respectively, indicating the amino acid species that 4e0r binding peptide has lower selectivity than 4d0d; and because of large side chain conformation of Arg (especially Arg111) of 4e0r replaced by small side chain Tyr111 of 4d0d, the volume of central part of the binding groove of 4d0d is obviously larger than that of 4e0r, indicating that the restrictive of binding antigenic peptides for 4d0d is narrower than that of 4e0r; and on account of the chargeability of the binding groove of the two are different, namely the binding groove chargeability of 4e0r (strong positive polarity) and 4d0d (weak negative polarity). Conclusion: There are generally more peptides presented by the BF2 of B2 haplotype than by that of B4 haplotype, leading to more resistance of B2 than that of B4 to virus. [ABSTRACT FROM AUTHOR]

Between 1969 and 1983 the lab of Kevin Lafferty in Canberra developed the concept of the T‐cell "costimulator," an essential second signal for activation. A great deal of the work appeared in this journal before it was known as Immunology & Cell Biology (ICB). As part of the 100‐year anniversary of the journal, I offer a personal reflection on Kevin's legacy and impact. [ABSTRACT FROM AUTHOR]

MHC class I molecules on the cellular surface display peptides that either derive from endogenous proteins (self or viral), or from endocytosis of molecules, dying cells or pathogens. The conventional antigen‐processing pathway for MHC class I presentation depends on proteasome‐mediated degradation of the protein followed by transporter associated with antigen‐processing (TAP)‐mediated transport of the generated peptides into the endoplasmic reticulum (ER). Here, peptides are loaded onto MHC I molecules before transportation to the cell surface. However, several alternative mechanisms have emerged. These include TAP‐independent mechanisms, the vacuolar pathway and involvement of autophagy. Autophagy is a cell intrinsic recycling system. It also functions as a defence mechanism that removes pathogens and damaged endocytic compartments from the cytosol. Therefore, it appears likely that autophagy would intersect with the MHC class I presentation pathway to alarm CD8+ T cells of an ongoing intracellular infection. However, the importance of autophagy as a source of antigen for presentation on MHC I molecules remains to be defined. Here, original research papers which suggest involvement of autophagy in MHC I antigen presentation are reviewed. The antigens are from herpesvirus, cytomegalovirus and chlamydia. The studies point towards autophagy as important in MHC class I presentation of endogenous proteins during conditions of immune evasion. Because autophagy is a regulated process which is induced upon activation of, for example, pattern recognition receptors (PRRs), it will be crucial to use relevant stimulatory conditions together with primary cells when aiming to confirm the importance of autophagy in MHC class I antigen presentation in future studies. [ABSTRACT FROM AUTHOR]

Background: The heterogeneity of tumor endothelial cells (TECs) hinders the efficacy of antiangiogenic therapies (AATs). Only a small percentage of angiogenic TECs are considered effective targets for AATs. Immunomodulatory ECs (IMECs), as a newly focused functional subgroup of endothelial cells (ECs), are being evaluated for their ability to regulate tumor immune balance and influence existing AATs. Methods: Based on single‐cell transcriptome data from colorectal cancer in a publicly available database, we conducted a wide array of bioinformatic approaches to study EC subsets that meet the IMECs definition. Our investigation encompassed the gene expression signatures of these subsets, cellular composition differences, cell–cell interactions. Results: Two subsets that meet the IMECs definition were found in tumors and para‐cancerous tissues. Combined with the results of gene ontological analysis and interaction with CD4+ T cells, we found that IMECs can present MHC‐II antigens to mature CD4+ T cells. There were differences in the level of interaction between IMECs and different types of mature CD4+ T cell subsets. In addition, IMEC subsets had different expression levels of angiogenesis related genes. The angiogenesis score of IMECs decreased after patients received immunotherapy. IMEC subsets do not depend on a single proangiogenic receptor and are involved in regulating angiogenesis, which may reduce the efficacy of AATs. The adverse effects of specific IMEC subsets on AATs were validated in the RNA‐seq dataset of the bevacizumab treatment group. Conclusion: Our study suggests the potential MHC‐II antigen presentation capacity of IMECs and the enhanced angiogenesis characteristics within tumors. The function of IMECs in the vascular network may have a potentially adverse effect on AATs. Controlling the functional properties of IMECs may be a new angle for tumor therapy. [ABSTRACT FROM AUTHOR]

IgE, the key molecule in atopy has been shown to bind two receptors, FcεRI, the high‐affinity receptor, and FcεRII (CD23), binding IgE with lower affinity. Whereas cross‐linking of IgE on FcεRI expressed by mast cells and basophils triggers the allergic reaction, binding of IgE to CD23 on B cells plays an important role in both IgE regulation and presentation. Furthermore, IgE‐immune complexes (IgE‐ICs) bound by B cells enhance antibody and T cell responses in mice and humans. However, the mechanisms that regulate the targeting of the two receptors and the respective function of the two pathways in inflammation or homeostasis are still a matter of debate. Here, we focus on CD23 and discuss several mechanisms related to IgE binding, as well as the impact of the IgE/antigen‐binding on different immune cells expressing CD23. One recent paper has shown that free IgE preferentially binds to FcεRI whereas IgE‐ICs are preferentially captured by CD23. Binding of IgE‐ICs to CD23 on B cells can, on one hand, regulate serum IgE and prevent effector cell activation and on the other hand facilitate antigen presentation by delivering the antigen to dendritic cells. These data argue for a multifunctional role of CD23 for modulating IgE serum levels and immune responses. [ABSTRACT FROM AUTHOR]

In a companion article to this study,1 the successful programming of a JAWSII dendritic cell ( DC) line's antigen uptake and processing was demonstrated based on pre-treatment of DCs with a specific 'cocktail' of select chemokines. Chemokine pre-treatment modulated cytokine production before and after DC maturation [by lipopolysaccharide (LPS)]. After DC maturation, it induced an antigen uptake and processing capacity at levels 36% and 82% higher than in immature DCs, respectively. Such programming proffers a potential new approach to enhance vaccine efficiency. Unfortunately, simply enhancing antigen uptake does not guarantee the desired activation and proliferation of lymphocytes, e.g. CD4+ T cells. In this study, phenotype changes and antigen presentation capacity of chemokine pre-treated murine bone marrow-derived DCs were examined in long-term co-culture with antigen-specific CD4+ T cells to quantify how chemokine pre-treatment may impact the adaptive immune response. When a model antigen, ovalbumin ( OVA), was added after intentional LPS maturation of chemokine-treated DCs, OVA-biased CD4+ T-cell proliferation was initiated from ~ 100% more undivided naive T cells as compared to DCs treated only with LPS. Secretion of the cytokines interferon-γ, interleukin-1β, interleukin-2 and interleukin-10 in the CD4+ T cell : DC co-culture (with or without chemokine pre-treatment) were essentially the same. Chemokine programming of DCs with a 7 : 3 ratio of CCL3 : CCL19 followed by LPS treatment maintained partial immature phenotypes of DCs, as indicated by surface marker ( CD80 and CD86) expression over time. Results here and in our companion paper suggest that chemokine programming of DCs may provide a novel immunotherapy strategy to obviate the natural endocytosis limit of DC antigen uptake, thus potentially increasing DC-based vaccine efficiency. [ABSTRACT FROM AUTHOR]

The development of an optimal treatment modality to improve the therapeutic outcome of breast cancer patients is still difficult. Poor antigen presentation to T cells is a major challenge in cancer immunotherapy. In this study, a synergistic immunotherapy strategy for breast cancer incorporating immune cell infiltration, immunogenic cell death (ICD), and dendritic cell (DC) maturation through a reactive oxygen species (ROS)‐responsive dual‐targeted smart nanosystem (anti‐PD‐L1‐TKNP) for the simultaneous release of DOX, R848, and MIP‐3α in the tumor microenvironment is reported. Following local injection, anti‐PD‐L1‐DOX‐R848‐MIP‐3α/thioketal nanoparticle (TKNP) converts tumor cells to a vaccine owing to the combinatorial effect of DOX‐induced ICD, R848‐mediated immunostimulatory properties, and MIP‐3α‐induced immune cell recruitment in the tumor microenvironment. Intratumoral injection of anti‐PD‐L1‐DOX‐R848‐MIP‐3α/TKNP caused significant regression of breast cancer. Mechanistic studies reveal that anti‐PD‐L1‐DOX‐R848‐MIP‐3α/TKNP specifically targets tumor tissue, resulting in maximum exposure of calreticulin (CRT) and HMGB1 in tumors, and significantly enhances intratumoral infiltration of CD4+ and CD8+ T cells in tumors. Therefore, a combined strategy using dual‐targeted ROS‐responsive TKNP highlights the significant application of nanoparticles in modulating the tumor microenvironment and could be a clinical treatment strategy for effective breast cancer management. [ABSTRACT FROM AUTHOR]

Immunotherapy holds great promise for the treatment of malignant cancer. However, the lack of sufficient tumor neoantigens and incomplete dendritic cell (DC) maturation compromise the efficacy of immunotherapy. Here, a modular hydrogel‐based vaccine capable of eliciting a powerful and sustained immune response is developed. Briefly, CCL21a and ExoGM‐CSF+Ce6 (tumor cell‐derived exosomes with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) mRNA encapsulated inside and sonosensitizer chlorin e6 (Ce6) incorporated in the surface) are mixed with nanoclay and gelatin methacryloyl, forming the hydrogel designated as CCL21a/ExoGM‐CSF+Ce6@nanoGel. The engineered hydrogel releases CCL21a and GM‐CSF with a time gap. The earlier released CCL21a diverts the tumor‐draining lymph node (TdLN) metastatic tumor cells to the hydrogel. Consequently, the trapped tumor cells in the hydrogel, in turn, engulf the Ce6‐containing exosomes and thus are eradicated by sonodynamic therapy (SDT), serving as the antigen source. Later, together with the remnant CCL21a, GM‐CSF produced by cells engulfing ExoGM‐CSF+Ce6 continuously recruits and provokes DCs. With the two programmed modules, the engineered modular hydrogel vaccine efficiently inhibits tumor growth and metastasis via diverting TdLN metastatic cancer to hydrogel, killing the trapped tumor cells, and eliciting prolonged and powerful immunotherapy in an orchestrated manner. The strategy would open an avenue for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR‐deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR‐deficient cancers leads to a counter‐selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors. [ABSTRACT FROM AUTHOR]

Background and Purpose: Alveolar macrophages (AMs) contribute to airway inflammation and remodelling in allergic asthma. Calcaratarin D (CalD), a labdane diterpenoid from rhizomes of the medicinal plant Alpinia calcarata, has recently been shown to possess anti‐inflammatory properties. The present study evaluated protective effects of CalD in a house dust mite (HDM)‐induced asthma mouse model. Experimental Approach: The effects of CalD on AMs in contributing to anti‐inflammatory effects in asthma were investigated through in vivo, ex vivo, and in vitro experiments. Key Results: CalD reduced total bronchoalveolar lavage fluid and differential cell count, serum IgE levels, mucus hypersecretion, and airway hyperresponsiveness in HDM‐challenged mice. Additionally, CalD affected a wide array of pro‐inflammatory cytokines and chemokines and oxidative damage markers in isolated lung tissues. CalD suppressed the HDM‐induced increase in Arg1 (M2 macrophage marker) in AMs from lung tissue and reduced lung polyamine levels. CalD weakened antigen presentation capability of AMs by reducing CD80 expression, reduced AM‐derived CCL17 and CCL22 levels, and lessened Th2 cytokines from CD4+ T‐cells from asthma lung digest. CalD blocked the HDM‐induced FoxO1/IRF4 pathway and restored impaired the Nrf2/HO‐1 antioxidant pathway in lung tissues. CalD inhibited IL‐4/IL‐13‐stimulated JAK1/STAT6 pathway, FoxO1 protein expression, and chemokine production in primary AMs. Structure–activity relationship study revealed the α,β‐unsaturated γ‐butyrolactone in CalD is capable of forming covalent bonds with cellular protein targets essential for its action. Conclusion and Implications: Our results demonstrate for the first time that CalD is a novel anti‐inflammatory natural compound for allergic asthma that modulates AM function. [ABSTRACT FROM AUTHOR]

The direct modulation of T cell responses is an emerging therapeutic strategy with the potential to modulate undesired immune responses including, autoimmune disease, and allogeneic cells transplantation. We have previously demonstrated that poly(lactide‐co‐glycolide) particles were able to modulate T cell responses indirectly through antigen‐presenting cells (APCs). In this report, we investigated the design of nanoparticles that can directly interact and modulate T cells by coating the membranes from APCs onto nanoparticles to form membrane‐coated nanoparticles (MCNPs). Proteins within the membranes of the APCs, such as Major Histocompatibility Complex class II and co‐stimulatory factors, were effectively transferred to the MCNP. Using alloreactive T cell models, MCNP derived from allogeneic dendritic cells were able to stimulate proliferation, which was not observed with membranes from syngeneic dendritic cells and influenced cytokine secretion. Furthermore, we investigated the engineering of the membranes either on the dendritic cells or postfabrication of MCNP. Engineered membranes could be to promote antigen‐specific responses, to differentially activate T cells, or to directly induce apoptosis. Collectively, MCNPs represent a tunable platform that can directly interact with and modulate T cell responses. [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]

BACKGROUND: To improve the adjuvant activity of polysaccharides from Eucommia ulmoides leaves (PsEUL) in inducing an effective immune response against ovalbumin (OVA), PsEUL were conjugated to OVA using the N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride (EDC) method. The synthesized PsEUL‐OVA was encapsulated using phytantriol and F127 to produce PsEUL‐OVA cubosomes (Cubs), a novel delivery system. The physicochemical properties and immune modulation effects of this novel delivery system were explored. RESULTS: In vitro, PsEUL‐OVA/Cubs carrying large amounts of OVA were rapidly phagocytized by macrophages and upregulated macrophage proliferation, thereby stimulating cytokine production (interleukin (IL)‐6 and IL‐4). In vivo, PsEUL‐OVA/Cubs increased the titer of OVA‐specific antibodies (immunoglobulin (Ig)G, IgG2b, IgG2a and IgG1) and cytokine levels (IL‐2, IL‐6, IL‐4 and interferon‐γ). In addition, the cubosomes promoted the differentiation of CD8+ and CD4+ T cells in the spleen and the maturation of dendritic cells (DCs). These results indicated that PsEUL‐OVA/Cubs stimulated both cellular and humoral immune responses by enhancing the phagocytic activity of DCs and macrophages and increasing the antigen presentation efficiency. CONCLUSION: Collectively, the findings demonstrate that PsEUL‐antigen/Cubs can be a useful delivery vehicle with immune response‐promoting effects. Therefore, this study lays the foundation for the development of novel adjuvant–antigen delivery systems with potential applications in vaccine design. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

DCs do not just excel in antigen presentation. They orchestrate information transfer from innate to adaptive immunity by sensing and integrating a variety of danger signals, and translating them to naïve T cells, to mount specifically tailored immune responses. This is accomplished by distinct DC types specialized in different functions and because each DC is functionally plastic, assuming different activation states depending on the input signals received. Mouse models hold the key to untangle this complexity and determine which DC types and activation states contribute to which functions. Here, we aim to provide comprehensive information for selecting the most appropriate mutant mouse strains to address specific research questions on DCs, considering three in vivo experimental approaches: (i) interrogating the roles of DC types through their depletion; (ii) determining the underlying mechanisms by specific genetic manipulations; (iii) deciphering the spatiotemporal dynamics of DC responses. We summarize the advantages, caveats, suggested use, and perspectives for a variety of mutant mouse strains, discussing in more detail the most widely used or accurate models. Finally, we discuss innovative strategies to improve targeting specificity and next‐generation mutant mouse models, and briefly address how humanized mouse models can accelerate translation into the clinic. [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]

Aluminum salts have been successfully utilized as adjuvants to enhance the immunogenicity of vaccine antigens since the 1930s. However, the cellular mechanisms behind the immune adjuvanticity effect of these materials in antigen‐presenting cells are poorly understood. In this study, we investigated the uptake and trafficking of aluminum oxy‐hydroxide (AlOOH), in RAW 264.7 murine and U‐937 human macrophages‐like cells. Furthermore, we determined the impact that the adsorption to AlOOH particulates has on the trafficking of a Bordetella pertussis vaccine candidate, the genetically detoxified pertussis toxin (gdPT). Our results indicate that macrophages internalize AlOOH by constitutive macropinocytosis assisted by the filopodial protrusions that capture the adjuvant particles. Moreover, we show that AlOOH has the capacity to nonspecifically adsorb IgG, engaging opsonic phagocytosis, which is a feature that may allow for more effective capture and uptake of adjuvant particles by antigen‐presenting cells (APCs) at the site of vaccine administration. We found that AlOOH traffics to endolysosomal compartments that hold degradative properties. Importantly, while we show that gdPT escapes degradative endolysosomes and traffics toward the retrograde pathway, as reported for the wild‐type pertussis toxin, the adsorption to AlOOH diverts gdPT to traffic to the adjuvant's lysosome‐type compartments, which may be key for MHC‐II‐driven antigen presentation and activation of CD4+ T cell. Thus, our findings establish a direct link between antigen adsorption to AlOOH and the intracellular trafficking of antigens within antigen‐presenting cells and bring to light a new potential mechanism for aluminum adjuvancy. Moreover, the in‐vitro single‐cell approach described herein provides a general framework and tools for understanding critical attributes of other vaccine formulations. [ABSTRACT FROM AUTHOR]

Microglia are the static resident cells possessing the phagocytic properties in the central nervous system (CNS). In many relevant studies, the immortalized murine microglial cell line BV2 has been used as a tool in primary microglia (PM) relevant studies. Microglia participate in neuroinflammation by converting into M1‐ and M2‐like phenotypes. In this study, we established M1‐ and M2‐like phenotype response models by exposing PM and BV2 cells to lipopolysaccharides (LPS) and interlukin‐4 (IL‐4), respectively, and discovered the proteomic differences between the two types of microglia. It turned out that the BV2 cell responses to LPS and IL‐4 were narrower and weaker than that of PM. In addition, irradiation, which has been shown to activate microglia and induces neuroinflammation, was also used as a treatment in this study. The results showed that BV2 cells have stronger capacity of DNA damage repair. Besides, irradiation had a negative effect on the regulation of KEGG pathways such as proteasome, ribosome, oxidative phosphorylation and TCA cycle in both cells. Furthermore, the KEGG pathways including cell cycle and DNA replication (significantly downregulated), and antigen processing and presentation and FC γ R mediated phagocytosis (significantly up‐regulated) were only found in irradiated PM. These data demonstrate that PM is more fragile to irradiation. Results in this study indicate that BV2 cells only partially model PM, and thus, using BV2 in microglia related studies should be carefully considered. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are crucial for the appropriate initiation of adaptive immune responses. During inflammation, DCs capture antigens, mature, and migrate to lymphoid tissues to present foreign material to naïve T cells. These cells get activated and differentiate either into pathogen‐specific cytotoxic CD8+ T cells that destroy infected cells or into CD4+ T helper cells that, among other effector functions, orchestrate antibody production by B cells. DC‐mediated antigen presentation is equally important in non‐inflammatory conditions. Here, DCs mediate induction of tolerance by presenting self‐antigens or harmless environmental antigens and induce differentiation of regulatory T cells or inactivation of self‐reactive immune cells. Detailed insights into the biology of DCs are, therefore, crucial for the development of novel vaccines as well as the prevention of autoimmune diseases. As in many other life science areas, our understanding of DC biology would be extremely restricted without bioimaging, a compilation of methods that visualize biological processes. Spatiotemporal tracking of DCs relies on various imaging tools, which not only enable insights into their positioning and migration within tissues or entire organs but also allow visualization of subcellular and molecular processes. This review aims to provide an overview of the imaging toolbox and to provide examples of diverse imaging techniques used to obtain fundamental insights into DC biology. [ABSTRACT FROM AUTHOR]

Food allergy (FA) is now one of the most common chronic diseases of childhood often lasting throughout life and leading to significant worldwide healthcare burden. The precise mechanisms responsible for the development of this inflammatory condition are largely unknown; however, a multifactorial aetiology involving both environmental and genetic contributions is well accepted. A precise understanding of the pathogenesis of FA is an essential first step to developing comprehensive prevention strategies that could mitigate this epidemic. As it is frequently preceded by atopic dermatitis and can be prevented by early antigen introduction, the development of FA is likely facilitated by the improper initial presentation of antigen to the developing immune system. Primary oral exposure of antigens allowing for presentation via a well‐developed mucosal immune system, rather than through a disrupted skin epidermal barrier, is essential to prevent FA. In this review, we present the data supporting the necessity of (1) an intact epidermal barrier to prevent epicutaneous antigen presentation, (2) the presence of specific commensal bacteria to maintain an intact mucosal immune system and (3) maternal/infant diet diversity, including vitamins and minerals, and appropriately timed allergenic food introduction to prevent FA. [ABSTRACT FROM AUTHOR]

Ovalbumin (OVA) is a model antigen commonly incorporated in smartly designed nanoparticles for delivery into antigen‐presenting cells (APC), aiming to investigate the immune activity and therapeutic efficacy of nanoparticles that contain immunoregulatory compounds. However, the immunoresponse observed in nano‐immunotherapy may unexpectedly arise from endotoxin impurity of OVA in the nanoparticles. Literature review shows that most researchers did not notice the importance of endotoxin‐free OVA when used in nano‐immunotherapy studies. Concentration at as low as 5 μg/ml OVA from Sigma‐Aldrich (contains 0.625 ng/ml endotoxin) was able to activate APC such as dendritic cells and macrophages. Here, we proposed that the endotoxin impurity in OVA or the finished nanoproducts should be determined by both Limulus Amebocyte Lysate (LAL) and cell‐based assay, to ensure the endotoxin‐free quality of the nanoparticles. The endotoxin in OVA can be removed by endotoxin removal column and phase separation methods and endotoxin‐free OVA can be purchased. This perspective alerts the researchers of endotoxin impurity of OVA that may transfer into the finished nanoparticles and introduce an unfavorable immunoregulatory function with false‐positive results. OVA with minimal endotoxin level should be used in nano‐immunotherapy studies to accurately reflect the true effects of nanoparticles on the immune system. This article is categorized under:Toxicology and Regulatory Issues in Nanomedicine > Toxicology of NanomaterialsNanotechnology Approaches to Biology > Nanoscale Systems in Biology [ABSTRACT FROM AUTHOR]

The "traditional" vaccines generally do not induce human cells to produce viral proteins, and thus, human cells do not expose viral antigens deriving from their proteosynthetic activity. On the contrary, the genetic vaccines against COVID-19 induce human cells to produce the spike protein, relying intrinsically to an autoimmune reaction, extended to all the cells that intake the genetic material and start the protein synthesis. Circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine antigen detected in the plasma of mRNA-1273 vaccine recipients. [Extracted from the article]

The persistence of Helicobacter pylori in the human gastric mucosa implies that the immune response fails to clear the infection. We found that H. pylori compromises the antigen presentation ability of macrophages, because of the decline of the presenting molecules HLA‐II. Here, we reveal that the main bacterial factor responsible for this effect is ADP‐heptose, an intermediate metabolite in the biosynthetic pathway of lipopolysaccharide (LPS) that elicits a pro‐inflammatory response in gastric epithelial cells. In macrophages, it upregulates the expression of miR146b which, in turn, would downmodulate CIITA, the master regulator for HLA‐II genes. Hence, H. pylori, utilizing ADP‐heptose, exploits a specific arm of macrophage response to establish its survival niche in the face of the immune defense elicited in the gastric mucosa. [ABSTRACT FROM AUTHOR]

CD4 T cells are critical for generating protective immune responses to infection with influenza virus. Although most CD4 T cells react with peptides from extracellular sources, many react with peptides from viral particles synthesized inside cells; however, the pathways employed for processing the latter antigens remain uncertain. Deng et al. provide evidence for a role of autophagy, a cellular self‐eating process, in this unconventional antigen processing route, with potential implications for the development of influenza virus vaccines. [ABSTRACT FROM AUTHOR]

Upon infection, mycobacteria, such as Mycobacterium tuberculosis (Mtb) and nontuberculous mycobacteria (NTM), are recognized by host innate immune cells, triggering a series of intracellular processes that promote mycobacterial killing. Mycobacteria, however, have developed multiple counter‐strategies to persist and survive inside host cells. By manipulating host effector mechanisms, including phagosome maturation, vacuolar escape, autophagy, antigen presentation, and metabolic pathways, pathogenic mycobacteria are able to establish long‐lasting infection. Counteracting these mycobacteria‐induced host modifying mechanisms can be accomplished by host‐directed therapeutic (HDT) strategies. HDTs offer several major advantages compared to conventional antibiotics: (a) HDTs can be effective against both drug‐resistant and drug‐susceptible bacteria, as well as potentially dormant mycobacteria; (b) HDTs are less likely to induce bacterial drug resistance; and (c) HDTs could synergize with, or shorten antibiotic treatment by targeting different pathways. In this review, we will explore host‐pathogen interactions that have been identified for Mtb for which potential HDTs impacting both innate and adaptive immunity are available, and outline those worthy of future research. We will also discuss possibilities to target NTM infection by HDT, although current knowledge regarding host‐pathogen interactions for NTM is limited compared to Mtb. Finally, we speculate that combinatorial HDT strategies can potentially synergize to achieve optimal mycobacterial host immune control. [ABSTRACT FROM AUTHOR]

Summary As a commentary on a recently published paper in Immunology, this article summaries the principle of norovirus P particle as a promising vaccine against noroviruses. It emphasizes the importance of P particle formation in the immune enhancement of the vaccine and methods for production/verification of high quality P particles which may be easily neglected by researchers. [ABSTRACT FROM AUTHOR]

Objective: Age‐associated decreases in immune functions are precipitated by a variety of mechanisms and affect nearly every immune cell subset. In myeloid cells, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we described an aging effect on several functions in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide. We hypothesized that circulating factors altered by the aging process underly these changes. Growth differentiation factor‐15 (GDF‐15) is a distant member of the transforming growth factor‐β superfamily that has known anti‐inflammatory effects in macrophages and has been shown to be highly differentially expressed during aging. Methods: We used biobanked plasma samples to assay circulating GDF‐15 levels in subjects from our previous studies and examined correlations between GDF‐15 and monocyte function. Results: Monocyte interleukin‐6 production due to lipopolysaccharide stimulation was negatively correlated to plasma GDF‐15. Additionally, GDF‐15 was positively correlated to circulating CD16 + monocyte proportions and negatively correlated to monocyte mitochondrial respiratory capacity. Conclusions: These results suggest that GDF‐15 is a potential circulating factor affecting a variety of monocyte functions and promoting monocyte immunosenescence and thus may be an attractive candidate for therapeutic intervention to ameliorate this. [ABSTRACT FROM AUTHOR]

Summary: Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen‐derived peptides to CD4+ T lymphocytes. At the molecular level, they are constituted by α/β‐heterodimers on the surface of professional antigen‐presenting cells. Here, we report that the acceptor variant (rs8084) in the HLA‐DRA gene mediates the transcription of an alternative version of the α‐chain lacking 25 amino acids in its extracellular domain. Molecular dynamics simulations suggest this isoform undergoes structural refolding which in turn affects its stability and cellular trafficking. The short HLA‐DRA isoform cannot reach the cell surface, although it is still able to bind the corresponding β‐chain. Conversely, it remains entrapped within the endoplasmic reticulum where it is targeted for degradation. Furthermore, we demonstrate that the short isoform can be transported to the cell membrane via interactions with the peptide‐binding site of canonical HLA heterodimers. Altogether, our findings indicate that short HLA‐DRA functions as a novel intact antigen for class II HLA molecules. [ABSTRACT FROM AUTHOR]

The identification of individuals with null alleles enables studying how the loss of gene function affects infection. We previously described a non‐functional variant in SIGLEC1, which encodes the myeloid‐cell receptor Siglec‐1/CD169 implicated in HIV‐1 cell‐to‐cell transmission. Here we report a significant association between the SIGLEC1 null variant and extrapulmonary dissemination of Mycobacterium tuberculosis (Mtb) in two clinical cohorts comprising 6,256 individuals. Local spread of bacteria within the lung is apparent in Mtb‐infected Siglec‐1 knockout mice which, despite having similar bacterial load, developed more extensive lesions compared to wild type mice. We find that Siglec‐1 is necessary to induce antigen presentation through extracellular vesicle uptake. We postulate that lack of Siglec‐1 delays the onset of protective immunity against Mtb by limiting antigen exchange via extracellular vesicles, allowing for an early local spread of mycobacteria that increases the risk for extrapulmonary dissemination. [ABSTRACT FROM AUTHOR]

Allergic responses are characterized by the activation of a specific subset of effector CD4+ T cells, the T‐helper type 2 (Th2) cells, that respond to harmless environmental antigens causing inflammation and pathology. Th2 cells are also found in the context of parasite infections, where they can mediate parasite clearance and expulsion, and support tissue repair. The process that leads to the activation of Th2 cells in vivo is incompletely understood: while it has become clear that "conventional" dendritic cells are essential antigen‐presenting cells for the initiation of Th2 immune responses, the molecules that are expressed by dendritic cells exposed to allergens, and the mediators that are produced as a consequence and signal to naïve CD4+ T cells to promote their development into effector Th2, remain to be defined. Here we summarize recent developments in the identification of the dendritic cell subsets involved in Th2 responses, review potential mechanisms proposed to explain the generation of these immune responses, and discuss the direct and indirect signals that condition dendritic cells to drive the development of Th2 responses during allergen or parasite exposure. [ABSTRACT FROM AUTHOR]

Several enveloped viruses, particularly some RNA viruses, have high rates of mutation or replication, which can make them virulent pathogens in humans and other mammals. A proposed treatment could use synthesized proteins to mask pathogenic viral surface proteins to quickly induce an immune attack on specific enveloped viruses by using existing immune cells. One treatment could inject dual‐protein ligand masks into patients' bloodstreams to mask pathogenic surface proteins used to infect mammalian cells. The mammalian immune system already uses an analogous, more complex structure called a pentraxin to neutralize some pathogens by connecting their surface proteins to immune cells. And several types of antiviral peptides have already experimentally demonstrated effectiveness in blocking various viral pathogen infections. These treatments offer advantages, especially for currently untreatable viral pathogens. Furthermore, using dual‐protein ligands and the antigenic memory of some sub‐populations of NK cells would also allow the creation of defacto vaccines based on a host's NK cells, instead of vaccines utilizing CD4 and CD8 α:β T cells, which are limited by the requirement of MHC presentation of the target antigens to α:β T cells. Targeted NK cell vaccines could attack host cells latently or actively infected by intracellular pathogens, even host cells having pathogen downregulated MHC antigen presentation. Eight postulates concerning the effects of pathogen mutation, or change in phenotype from genetic recombination or rearrangement, and replication rates on pathogen vs host dominance are also listed, which should be applicable to viral and non‐viral pathogens. [ABSTRACT FROM AUTHOR]

Platelets are the critical cellularmediators of hemostasis; however,many studies have now suggested that these tiny offspring ofmegakaryocytes can also performmultiple immunelike functions that significantly affect both innate and adaptive immunity. For example, like whole blood, platelets can mediate transfusion-related immunomodulation (TRIM) and it appears that activated platelets are more immunoregulatory that their resting counterparts. In addition, platelets express and secrete a wide variety of critical immune molecules such as TGF-b, CD40/CD40L and MHC class I molecules. This allows platelets to directly influence adaptive immune mechanisms and a variety of immune disease processes. It has also been demonstrated that both platelets and megakaryocytes can process and present both foreign and self-antigens to CD8+ T cells. This manuscript will highlight several non-haemostatic attributes of platelets that deservedly categorize them as integral players in immunity. [ABSTRACT FROM AUTHOR]

Since the neonatal IgG Fc receptor (FcRn) was discovered, it was found to be involved in immunoglobulin recycling and biodistribution, immune complexes routing, antigen presentation, humoral immune response, and cancer immunosurveillance. The latest data show that FcRn plays a part in cancer pathophysiology. In various types of cancers, such as lung and colorectal cancer, FcRn has been described as an early marker for prognosis. Dysregulation of FcRn expression by cancer cells allows them to increase their metabolism, and this process could be exploited for passive targeting of cytotoxic drugs. However, the roles of this receptor depend on whether the studied cell population is the tumor tissue or the infiltrating cells, bringing forward the need for further studies. [ABSTRACT FROM AUTHOR]

Hidradenitis Suppurativa (HS) is a chronic inflammatory dermatosis in which B cells play a prominent but unclear role. Our understanding of the role of B cells in innate and adaptive immunity (including antibody production, antigen presentation and effector functions) is rapidly evolving; and these novel findings require integration into the pathophysiologic model of HS. B cells are transiently present in normal human skin and have functions in the maintenance of innate cutaneous immunity. Recruitment and trafficking of B cells in significant numbers to skin is mediated via B cell‐specific chemokines as well as shared signalling with T‐cells. The evidence suggests that the presence of antibody‐secreting B cells is not sufficient to induce clinical disease and T‐cell interaction is required to induce clinical disease. Such interactions can occur in secondary lymphoid organs adjacent to involved tissue or in tertiary lymphoid organs which develop in response to the HS inflammatory milieu. This milieu directly mediates the types of antibodies produced by B cells, given the role of cytokines in B‐cell class switching. Identified antibodies in HS (IgG, IgM, ASCA, ACPA) currently demonstrate no evidence of pathogenicity, but may be novel biomarkers for disease severity. B cells also have anti‐inflammatory properties through production of IL‐10 and IL‐35 which require experimental validation. Overall, B cells in HS are likely to be involved in amplification of a pre‐existing inflammatory response; but it remains unclear whether they may be directly pathogenic. [ABSTRACT FROM AUTHOR]

The vertebrate immune system uses an impressive arsenal of mechanisms to combat harmful cellular states such as infection. One way is via cells delivering real‐time snapshots of their protein content to the cell surface in the form of short peptides. Specialized immune cells (T cells) sample these peptides and assess whether they are foreign, warranting an action such as destruction of the infected cell. The delivery of peptides to the cell surface is termed antigen processing and presentation, and decades of research have provided unprecedented understanding of this process. However, predicting the capacity for a given peptide to be immunogenic—to elicit a T cell response—has remained both enigmatic and a long sought‐after goal. In the era of big data, a point is being approached where the steps of antigen processing and presentation can be quantified and assessed against peptide immunogenicity in order to build predictive models. This review presents new findings in this area and contemplates challenges ahead. [ABSTRACT FROM AUTHOR]

The CD1 protein family present lipid antigens to the immune system. CD1d has been observed in the CNS of MS patients, yet no studies have quantitatively characterized this expression and related it to inflammatory demyelinative activity in MS plaques. In this study, we set out to localize and quantify the presence of CD1d expression by astrocytes in MS brain tissue lesions. Formalin‐fixed, paraffin‐embedded MS and control brain tissues were examined. Lesions were classified as active, chronic active or chronic silent. Using immunofluorescence, the density of CD1d‐positive cells was determined in active lesions, chronic active lesion edges and chronic active lesion centers. The percentage of CD1d‐positive cells that were GFAP‐positive was also determined in each of these regions. CD1d immunoreactivity was significantly increased in MS compared to control tissue, was significantly more prevalent in areas of active demyelination, and colocalized with GFAP‐positive reactive astrocytes. Increases of CD1d immunoreactivity in the CNS of MS patients being greatest in areas of active demyelination and localized to GFAP‐positive astrocytes lend support to the hypothesis of a lipid‐targeted autoimmune process contributing to the pathogenesis of MS. [ABSTRACT FROM AUTHOR]

Summary: The initiation of T lymphocyte responses within secondary lymphoid organs involves interactions with different subsets of dendritic cells (DCs). Recent studies have revealed the complexity of microanatomical organization within lymphoid organs. Exactly how T cells and DCs locate each other and the type of cellular interactions required for optimal priming of effector and memory T cell responses are beginning to be unraveled. Here we review advances in our understanding of how T cell priming is choreographed during infections, highlight the importance of cell positioning in this process and discuss how a spectrum of cellular interactions shapes T cell activation and differentiation. [ABSTRACT FROM AUTHOR]

Abstract: CD4 T cells play a central role as helper cells in adaptive immunity. Presentation of exogenous antigens in MHC class II by professional antigen‐presenting cells is a crucial step in induction of specific CD4 T cells in adaptive immune responses. For efficient induction of immunity against intracellular threats such as viruses or malignant transformations, antigens from HLA class II‐negative infected or transformed cells need to be transferred to surrounding antigen‐presenting cells to allow efficient priming of naive CD4 T cells. Here we show indirect antigen presentation for a subset of natural HLA class II ligands that are created by genetic variants and demonstrated that (neo)antigens can be transferred between cells by extracellular vesicles. Intercellular transfer by extracellular vesicles was not dependent on the T‐cell epitope, but rather on characteristics of the full‐length protein. This mechanism of (neo)antigen transfer from HLA class II‐negative cells to surrounding antigen‐presenting cells may play a crucial role in induction of anti‐tumor immunity. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T ( MAIT) cells are conserved T cells that express a semi-invariant T-cell receptor (V α7.2 in humans and V α19 in mice). The development of MAIT cells requires the antigen-presenting MHC-related protein 1 ( MR1), as well as commensal bacteria. The mechanisms that regulate the functional expression of MR1 molecules and their loading with bacterial antigen in antigen-presenting cells are largely unknown. We have found that treating B cells with the Toll-like receptor 9 ( TLR9) agonist CpG increases MR1 surface expression. Interestingly, activation of TLR9 by CpG-A (but not CpG-B) enhances MR1 surface expression. This is limited to B cells and not other types of cells such as monocytes, T or natural killer cells. Knocking-down TLR9 expression by short hairpin RNA reduces MR1 surface expression and MR1-mediated bacterial antigen presentation. CpG-A triggers early endosomal TLR9 activation, whereas CpG-B is responsible for late endosomal/lysosomal activation of TLR9. Consistently, blocking endoplasmic reticulum to Golgi protein transport, rather than lysosomal acidification, suppressed MR1 antigen presentation. Overall, our results indicate that early endosomal TLR9 activation is important for MR1-mediated bacterial antigen presentation. [ABSTRACT FROM AUTHOR]

Cross-presentation of internalized antigens by dendritic cells requires efficient delivery of Major Histocompatibility Complex (MHC) class I molecules to peptide-loading compartments. Strong evidence suggests that such loading can occur outside of the endoplasmic reticulum; however, the trafficking pathways and sources of class I molecules involved are poorly understood. Examination of non-professional, non-phagocytic cells has revealed a clathrin-independent, Arf6-dependent recycling pathway likely traveled by internalized optimally loaded (closed) class I molecules. Some closed and all open MHC class I molecules travel to late endosomes to be degraded but might also partly be re-loaded with peptides and recycled. Studies of viral interference revealed pathways in which class I molecules are directed to degradation in lysosomes upon ubiquitination at the surface, or upon AP-1 and HIV-nef-dependent misrouting from the Golgi network to lysosomes. While many observations made in non-professional cells remain to be re-examined in dendritic cells, available evidence suggests that both recycling and neo-synthesized class I molecules can be loaded with cross-presented peptides. Recycling molecules can be recruited to phagosomes triggered by innate signals such as TLR4 ligands, and may therefore specialize in loading with phagocytosed antigens. In contrast, AP-1-dependent accumulation at, or trafficking through, a Golgi compartment of newly synthesized molecules appears to be important for cross-presentation of soluble proteins and possibly of long peptides that are processed in the so-called vacuolar pathway. However, significant cell biological work will be required to confirm this or any other model and to integrate knowledge on MHC class I biochemistry and trafficking in models of CD8+ T-cell priming by dendritic cells. [ABSTRACT FROM AUTHOR]

Over the past 15 years, our understanding of neutrophils has undergone an enormous shift - particularly for those of us who work in adaptive immunology. Secondly, the realization that neutrophil life span may be much longer than previously considered [16], and the observation of neutrophils persisting long term in chronic human inflammatory disease [17], means that we need to examine the importance of these interactions in chronic disease and in acute infections. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. [Extracted from the article]

Over 500 missense F8 mutations have been reported to cause non-severe haemophilia A. Some F8 genotypes appear to confer a higher risk of inhibitor formation than others and individuals with the same F8 genotype may have differing risks of inhibitor formation. We present an in silico strategy demonstrating the heterogeneity of factor VIII (FVIII)-derived antigen presentation whilst identifying patterns of human leucocyte antigen (HLA) peptide binding that might predict future inhibitor risk. A well-validated computational tool, NetMHCII, enabled large-scale comparison of predicted antigen presentation between endogenous, mutated FVIII-derived peptides and wild-type, therapeutic FVIII-derived peptides spanning all F8 missense mutation positions reported to The Haemophilia A Mutation, Structure and Resource Site (HADB). We identify 40 F8 genotypes to be 'low risk' at a 50% inhibitory concentration (IC50)-binding threshold of 300 nmol/l ( P = 0·00005), defined as absence of novel peptide-major histocompatibility complex (MHC) surfaces for all 14 common HLA-DR alleles assessed. Analysing each of the possible 7280 F8 genotype/HLA-DR permutations individually at an IC50 threshold of 300 nmol/l, 65% are predicted to not generate a novel peptide-MHC surface that would be necessary to engage T cell help for subsequent anti-FVIII antibody generation. This study demonstrates the future importance of interpreting F8 genotype in the context of an individual's HLA profile to personalize inhibitor risk prediction. [ABSTRACT FROM AUTHOR]

The rapid differentiation of monocytes into macrophages ( MΦ) and dendritic cells is a pivotal aspect of the innate immune response. Differentiation is triggered following recognition of microbial ligands that activate pattern recognition receptors or directly by pro-inflammatory cytokines. We demonstrate that interleukin-1β ( IL-1β) induces the rapid differentiation of monocytes into CD209+ MΦ, similar to activation via Toll-like receptor 2/1, but with distinct phenotypic and functional characteristics. The IL-1β induced MΦ express higher levels of key markers of phagocytosis, including the Fc-receptors CD16 and CD64, as well as CD36, CD163 and CD206. In addition, IL-1β-induced MΦ exert potent phagocytic activity towards inert particles, oxidized low-density lipoprotein and mycobacteria. Furthermore, IL-1β-induced MΦ express higher levels of HLA- DR and effectively present mycobacterial antigens to T cells. Therefore, the ability of IL-1β to induce monocyte differentiation into MΦ with both phagocytosis and antigen-presenting function is a distinct part of the innate immune response in host defence against microbial infection. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin (IVIg) is successfully used in the treatment of autoimmune diseases involving self-reactive CD8+ T cells. However, its direct influence on the cytotoxic response remains unknown. Using an antigen cross-presentation assay and a mouse model of ovalbumin (OVA) immunization, we showed that IVIg decreases the in vitro activation, proliferation and cytokine secretion of OVA-specific CD8+ T cells (OT-I), as well as the in vivo generation of OVA-specific CD8+ T cells. In addition, IVIg significantly decreases the proportion of perforin- and CD107a-expressing CD8+ T cells, and inhibits the cytotoxic activity of OVA-activated OT-I cells. The interference of IVIg with the CD8+ T-cell response is associated with T-cell receptor blockade, therefore reducing the interaction between effector and target cells. A similar blockade is observed on human CD8+ T cells, suggesting that the observations reported here could apply to the IVIg-mediated improvement of CD8+ T-cell-mediated autoimmune conditions in human patients. [ABSTRACT FROM AUTHOR]

The MHC-related 1 (MR1) protein is a monomorphic, evolutionarily conserved MHC class I-like molecule, which is necessary for the development and functions of mucosal-associated invariant T (MAIT) cells, a new subset of innate-like lymphocytes. Multiple isoforms of the MR1 gene are naturally transcribed, but only the full-length MR1A has been analyzed so far. Using transfected cell lines expressing an alternative spliced transcript, MR1B, characterized by the absence of the α3 extracellular domain, we show that MR1B is transcribed and glycosylated but remains in an immature (endoglycosidase H-sensitive) state. MR1B mostly accumulates in the ER, without interacting with proteins of the peptide-loading complex such as tapasin. Interestingly, it is nevertheless found expressed at the cell surface, independently of β2-microglobulin, in a homodimeric form. MR1B is functional as its overexpression induces MAIT cell activation in vitro in the presence of bacteria. Altogether, these data show that MR1B displays several remarkable features, and probably plays a physiological role complementary to MR1A with respect to MAIT cell development and/or function. [ABSTRACT FROM AUTHOR]

Summary Although a physiological role of heat-shock proteins (HSP) in antigen presentation and immune response activation has not been directly demonstrated, their use as vaccine components is under clinical trial. We have previously demonstrated that the structure of plant-derived HSP70 (pHSP70) can be superimposed to the mammalian homologue and similarly to the mammalian counterpart, pHSP70-polypeptide complexes can activate the immune system. It is here shown that pHSP70 purified from plant tissues transiently expressing the influenza virus nucleoprotein are able to induce both the activation of major histocompatibility complex class I-restricted polyclonal T-cell responses and antibody production in mice of different haplotypes without the need of adjuvant co-delivery. These results indicate that pHSP70 derived from plants producing recombinant antigens may be used to formulate multiepitope vaccines. [ABSTRACT FROM AUTHOR]

Approximately five decades ago, alloimmunization to human leukocyte antigens (HLA) and platelet refractoriness were recognized as potentially serious complications of platelet transfusions. The mechanisms that result in stimulating immunity against blood products are still incompletely understood but are related to both the composition of the donor product transfused and the immune status of the recipient. Based on murine studies of platelet immunity, platelets are inherently immunogenic and there are at least two independent levels of immunoregulation against platelet transfusions. The first level resides within the recipient and is related to antigen processing/presentation events and CD8+ T cell-mediated immunosuppression. The second level relates to the donor product and includes donor antigen presenting cells (APC) levels as well as age-induced changes in donor APC and/or platelets. Implementation of pre-storage leukoreduction of cellular blood components led to a marked reduction in platelet alloimmunization and its dreaded complication, platelet refractoriness. Platelet refractoriness is usually managed by transfusion of matched platelets, selected according to one of the many published methods. It is unclear which of these methods is superior, and given the difficulty of obtaining a perfectly matched product, perhaps the most logical approach is to use a combination of selection strategies. This review discusses the various aspects of platelet alloimmunization and the clinical consequences that may result. It highlights how animal studies have shed light on the immune mechanisms responsible for allogeneic platelet immunity and immunomodulation and reviews relevant literature on clinical and laboratory manifestations of immune platelet refractoriness. [ABSTRACT FROM AUTHOR]

Background and Objectives Albumin is the most abundant protein in plasma and is considered to be immunologically inert. However, we recently observed that therapeutichuman albumin preparations, used as protein control in studies involving high doses of IVIg, modulated the MHC II-restricted activation of antigen-specific T cells. In the present work, we characterized this effect in more details. Materials and Methods An in vitro antigen presentation assay using mouse cells was used to evaluate the effect of therapeutic human albumin preparations on the activation of ovalbumin-specific T cells. Flow cytometry and quantitative real-time PCR were used to monitor the expression of genes involved in this process. Results Therapeutic human albumin preparations increased T cell activation in a dose-dependent manner. The effect was explained by an increase in the expression of MHC II and of two other genes (CIITA and H2-M) involved in antigen presentation by murine monocytic cells. Similarly, the expression of HLA-DR on the surface of human monocytic cells was increased following incubation with therapeutic human albumin preparations. Conclusion Altogether, these results reveal a possible physiological role of albumin in immunological processes, leading to an increased ability of antigen presenting cells to trigger T cell activation. This immunomodulatory effect needs to be considered, at least in studies in which albumin is used as a presumably inert control protein. [ABSTRACT FROM AUTHOR]