Search

Observational studies suggested that immune system disorder is associated with depression. However, the causal association has not been fully elucidated. Thus, we aim to assess the causality of the associations of immune cell profiles with risk of depression through Mendelian randomization analysis. We extracted genetic variances of immune cell traits from a large publicly available genome-wide association study (GWAS) involving 3757 participants and depression from a GWAS containing 246,363 cases and 561,190 controls of European ancestry. Inverse variance weighting (IVW) was performed as the MR primary analysis. Simultaneously apply MR-Egger and weighted median as supplementary enhancements to the final result. We further performed heterogeneity and horizontal pleiotropy test to validate the main MR results. Five immunophenotypes were identified to be significantly associated with depression risk: CD27 on IgD − CD38 dim B cell (OR = 1.019, 95 % CI = 1.010–1.028, P = 1.24 × 10−5), CD45RA − CD4 + T cell Absolute Count (OR = 0.974, 95 % CI = 0.962–0.986, P = 3.88 × 10−5), CD40 on CD14 − CD16 + monocyte (OR = 0.987, 95 % CI = 0.981–0.993, P = 2.1 × 10−4), CD27 on switched memory B cell (OR = 1.015, 95 % CI = 1.006–1.023, P = 2.6 × 10−4), CD27 on IgD − CD38 − B cell (OR = 1.017, 95 % CI = 1.008–1.027, P = 3.1 × 10−4). Our findings shed light on the intricate interaction pattern between the immune system and depression, offering a novel direction for researchers to investigate the underlying biological mechanisms of depression. • This study aims to explore the causality of the associations of immune cell profiles with risk of depression through Mendelian randomization analysis. • Five immunophenotypes were identified to be significantly associated with depression risk: CD27 on IgD- CD38dim B cell, CD45RA- CD4+ T cell Absolute Count, CD40 on CD14- CD16+ monocyte, CD27 on switched memory B cell, CD27 on IgD- CD38- B cell. • Our findings shed light on the intricate interaction pattern between the immune cells and depression, offering a novel direction for researchers to investigate the underlying biological mechanisms of depression. [ABSTRACT FROM AUTHOR]

• Higher doses of Ad26.COV2.S tended to be more immunogenic and more reactogenic than lower doses. • VNAs and S-bAbs persisted for at least 6 months after just 1 dose of Ad26.COV2.S 5 × 1010 vp. • Immune responses increased when the time interval between dose 1 and dose 2 increased. • Rapid, marked responses in all groups after vaccine antigen exposure indicate immune memory. • Durable immune responses were observed in all groups up to at least 6 months post vaccine antigen exposure. A single dose of Ad26.COV2.S is well-tolerated and effective in preventing moderate-to-severe disease outcomes due to COVID-19. We evaluated the impact of dose level, number of doses, and dose interval on immunogenicity, reactogenicity, and safety of Ad26.COV2.S in adults. Anamnestic responses were also explored. This randomised, double-blind, placebo-controlled, Phase 2a study was conducted in adults aged 18–55 years and ≥ 65 years (NCT04535453). Four dose levels (1.25 × 1010, 2.5 × 1010, 5 × 1010, and 1 × 1011 viral particles [vp], single and 2-dose schedules, and dose intervals of 56 and 84 days, were assessed. Four or 6 months post-primary vaccination, Ad26.COV2.S 1.25 × 1010 vp was given to evaluate anamnestic responses. Humoral and cell-mediated immune responses were measured. Reactogenicity and safety were assessed in all participants. All Ad26.COV2.S schedules induced humoral responses with evidence of a dose response relationship. A single dose of Ad26.COV2.S (5 × 1010 vp) induced antibody and cellular immune responses that persisted for up to at least 6 months. In the 2-dose regimens, antibody responses were higher than 1-dose regimens at comparable dose levels, and the magnitude of the immune response increased when the interval between doses was increased (84 days vs 56 days). Rapid, marked immune responses were observed in all groups after vaccine antigen exposure indicating immune memory. Durable immune responses were observed in all groups for up to at least 6 months post-antigen exposure. Strong and consistent correlations between neutralising and binding antibodies were observed CD4 + and CD8 + T cell responses were similar after all regimens. Reactogenicity within 7 days post-vaccination tended to be dose-related. The study supports the primary, single dose schedule with Ad26.COV2.S at 5 × 1010 vp and homologous booster vaccination after a 6 month interval. Rapid and marked responses to vaccine antigen exposure indicate induction of immune memory by 1- and 2-dose primary vaccination. [ABSTRACT FROM AUTHOR]

Sarcoidosis results from a combination of genetic variants and environmental factors but its exact cause remains unknown. Evidence highlights a major role of monocytes as important drivers of sarcoidosis immunopathogenesis. The emerging concept of trained immunity opens new perspectives for the comprehension of sarcoidosis pathology, with a particular presumed role played by immune metabolism and epigenetics. We posit that maladaptive innate immune training may drive sarcoidosis pathogenesis. The confirmation of maladaptive innate immune training in sarcoidosis might allow the development of new candidate therapeutic strategies. The pathogenesis of sarcoidosis, an immune-mediated granulomatous disease, has long remained elusive. Recent discoveries on trained immunity might help decipher immunological mechanisms underlying the disease which in turn may inform novel putative treatment options. Sarcoidosis is a chronic immune disease of unknown origin for which we still lack an immunological framework unifying causal agents, host factors, and natural history of disease. Here, we discuss the initial triggers of disease, and how myeloid cells drive granuloma formation and contribute to immunopathogenesis. We highlight recent advances in our understanding of innate immune memory and propose the hypothesis that maladaptive innate immune training connects previous environmental exposure to granuloma maintenance and expansion. Lastly, we consider how this hypothesis may open novel therapeutic avenues, while corticosteroids remain the front-line treatment. [ABSTRACT FROM AUTHOR]

The CliniMACS Prodigy closed system is widely used for the manufacturing of chimeric antigen receptor T cells (CAR-T cells). Our study presents an extensive immunophenotypic and functional characterization and comparison of the properties of anti-CD19 CAR-T cell products obtained during long (11 days) and short (7 days) manufacturing cycles using the CliniMACS Prodigy system, as well as cell products manufactured from different donor sources of T lymphocytes: from patients, from patients who underwent HSCT, and from haploidentical donors. We also present the possibility of assessing the efficiency of transduction by an indirect method. Seventy-six CD19 CAR-T cell products were manufactured using the CliniMACS Prodigy automated system. Immunophenotypic properties, markers of cell activation and exhaustion, antitumor, anti-CD19 specific activity in vitro of the manufactured cell products were evaluated. As an indirect method for assessing the efficiency of transduction, we used the method of functional assessment of cytokine secretion and expression of the CD107a marker after incubation of CAR-T cells with tumor targets. The CliniMACS Prodigy platform can produce a product of CD19 CAR-T cells with sufficient cell expansion (4.6 × 109 cells—median for long process [LP] and 1.6 × 109—for short process [SP]), transduction efficiency (43.5%—median for LP and 41.0%—for SP), represented mainly by T central memory cell population, with low expression of exhaustion markers, and with high specific antitumor activity in vitro. We did not find significant differences in the properties of the products obtained during the 7- and 11-day manufacturing cycles, which is in favor of reducing the duration of production to 7 days, which may accelerate CAR-T therapy. We have shown that donor sources for CAR-T manufacturing do not significantly affect the composition and functional properties of the cell product. This study demonstrates the possibility of using the CliniMACS Prodigy system with a shortened 7-day production cycle to produce sufficient amount of functional CAR-T cells. CAR transduction efficiency can be measured indirectly via functional assays. [ABSTRACT FROM AUTHOR]

Vaccination is essential for preventing and controlling infectious diseases, along with reducing mortality. Developing safe and versatile adjuvants to enhance humoral and cellular immune responses to vaccines remains a key challenge in vaccine development. Here, we designed hierarchical mesoporous MOF-801 (HM801) using a Cocamidopropyl betaine (CAPB) and a Pluronics F127 in an aqueous phase system. Meanwhile, we synthesized a novel SARS-CoV-2 nanovaccine (R@M@HM801) with a high loading capacity for both the STING agonist (MSA-2) and the Delta receptor binding domain (Delta-RBD) antigen. R@M@HM801 enhanced MSA-2 and RBD utilization and effectively co-delivered MSA-2 and RBD antigens to antigen-presenting cells in the draining lymph nodes, thereby promoting the activation of both T and B cells. Lymphocyte single-cell analysis showed that R@M@HM801 stimulated robust CD11b+CD4+ T cells, CXCR5+CD4+ T follicular helper (T fh), and durable CD4+CD44+CD62L−, CD8+CD44+CD62L− effector memory T cell (T EM) immune responses, and promoted the proliferative activation of CD26+ B cells in vivo. Meanwhile, R@M@HM801 induced stronger specific antibodies and neutralization of pseudovirus against Delta compared to the RBD + MAS-2 and RBD + MAS-2 + Alum vaccines. Our study demonstrated the efficacy of a hierarchical mesoporous HM801 and its potential immune activation mechanism in enhancing adaptive immune responses against viruses and other diseases. [Display omitted] • HM801 efficiently co-delivers MSA-2 and RBD antigens to DCs in lymph nodes, promotes maturation of DCs, and induces humoral and cellular immunity. • Single-cell analysis indicates a potential synergistic mechanism among DC cells, T cells, and B cells. • R@M@HM801 induces stronger specific antibody responses. • Our study provides new insights into the adjuvants based on hierarchical mesoporous MOFs. [ABSTRACT FROM AUTHOR]

[Display omitted] Chemo-immunotherapy, in which chemotherapeutic drugs activate immune system to suppress tumor growth and metastases, has great potential for clinical application. However, insufficient immunogenic cell death and serious side effects caused by tumor multidrug resistance and non-specific drug distribution, as well as inadequate and dysfunctional immune cells, greatly impair the effectiveness of chemo-immunotherapy. Herein, taking advantage of the functional diversity and structural programmability of nucleic acids, a DNA-based bioorthogonal nanoagonist is constructed to initiate and augment immune responses for robust chemo-immunotherapy. Benefiting from polyvalent targeting and template effects of DNA, the tailor-made nanoagonist shows prior bioorthogonal catalytic performance. Chemotherapeutic drug is bioorthogonally synthesized in situ under the catalysis of the nanoagonist, maximizing immunogenic cell death and minimizing systemic toxicity. The large amount of antigen and damage-associated molecular patterns released from dying tumor cells effectively initiates antitumor immunity. Meanwhile, the integration of high density of immunologic adjuvant can more effectively stimulate immune cells. The combination of bioorthogonal catalytic drug synthesis and immunostimulatory effect of DNA adjuvant not only destroys local primary tumors, but also eliminates distal metastasis. Moreover, the nanoagonist triggered the immune memory effect. The work extends the application of bioorthogonal chemistry to immunotherapy and provides a safe and powerful strategy for cancer chemo-immunotherapy. [ABSTRACT FROM AUTHOR]

Core homeostatic and activation signatures have been defined for mammalian microglia in new transcriptomic and functional studies. Microglia respond to changes in the homeostatic environment using similar signal modules during neurodevelopment as those seen for different types of neurodegenerative diseases. Danger signals present in neurodevelopment often mirror those encountered by microglia in neurodegenerative conditions. The mechanisms microglia utilize to sense their environment (sensome) are akin to those defined in other tissue-resident macrophage populations. Convergent versus divergent responses among microglia might reflect differences in expressed/engaged receptors, microenvironment, and immunological memory. Interest in microglia is surging with increased recognition that these cells significantly influence brain function and neurologic disease pathogenesis. When aiming to treat different neurologic diseases, a fine-tuned approach to enhance the protective abilities of microglia while dampening destructive off-target effects is an attractive and compelling one. Understanding the receptors, downstream signaling, and functional outputs that microglia employ throughout a healthy lifespan and in diverse disease states (their toolkit) is essential for harnessing their therapeutic potential. After decades of being overlooked, a recent wave of studies have explored the roles of microglia in brain health and disease. Microglia perform important physiological functions to set up and maintain proper neural network functions, as well as orchestrate responses to toxic stimuli to limit harm. Many microglial transcriptional programs, extracellular sensing molecules, and functional outputs are seen throughout life. A stark example is the similarity of microglial responses to stressors during neurodevelopment and neurodegeneration. The same themes often match that of other tissue-resident macrophages, presenting an opportunity to apply known concepts as therapeutics develop. We argue that microglial signaling during development and neurologic disease overlap with one another and with other tissue-resident macrophage pathways, in part due to similar sensed stimuli and a conserved sensome of receptors and signaling molecules, akin to a toolkit. [ABSTRACT FROM AUTHOR]

Vaccines represent one of the most powerful and cost-effective innovations for controlling a wide range of infectious diseases caused by various viruses and bacteria. Unlike mRNA and DNA-based vaccines, subunit vaccines carry no risk of insertional mutagenesis and can be lyophilized for convenient transportation and long-term storage. However, existing adjuvants are often associated with toxic effect and reactogenicity, necessitating expanding the repertoire of adjuvants with better biocompatibility, for instance, designing self-adjuvating polymeric carriers. We herein report a novel subunit vaccine delivery platform constructed via in situ free radical polymerization of C7A (2-(Hexamethyleneimino) ethyl methacrylate) and acrylamide around the surface of individual protein antigens. Using ovalbumin (OVA) as a model antigen, we observed substantial increases in both diameter (∼70 nm) and surface potential (−1.18 mV) following encapsulation, referred to as n(OVA)C7A. C7A's ultra pH sensitivity with a transition pH around 6.9 allows for rapid protonation in acidic environments. This property facilitates crucial processes such as endosomal escape and major histocompatibility complex (MHC)-I-mediated antigen presentation, culminating in the substantial CD8+ T cell activation. Additionally, compared to OVA nanocapsules without the C7A components and native OVA without modifications, we observed heightened B cell activation within the germinal center, along with remarkable increases in serum antibody and cytokine production. It's important to note that mounting evidence suggests that adjuvant effects, particularly its targeted stimulation of type I interferons (IFNs), can contribute to advantageous adaptive immune responses. Beyond its exceptional potency, the nanovaccine also demonstrated robust formation of immune memory and exhibited a favorable biosafety profile. These findings collectively underscore the promising potential of our nanovaccine in the realm of immunotherapy and vaccine development. Schematic illustration of the preparation process of bioresponsive nanovaccine (n(OVA)C7A) and the induction of adaptive immune responses. Firstly, pH-responsive 2-(hexamethyleneimino) ethyl methacrylate (C7A-MA) and acrylamide (AAm), along with the biodegradable crosslinker N,N′ -Bis(acryloyl) cystamine, were initially enriched on the surface of OVA through non-covalent bonding. Secondly, after subcutaneous injection of mice at the hind footpad, the developed nanovaccine n(OVA)C7A rapidly were accumulated in lymph nodes and promoted the uptake and maturation of lymph node-resident DCs, triggering a series of adaptive humoral and cellular immune responses. [Display omitted] • Vaccine carriers with dispersed C7A groups form polymer networks encompassing the antigen. • C7A's ultra pH sensitivity facilitates endosomal escape and MHC-I-mediated antigen presentation. • Self-adjuvanting polymeric nanovaccines (n(OVA)C7A) foster substantial cytotoxic T cell activation and IFNs production. • This nanoplatform has the potential to deliver a variety of protein antigens against viral infections and cancer. [ABSTRACT FROM AUTHOR]

Immunotherapy is currently a standard of care in the treatment of many malignancies. However, predictable side effects caused by systemic administration of highly immunostimulatory molecules have been a serious concern within this field. Intratumoural expression or silencing of immunogenic and immunoinhibitory molecules using nucleic acid-based approaches such as plasmid DNA (pDNA) and small interfering RNA (siRNA), respectively, could represent a next generation of cancer immunotherapy. Here, we employed lipid nanoparticles (LNPs) to deliver either non-specific pDNA and siRNA, or constructs targeting two prominent immunotherapeutic targets OX40L and indoleamine 2,3-dioxygenase-1 (IDO), to tumours in vivo. In the B16F10 mouse model, intratumoural delivery of LNP-formulated non-specific pDNA and siRNA led to strong local immune activation and tumour growth inhibition even at low doses due to the pDNA immunogenic nature. Replacement of these non-specific constructs by pOX40L and siIDO resulted in more prominent immune activation as evidenced by increased immune cell infiltration in tumours and tumour-draining lymph nodes. Consistently, pOX40L alone or in combination with siIDO could prolong overall survival, resulting in complete tumour regression and the formation of immunological memory in tumour rechallenge models. Our results suggest that intratumoural administration of LNP-formulated pDNA and siRNA offers a promising approach for cancer immunotherapy. [Display omitted] • I.t injection of non-specific LNPs led to strong local immune activation and tumour growth inhibition even at low doses. • pOX40L + siIDO LNPs induced more prominent immune activation than non-specific pDNA+siRNA LNPs. • pOX40L or pOX40L + siIDO LNPs prolonged survival, led to complete tumour regression and immunological memory generation. • I.t injection of LNP-formulated pDNA and siRNA offers a promising approach for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Immune effector cells in patients with multiple myeloma (MM) are at the forefront of many immunotherapy treatments, and several methods have been developed to fully utilise the antitumour potential of immune cells. T and NK cell-derived immune lymphocytes both expressed activating NK receptor group 2 member D(NKG2D). This receptor can identify eight distinct NKG2D ligands (NKG2DL), including major histocompatibility complex class I (MHC) chain-related protein A and B (MICA and MICB). Their binding to NKG2D triggers effector roles in T and NK cells. NKG2DL is polymorphic in MM cells. The decreased expression of NKG2DL on the cell surface is explained by multiple mechanisms of tumour immune escape. In this review, we discuss the mechanisms by which the NKG2D/NKG2DL axis regulates immune effector cells and strategies for promoting NKG2DL expression and inhibiting its release in multiple myeloma and propose therapeutic strategies that increase the expression of NKG2DL in MM cells while enhancing the activation and killing function of NK cells. [Display omitted] • NKG2D/NKG2DL is pivotal in MM immunotherapy, aiding immune cell-MM cell interaction. • NKG2D may promote the development of CD8+ memory T cells. • Soluble NKG2DL (sNKG2DL) shedding hampers NK cell activation, contributing to MM immune escape. • Therapeutic strategy: Increase NKG2DL expression in MM cells, enhance NK cell activation, and killing function. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults with a 5-year survival rate of 30.5%. These poor patient outcomes are attributed to tumor relapse, stemming from ineffective innate immune activation, T cell tolerance, and a lack of immunological memory. Thus, new strategies are needed to activate innate and effector immune cells and evoke long-term immunity against AML. One approach to address these issues is through Stimulator of Interferon Genes (STING) pathway activation, which produces Type I Interferons (Type I IFN) critical for innate and adaptive immune activation. Here, we report that systemic immunotherapy with a lipid-based nanoparticle platform (CMP) carrying Mn2+ and STING agonist c -di-AMP (CDA) exhibited robust anti-tumor efficacy in a mouse model of disseminated AML. Moreover, CMP immunotherapy combined with immune checkpoint blockade against cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) elicited robust innate and adaptive immune activation with enhanced cytotoxic potential against AML, leading to extended animal survival after re-challenge with AML. Overall, this CMP combination immunotherapy may be a promising approach against AML and other disseminated cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Designing effective nanomedicines to induce durable anti-tumor immunity represents a promising strategy for improving moderate immune stimulation. In this study, we engineered a multifunctional nanoreactor (named SCGFP NPs) for remodeling the tumor microenvironment (TME) to improve the therapeutic efficacy of immunotherapy. The core of SCGFP NPs consists of CaCO 3 loaded with SN38, prepared by the gas diffusion method, and coated with a significant amount of gallic acid-Fe3+-PEG coordination polymer on the surface. In the acidic TME, SCGFP NPs explosively release exogenous Ca2+ and SN38. The SN38-induced intracellular Ca2+ accumulation and exogenous Ca2+ synergistically trigger immunogenic cell death (ICD) through sustained Ca2+ overload. The ablation of tumors with high-intensity photothermal therapy (PTT) by near-infrared (NIR) irradiation of GA-Fe3+ induces tumor cell necrosis, further enhancing ICD activation. Additionally, SN38 upregulates PD-L1, amplifying tumor responsiveness to immune checkpoint inhibitors (ICIs). This study indicates that SCGFP NPs, through the integration of a trimodal therapeutic strategy, hold enormous potential for various types of tumor immunotherapy through distinct mechanisms or synergistic effects. The multifunctional CaCO 3 -bioreactor SCGFP NPs for tumor immunotherapy elicited substantial anti-tumor immune responses and immunological memory through synergistically driving Ca2+ overload, inducing immunogenic cell death, as well as enhancing the responsiveness to immune checkpoint inhibitors. [Display omitted] [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae is an important human pathogen. Currently used conjugate vaccines are effective against invasive disease, but protection is restricted to serotypes included in the formulation, leading to serotype replacement. Furthermore, protection against non-invasive disease is reported to be considerably lower. The development of a serotype-independent vaccine is thus important and Pneumococcal surface protein A (PspA) is a promising vaccine candidate. PspA shows some diversity and can be classified in 6 clades and 3 families, with families 1 and 2 being the most frequent in clinical isolates. The ideal vaccine should thus induce protection against the two most common families of PspA. The aim of this work was to develop a liposome-based vaccine containing PspAs from family 1 and 2 and to characterize its immune response. Liposomes (LP) composed of dipalmitoylphosphatidylcholine (DPPC) and 3β-[N-(N′, N ′-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol) with or without α-galactosylceramide (α-GalCer) were produced by microfluidics, encapsulating PspA from clade 1 (PspA1, family 1) and/or clade 4 (PspA4Pro, family 2) followed by spray-drying with trehalose to form nanocomposite microparticles carriers (NCMP). LP/NCMPs showed good stability and preservation of protein activity. LP/NCMPs containing PspA1 and/or PspA4Pro were used for immunization of mice targeting the lungs. High serum IgG antibody titers against both PspA1 and PspA4Pro were detected in animals immunized with LP/NCMPs containing α-GalCer, with a balance of IgG1 and IgG2a titers. IgG in sera from immunized mice bound to pneumococcal strains from different serotypes and expressing different PspA clades, indicating broad recognition. Mucosal IgG and IgA were also detected. Importantly, immunization with LP/NCMPs induced full protection against strains expressing PspAs from family 1 and 2. Furthermore, CD4+ resident memory T cells were detected in the lungs of the immunized animals that survived the challenge. [Display omitted] • Liposomes (LP) composed of DPPC:DC-Chol encapsulated PspA1 and PspA4Pro; • Spray-drying with trehalose formed nanocomposite microparticle carriers (LP/NCMP); • Incorporating α-GalCer to LPs enhanced immune response in lung immunization of mice; • Combining LP/NCMPs with PspA1 and PspA4Pro led to broad recognition of strains; • Combining LP/NCMPs with PspA1 and PspA4Pro induced protection against pneumococci. [ABSTRACT FROM AUTHOR]

CD4 T cells shape the neutralizing antibody (nAb) response and facilitate viral clearance in various infections. Knowledge of their phenotype, specificity and dynamics in hepatitis E virus (HEV) infection is limited. HEV is enterically transmitted as a naked virus (nHEV) but acquires a host-derived quasi-envelope (eHEV) when budding from cells. While nHEV is composed of the open reading frame (ORF)-2-derived capsid, eHEV particles also contain ORF3-derived proteins. We aimed to longitudinally characterize the HEV-specific CD4 T cells targeting ORF1, 2 and 3 and antibodies against nHEV or eHEV in immunocompetent individuals with acute and resolved HEV infection. HEV-specific CD4 T cells were analyzed by intracellular cytokine staining after stimulation with in silico -predicted ORF1- and ORF2-derived epitopes and overlapping peptides spanning the ORF3 region. Ex vivo multiparametric characterization of capsid-specific CD4 T cells was performed using customized MHC class II tetramers. Total and neutralizing antibodies targeting nHEV or eHEV particles were determined. HEV-specific CD4 T-cell frequencies and antibody titers are highest in individuals with acute infection and decline in a time-dependent process with an antigen hierarchy. HEV-specific CD4 T cells strongly target the ORF2-derived capsid and ORF3-specific CD4 T cells are hardly detectable. NAbs targeting nHEV are found in high titers while eHEV particles are less efficiently neutralized. Capsid-specific CD4 T cells undergo memory formation and stepwise contraction, accompanied by dynamic phenotypical and transcriptional changes over time. The viral capsid is the main target of HEV-specific CD4 T cells and antibodies in acute-resolving infection, correlating with efficient neutralization of nHEV. Capsid-specific immunity rapidly emerges followed by a stepwise contraction several years after infection. The interplay of CD4 T cells and neutralizing antibody responses is critical in the host defense against viral infections, yet little is known about their characteristics in hepatitis E virus (HEV) infection. We conducted a longitudinal study of immunocompetent individuals with acute and resolved HEV infection to understand the characteristics of HEV-specific CD4 T cells and neutralizing antibodies targeting different viral proteins and particles. We found that HEV-specific CD4 T cells mainly target capsid-derived epitopes. This correlates with efficient neutralization of naked virions while quasi-enveloped particles are less susceptible to neutralization. As individuals with pre-existing liver disease and immunocompromised individuals are at risk for fulminant or chronic courses of HEV infection, these individuals might benefit from the development of vaccination strategies which require a detailed knowledge of the composition and longevity of HEV-specific CD4 T-cell and antibody immunity. [Display omitted] • HEV-specific CD4 T cells target capsid-derived epitopes encoded by ORF2, while ORF3-specific responses are rare. • Neutralizing antibodies target naked virions more efficiently than quasi-enveloped particles. • Capsid-specific CD4 T cells rapidly emerge, undergo memory formation and stepwise contraction years after infection. [ABSTRACT FROM AUTHOR]

The capability of ultrahigh dose rate FLASH radiation therapy to generate the FLASH effect has opened the possibility to enhance the therapeutic index of radiation therapy. The contribution of the immune response has frequently been hypothesized to account for a certain fraction of the antitumor efficacy and tumor kill of FLASH but has yet to be rigorously evaluated. To investigate the immune response as a potentially important mechanism of the antitumor effect of FLASH, various murine tumor models were grafted either subcutaneously or orthotopically into immunocompetent mice or in moderately and severely immunocompromised mice. Mice were locally irradiated with single dose (20 Gy) or hypofractionated regimens (3 × 8 or 2 × 6 Gy) using FLASH (≥2000 Gy/s) and conventional (CONV) dose rates (0.1 Gy/s), with/without anti-CTLA-4. Tumor growth was monitored over time and immune profiling performed. FLASH and CONV 20 Gy were isoeffective in delaying tumor growth in immunocompetent and moderately immunodeficient hosts and increased tumor doubling time to >14 days versus >7 days in control animals. Similar observations were obtained with a hypofractionated scheme, regardless of the microenvironment (subcutaneous flank vs ortho lungs). Interestingly, in profoundly immunocompromised mice, 20 Gy FLASH retained antitumor activity and significantly increased tumor doubling time to >14 days versus >8 days in control animals, suggesting a possible antitumor mechanism independent of the immune response. Analysis of the tumor microenvironment showed similar immune profiles after both irradiation modalities with significant decrease of lymphoid cells by ∼40% and a corresponding increase of myeloid cells. In addition, FLASH and CONV did not increase transforming growth factor-β1 levels in tumors compared with unirradiated control animals. Furthermore, when a complete and long-lasting antitumor response was obtained (>140 days), both modalities of irradiation were able to generate a long-term immunologic memory response. The present results clearly document that the tumor responses across multiple immunocompetent and immunodeficient mouse models are largely dose rate independent and simultaneously contradict a major role of the immune response in the antitumor efficacy of FLASH. Therefore, our study indicates that FLASH is as potent as CONV in modulating antitumor immune response and can be used as an immunomodulatory agent. [ABSTRACT FROM AUTHOR]

Esthesioneuroblastoma (ENB) is a rare cancer deriving from the olfactory mucosa. Among the basal or neural genomic subtypes, the basal subtype is associated with poorer survival, poor differentiation, and higher levels of tumor-infiltrating immune cells (TIICs). The immune microenvironment of these ENB subtypes remains unclear. We used an established machine learning algorithm on ENB transcriptomic profiles. The authors characterized 22 immune cell populations using the CIBERSORTx deconvolutional machine learning pipeline on RNA sequencing data from 18 ENB cases. The characterization aimed to elucidate differences in relative proportions and populations of TIICs between basal and neural ENB. No differences in age, Hyams, Dulguerov, IDH2 mutation, or PD-L1 expression were seen between basal and neural subtypes of ENB (P > 0.05). Also, no difference in median overall survival was appreciated (52.0 ± 13.1 months vs. 50.0 ± 43.2 months, P = 0.5). As a cohort, M2 macrophages were the most abundant subpopulation (14%) followed by naïve B cells (13%) and CD4 memory resting T cells (12%). No gross differences in CD20, CD4, or CD8 cells/mm2 were apparent on gross histology (P > 0.05). However, further analysis showed that activated CD4 memory T cells were significantly increased in the basal ENBs, whereas resting dendritic cells were increased in the neural ENB subtype. The TIIC profiles alone could not differentiate between basal and neural ENB, but did suggest immunoprofile differences. Basal and neural subtypes display distinct TIIC involvement, which may impact their difference in outcome. These findings provide the framework for further investigation in novel immunomodulation strategies for ENB. [ABSTRACT FROM AUTHOR]

Cancer presents a high mortality rate due to ineffective treatments and tumour relapse with progression. Cancer vaccines hold tremendous potential due to their capability to eradicate tumour and prevent relapse. In this study, we present a novel glycovaccine for precise targeting and immunotherapy of aggressive solid tumours that overexpress CD44 standard isoform (CD44s) carrying immature Tn and sialyl-Tn (sTn) O -glycans. We describe an enzymatic method and an enrichment strategy to generate libraries of well-characterized cancer-specific CD44s-Tn and/or sTn glycoproteoforms, which mimic the heterogeneity found in tumours. We conjugated CD44-Tn-derived glycopeptides with carrier proteins making them more immunogenic, with further demonstration of the importance of this conjugation to overcome the glycopeptides' intrinsic toxicity. We have optimized the glycopeptide-protein maleimide-thiol conjugation chemistry to avoid undesirable cross-linking between carrier proteins and CD44s glycopeptides. The resulting glycovaccines candidates were well-tolerated in vivo , inducing both humoral and cellular immunity, including immunological memory. The generated antibodies exhibited specific reactivity against synthetic CD44s-Tn glycopeptides, CD44s-Tn glycoengineered cells, and human tumours. In summary, we present a promising prototype of a cancer glycovaccine for future therapeutical pre-clinical efficacy validation. [Display omitted] [ABSTRACT FROM AUTHOR]

Pyroptosis, mediated by gasdermin proteins, has shown excellent efficacy in facilitating cancer immunotherapy. The strategies commonly used to induce pyroptosis suffer from a lack of tissue specificity, resulting in the nonselective activation of pyroptosis and consequent systemic toxicity. Moreover, pyroptosis activation usually depends on caspase, which can induce inflammation and metabolic disorders. In this study, inspired by the tumor-specific expression of SRY-box transcription factor 4 (Sox4) and matrix metalloproteinase 2 (MMP2), we constructed a doubly regulated plasmid, pGMD, that expresses a biomimetic gasdermin D (GSDMD) protein to induce the caspase-independent pyroptosis of tumor cells. To deliver pGMD to tumor cells, we used a hyaluronic acid (HA)-shelled calcium carbonate nanoplatform, H-CNP@pGMD, which effectively degrades in the acidic endosomal environment, releasing pGMD into the cytoplasm of tumor cells. Upon the initiation of Sox4, biomimetic GSDMD was expressed and cleaved by MMP2 to induce tumor-cell-specific pyroptosis. H-CNP@pGMD effectively inhibited tumor growth and induced strong immune memory effects, preventing tumor recurrence. We demonstrate that H-CNP@pGMD-induced biomimetic GSDMD expression and tumor-specific pyroptosis provide a novel approach to boost cancer immunotherapy. We designed a tumor-targeting nanoplatform HA-CaCO 3 @pGMD (H-CNP@pGMD) to express sufficient biomimetic gasdermin D (GSDMD) protein to activate tumor-specific pyroptosis to enhanced cancer immunotherapies. [Display omitted] • Current techniques for inducing pyroptosis lack tissue specificity, leading to nonselective activation. • Inspired by the tumor-specific expression of SRY-box transcription factor 4 and matrix metalloproteinase 2, we constructed a doubly regulated plasmid, pGMD. • We designed a tumor-targeting nanoplatform H-CNP@pGMD that expresses a biomimetic gasdermin D protein to induce the caspase-independent pyroptosis of tumor cells to enhance cancer immunotherapies. [ABSTRACT FROM AUTHOR]

• Innate immune memory underlies non-specific effects reported for some vaccines. • Vaccine non-specific effects have always been unknown at the time of licensure. • Non-specific effects if known, may influence benefit-risk ratio of new vaccines. • New approaches are required for early investigation of vaccine non-specific benefits. Immune memory was for a long time thought to be an exclusive feature of the adaptive immune system. Emerging evidence has shown that the innate immune system may exhibit memory which has been termed as trained immunity or innate immune memory. Trained immunity following vaccination may produce non-specific effects leading to reduction in morbidity and mortality from heterologous pathogens. This review looked at trained immunity as a mechanism for vaccine induced non-specific effects, mechanisms underlying trained immunity and known vaccine non-specific effects. A discussion is also made on the implications these vaccine non-specific effects may have on overall risk–benefit ratio evaluation by National Medicines Regulatory Authorities (NMRAs) during licensure of new vaccines. Epigenetic remodeling and "rewiring" of cellular metabolism in the innate immune cells especially monocytes, macrophages, and Natural Killer (NK) cells have been suggested to be the mechanisms underlying trained immunity. Trained immunity in other innate cells has largely remained elusive up to date. Non-specific effects have been extensively documented with Bacille Calmette-Guerin (BCG), measles vaccine and oral polio vaccine but it remains unclear if other vaccines may exhibit similar effects. All known vaccine non-specific effects have come from observations in epidemiological studies conducted post-vaccine licensure and roll out in target populations. It remains to be seen if early identification of non-specific effects especially those with protective benefits during the clinical development of new vaccines may contribute to the overall risk–benefit ratio evaluation during licensure by NMRAs. [ABSTRACT FROM AUTHOR]

The responsiveness/cross-binding of vaccine-induced memory B cells/MBCs to previous and emerging divergent SARS-CoV-2 variants (e.g., Omicron) is understudied. In this longitudinal study subjects receiving two or three doses of monovalent ancestral strain-containing COVID-19 mRNA vaccine were evaluated. In contrast to others, we observed significantly lower frequencies of MBCs reactive to the receptor-binding domain/RBD, the N-terminal domain/NTD, and the S1 of Omicron/BA.1, compared to Wuhan and Delta, even after a 3rd vaccine dose/booster. Our study is a proof of concept that MBC cross-reactivity to variants with greater sequence divergence from the vaccine strain may be overestimated and suggests that these variants may exhibit immune escape with reduced recognition by circulating pre-existing MBCs upon infection. [ABSTRACT FROM AUTHOR]

The field of genetic errors of human immunity has long provided basic and clinical insights elucidating essential immune functions and their molecular guardrails. A synthesis of findings from the ~500 human genetic errors of immunity reveals, on the one hand, essential immune relays governing defenses against infection and, on the other hand, maintenance of immune-tissue homeostasis to limit excessive immunopathology. Recent results suggest an integrated system in which the immune response upon pathogen exposure in the natural environment is determined by the combination of existing rapid defenses available to the host at that point in time. These defenses emerge from effector capacities that can be both general (e.g., intrinsic resistance – anti-viral state and cell death – and phagocyte responses) and/or conferred by previous exposures (e.g., pre-existing immunoglobulin, memory T and B cells with innate-like recall responses). The prevailing model of immune system function generally frames innate, fast, antigen non-specific responses in contrast to adaptive, slower, antigen-specific responses. Insights from human genetic errors of immunity blur these lines and converge on an 'adaptive arsenal' model of essential rapid defenses for most infections in most individuals. They further illuminate key immune regulatory mechanisms that ensure the collateral damage caused by these defenses is sufficiently counteracted to maintain host fitness. Dissecting the genetic basis of human immune disorders using unbiased, forward genetics offers translationally relevant insights into essential immune relays in outbred organisms living in natural environments. Layering key insights from human genetic errors of immunity on existing paradigms offers a new synthesis of the suite of rapid defenses against pathogens and the immunoregulatory circuits preventing tissue immunopathology. This proposed model of an 'adaptive arsenal of rapid defenses' can illuminate knowledge gaps and help reconceptualize the immune system as a system with well-resolved cellular and molecular circuits. New discoveries in the field of human monogenic immune diseases highlight critical genes and pathways governing immune responses. Here, I describe how the ~500 currently defined human inborn errors of immunity help shape what I propose is an 'adaptive arsenal model of rapid defenses', emphasizing the set of immunological defenses poised for rapid responses in the natural environment. This arsenal blurs the lines between innate and adaptive immunity and is established through molecular relays between cell types, often traversing from sensors (pathogen detection) to intermediates to executioners (pathogen clearance) via soluble factors. Predictions and missing information based on the adaptive arsenal model are discussed, as are emergent and outstanding questions fundamental to advances in the field. [ABSTRACT FROM AUTHOR]

[Display omitted] • High ENOX2 expression is associated with immune excluded/deserted phenotypes in NPC. • ENOX2 inhibitor, idronoxil enhances CD8+ memory T -cell immunity in response to chemotherapy. • Combined treatment with idronoxil and cisplatin enhances tumor response in humanized mice model. • Combined treatment increases CD8+ T -cell expansion with cytolytic effector memory (Tem) feature. • T -cell infiltrates and tumor-associated ENOX2 have predictive value for anti-tumor response. The immunosuppressive tumor microenvironment is a major barrier for chemotherapy. Different chemosensitization approaches to reinstate immunological surveillance for cancers that are immune quiescent at the outset, have thus been devised. Cancer-specific ENOX2 expression is correlated with abnormal cell growth and has been proposed as a cellular target for anti-cancer activity. However, the potential effects of ENOX2 on the interaction between immune system and tumor cells remain elusive. To understand the mechanisms by which tumor-intrinsic ENOX2-mediated alterations in anti-tumor activity of T -cells and response to chemotherapy. In situ multiplexed immunohistochemistry with single cell and bulk RNA sequencing data from nasopharyngeal carcinoma (NPC) human tissues were used to define tumor phenotypes. Two NPC cell lines, with distinct ENOX2 expression, were used in a co-culture platform to study tumor-immune interactions between cancer cells/spheroids and T -cells. The effect of cisplatin treatment with ENOX2 inhibition by idronoxil (IDX) were tested in vitro and in vivo. Multi-parametric flow cytometry was used to characterize T -cell infiltrates in an NPC tumor humanized mouse model treated with combined treatment. NPC predominantly displayed an immune-excluded profile. This "cold-phenotype" was shown to exhibit higher ENOX2 expression and was associate with poorer progression-free survival (PFS). The therapeutic combination of IDX with cisplatin was effective in promoting CD8+ effector memory T cell (Tem) differentiation and mobilization. This Tem signature was highly cytotoxic, with Tem-mediated preferential lysis of higher ENOX2-expressing NPC cells. A combination-treated humanized mouse model showing dramatic shrinkage in tumors, were intra-tumoral Tem-enriched. Tumor-intrinsic ENOX2 expression is associated with tumor phenotype and PFS in NPC. Targeting ENOX2 with IDX and cisplatin impose qualitative control of T -cell response by preferentially increasing immune cells infiltration, Tem differentiation and tumor suppression. We suggest that ENOX2 inhibition may be a promising therapeutic strategy to enhance the effects of chemotherapy. [ABSTRACT FROM AUTHOR]

• Single-dose CoVac-1 induces long-lasting T cell responses in 100% of participants. • Long-term follow-up shows good tolerability and no immune-related side effects. • Magnitude of T cell responses correlates with severity of injection site reactions. • Most CoVac-1-induced peptide-specific immunoglobulin G antibodies peaked at month 3. • Very low SARS-CoV-2 infection rate (8.3 %) in the study population. T cell immunity is key for the control of viral infections including SARS-CoV-2, in particular with regard to immune memory and protection against arising genetic variants. We recently evaluated a peptide-based SARS-CoV-2 T cell activator termed CoVac-1 in a first-in-human trial in healthy adults. Here, we report on long-term safety and efficacy data of CoVac-1 until month 12. CoVac-1 is well tolerated without long-term immune-related side effects and induces long-lasting anti-viral T cell responses in 100% of study participants, with potent expandability of clusters of differentiation (CD4+) and CD8+ T cells targeting multiple different CoVac-1 T cell epitopes. T cell responses were associated with stronger injection site reaction. Beyond induction of T cell immunity, 89% of subjects developed CoVac-1-specific immunoglobulin G antibodies which associated with the intensity of the T cell response, indicating that CoVac-1-specific CD4+ T cells support the induction of B-cell responses. Vaccination with approved COVID-19 vaccines boosted CoVac-1-specific T cell responses. Overall, a low SARS-CoV-2 infection rate (8.3%) was observed. Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B-cell defects. [ABSTRACT FROM AUTHOR]

[Display omitted] Efficient immune responses rely on the proper differentiation of CD8+ T cells into effector and memory cells. Here, we show a critical requirement of N6-Methyladenosine (m6A) methyltransferase Mettl3 during CD8+ T cell responses upon acute viral infection. Conditional deletion of Mettl3 in CD8+ T cells impairs effector expansion and terminal differentiation in an m6A-dependent manner, subsequently affecting memory formation and the secondary response of CD8+ T cells. Our combined RNA-seq and m6A-miCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators. Remarkably, Mettl3 binds to the Tbx21 transcript and stabilizes it, promoting effector differentiation of CD8+ T cells. Moreover, ectopic expression of T-bet partially restores the defects in CD8+ T cell differentiation in the absence of Mettl3. Thus, our study highlights the role of Mettl3 in regulating multiple target genes in an m6A-dependent manner and underscores the importance of m6A modification during CD8+ T cell response. [ABSTRACT FROM AUTHOR]

The first influenza virus infection (imprinting) can lead to long-term immune memory and influence subsequent vaccinations and infections. Previously, we reported a polyethyleneimine (PEI)-Aichi hemagglutinin (HA)/CpG (PHC) nanoparticle with cross-protective potential against homologous and heterologous influenza strains. Here we studied how influenza immune imprinting influences the antibody responses to the PHC vaccination and the protection against heterosubtypic virus challenges. We found that pre-existing virus immunity can maintain or synergize the vaccine-induced antibody titers, depending on the imprinting virus HA phylogenetic group. The HA group 1 virus (PR8, H1N1)-imprinted mice displayed comparable antigen-specific antibody responses to those without imprinting post-PHC vaccination. In contrast, the group 2 virus (Phi, H3N2)-imprinted mice showed significantly more robust and balanced antibodies post-vaccination, conferring complete protection against body weight loss and lung inflammation upon heterosubtypic reassortant A/Shanghai/2/2013 (rSH, H7N9) virus challenge. Our findings suggest that influenza imprinting from the same HA phylogenetic group can synergize subsequent vaccination, conferring heterosubtypic protection. [ABSTRACT FROM AUTHOR]

• AHSV4 VP1, -2, -4, -7 and NS3 contain regions with CD8+ T cell epitopes. • Overlapping peptides spanning these AHSV4 proteins were synthesized. • Recall immune assays identified T cell and linear B cell epitopes. • Conserved T cell and linear B cell epitopes will be used in NGV. The viral proteins VP1-1, VP2, VP4, VP7 and NS3, of African horse sickness virus serotype 4 (AHSV4), have previously been identified to contain CD8+ T cell epitopes. In this study, overlapping peptides spanning the entire sequences of these AHSV4 proteins were synthesized and used to map epitopes. Peripheral blood mononuclear cells (PBMC) isolated from five horses immunized with an attenuated AHSV4 were stimulated in vitro with the synthesized peptides. Various memory immune assays were used to identify the individual peptides that contain CD8+ T cell epitopes, CD4+ T cell epitopes and linear B cell epitopes. The newly discovered individual peptides of AHSV4 proteins VP1-1, VP4, VP7 and/or NS3 that contain CD8+ T cell, CD4+ T cell or linear B cell epitopes could contribute to the design and development of new generation AHS peptide-based vaccines and therapeutics. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces. [ABSTRACT FROM AUTHOR]

There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)–hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA− memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment. Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 106/kg CD45RA− memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2–specific response within the CD45RA− memory T cells and the most frequent human leukocyte antigen typing in the Spanish population. We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events. Adoptive cell therapy with off-the-shelf CD45RA− memory T cells containing SAR-CoV-2–specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia. NCT04578210 [ABSTRACT FROM AUTHOR]

With advances in tissue typing, organ preservation techniques, and clinical surgery, organ transplantation has gained popularity as a treatment option for various end-stage diseases. Allogeneic transplantation has been widely adopted and extensively researched in clinical practice. Despite significant breakthroughs and progress in immunosuppression, this procedure is still associated with several adverse reactions and complications. Therefore, there is a continuing need to explore new immunological approaches to provide fresh insights and guidance for clinical transplantation. CD8+ T cells, traditionally known for their cytotoxic function and their ability to recognize transplanted organs as "non-self entities, display cytotoxicity. However, recent studies have unveiled that CD8+ T cells have various subtypes and functions that extend beyond conventional cytotoxicity. These CD8+ T cell subtypes include Effector CD8+ T cells, Memory CD8+ T cells, and CD8Treg cells. This review examines the immune regulatory mechanisms of CD8i T cells in allogeneic transplantation and discusses the potential applications of CD8+ T cells in treating tumors in transplant recipients who are receiving immunosuppressive therapy. These findings offer theoretical guidance for reducing post-transplant rejection reactions and improving adverse prognoses, offering new hope for improved clinical survival rate. [ABSTRACT FROM AUTHOR]

Background: During allogeneic Hematopoietic stem cell transplantation (HSCT), frequent pathological scenarios include graft versus host disease (GVHD) and viral infections. We hypothesized if exogenous stimulus as alloantigen and viral antigens might impact on central and effector memory T cells in pediatric recipients. Patients and methods: Subjects included 21 pediatric recipients and 20 healthy children (control group). Peripheral blood samples of patients were collected along the first 712 days post-HSCT. T cell phenotyping of naive, central, and effector memory T cells (TCMs and TEMs, respectively) was conducted using flow cytometry. Viral nucleic acids were detected using real time PCR. Results: T cell reconstitution was not reached after 1 year post-HSCT. Chronic GVHD was associated with increased numbers of naïve CD4 T cells (p < 0.05) as well as an increase in TEM and TCM cells of the CD4 (p 0.0001 and p < 0.05, respectively) and CD8 T cell TEM (p < 0.0001). and TCM (p < 0.001) populations too. Moreover, BK and Epstein-Barr viruses were the main viral pathogens detected (<10'* copies), which were associated with a decrease in all T cell compartments. Conclusion: During chronic GVHD, alloantigen persistence generates TEM cell enrichment among CD4 and CD8 T cells, and viral infections are associated with deficient recovery of T cells after HSCT. [ABSTRACT FROM AUTHOR]

Since the skin limits the distribution of intradermal vaccines, a large number of dendritic cells in the skin cannot be fully utilized to elicit a more effective immune response. Here, we loaded the antigen to the surface of the flagellate bacteria that was modified by cationic polymer, thus creating antigen-loaded flagellate bacteria (denoted as 'FB-Ag') to overcome the skin barrier and perform the active delivery of antigen in the skin. The FB-Ag showed fast speed (∼0.2 μm s−1) and strong dendritic cell activation capabilities in the skin model in vitro. In vivo, the FB-Ag promoted the spread of antigen in the skin through active movement, increased the contact between Intradermal dendritic cells and antigen, and effectively activated the internal dendritic cells in the skin. In a mouse of pulmonary metastatic melanoma and in mice bearing subcutaneous melanoma tumor, the FB-Ag effectively increased antigen-specific therapeutic efficacy and produced long-lasting immune memory. More importantly, the FB-Ag also enhanced the level of COVID-19 specific antibodies in the serum and the number of memory B cells in the spleen of mice. The movement of antigen-loaded flagellate bacteria to overcome intradermal constraints may enhance the activation of intradermal dendritic cells, providing new ideas for developing intradermal vaccines. [Display omitted] [ABSTRACT FROM AUTHOR]

• vaccine induced higher Surrogate neutralizing antibody and RBD-targeted B cell responses were greater after mRNA compared to vector vaccine. • Although vector vaccine boosted antibodies against human Adenovirus, those titres did not correlate with anti-spike titres. • Further work is needed to improve the immunogenicity of vector vaccines as they remain an important option for pandemic and outbreak responses. Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. The aim of this study was to validate whether immunogenicity differs for adenoviral vectored (AdV) versus mRNA vaccines against SARS-CoV-2, and to investigate how anti-vector immunity and B cell dynamics modulate immunogenicity. We enrolled SARS-CoV-2 infection-naïve health care workers who had received two doses of either AdV AZD1222 (n = 184) or mRNA BNT162b2 vaccine (n = 274) between April and October 2021. Blood was collected at least once, 10–48 days after vaccine dose 2 for antibody and B cell analyses. Median ages were 42 and 39 years, for AdV and mRNA vaccinees, respectively. Surrogate virus neutralization test (sVNT) and spike binding antibody titres were a median of 4.2 and 2.2 times lower, respectively, for AdV compared to mRNA vaccinees (p < 0.001). Median percentages of memory B cells that recognized fluorescent-tagged spike and RBD were 2.9 and 8.3 times lower, respectively for AdV compared to mRNA vaccinees. Titres of IgG reactive with human adenovirus type 5 hexon protein rose a median of 2.2-fold after AdV vaccination but were not correlated with anti-spike antibody titres. Together the results show that mRNA induced substantially more sVNT antibody than AdV vaccine, which reflected greater B cell expansion and targeting of the RBD rather than an attenuating effect of anti-vector antibodies. ClinicalTrials.gov Identifier: NCT05110911. [ABSTRACT FROM AUTHOR]

One of the major reasons behind the limited success of vaccine candidates against all forms of leishmaniasis is the inability of parasitic antigens to induce robust cell-mediated immunity and immunological memory. Here we find, for the first time, that the adjuvantation of whole-killed Leishmania vaccine (Leishvacc) with anti-CD200 and anti-CD300a antibodies enhances CD4+ T cells mediated immunity in vaccinated mice and provides protection against wild-type parasites. The antibody adjuvantation, either alone or with a TLR4 agonist monophosphoryl A (MPL-A), induced the production of pro-inflammatory cytokines viz., IFN-γ, TNF-α, and IL-2 by antigen experienced CD4+ T cells, and also enhanced their rate of conversion into their memory phenotypes against Leishvacc antigens. The antibody adjuvanted vaccine also promoted the generation of IgG2a-mediated protective humoral immunity in vaccinated mice. Further, the mice vaccinated with antibodies adjuvanted vaccine showed strong resilience against metacyclic forms of L. donovani parasites as we observed reduced clinical features such as splenomegaly, hepatomegaly, granulomatous tissues in the liver, and parasitic load in their spleen. The findings of this study demonstrate that the anti-CD200 and anti-CD300a antibodies have potential to increase the protective efficacy of the whole-killed Leishmania vaccine, and opens up a new gateway to diversify the roles of immune checkpoints in vaccine development against leishmaniasis. • Anti-CD200/CD300a antibodies adjuvantation enhances vaccine antigen immunogenicity. • Antibodies (Abs) adjuvanted Leishvacc enhances dendritic and CD4 T cells functions. • Abs adjuvanted Leishvacc provides better protection against wild-type parasites. [ABSTRACT FROM AUTHOR]

Early-life environmental exposures influence long-lasting immune phenotypes and disease susceptibility. Immunity comprises durable programmable components that are affected by early environmental interactions and maintained in a stable manner. Some immune components are intrinsically programmable, whereas others are influenced by critical developmental processes during early life. Non-immune factors, including microbiota, hormones, and metabolites, strongly impact immune programming. Developmental immune programming may promote adaptation to anticipated future environments, but mismatches between predicted and actual environments can lead to disease. We propose that developmental programming of the immune system is possible due to programmable components of immunity. These developmentally programmable components are established by their interaction with an early-life environment and result in persistent immune alterations and disease susceptibility. Early-life environmental exposures play a significant role in shaping long-lasting immune phenotypes and disease susceptibility. Nevertheless, comprehensive understanding of the developmental programming of immunity is limited. We propose that the vertebrate immune system contains durable programmable components established through early environmental interactions and maintained in a stable and homeostatic manner. Some immune components, such as immunological memory, are intrinsically programmable. Others are influenced by conditions during critical developmental windows in early life, including microbiota, hormones, metabolites, and environmental stress, which impact programming. Developmental immune programming can promote adaptation to an anticipated future environment. However, mismatches between predicted and actual environments can result in disease. This is relevant because understanding programming mechanisms can offer insights into the origin of inflammatory diseases, ideally enabling effective prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

In Kilifi (Kenya), a pneumococcal conjugate vaccine (PCV10) was introduced in 2011 in infants (aged <1 year, 3 + 0 schedule) with a catch-up campaign in children aged 1–4 years. We aimed to measure the effect of PCV10 on population immunity. In this observational study, repeated cross-sectional serosurveys were conducted in independent random samples of 500 children younger than 15 years every 2 years between 2009 and 2017. During these surveys, blood samples were collected by venesection. Concentrations of anti-capsular IgGs against vaccine serotypes (VTs) 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F, and against serotypes 6A and 19A, were assayed by ELISA. We plotted the geometric mean concentrations (GMCs) by birth year to visualise age-specific antibody profiles. In infants, IgG concentrations of 0·35 μg/mL or higher were considered protective. Of 3673 volunteers approached, 2152 submitted samples for analysis across the five surveys. Vaccine introduction resulted in an increase in the proportion of young children with protective IgG concentrations, compared with before vaccine introduction (from 0–33% of infants with VT-specific levels over the correlate of protection in 2009, to 60–94% of infants in 2011). However, among those vaccinated in infancy, GMCs of all ten VTs had waned rapidly by the age of 1, but rose again later in childhood. GMCs among children aged 10–14 years were consistently high over time (eg, the range of GMCs across survey rounds were between 0·45 μg/mL and 1·00 μg/mL for VT 23F and between 2·00 μg/mL and 3·11 μg/mL for VT 19F). PCV10 in a 3 + 0 schedule elicited protective IgG levels during infancy, when disease risk is high. The high antibody levels in children aged 10–14 years might indicate continued exposure to vaccine serotypes due to residual carriage or to memory responses to cross-reactive antigens. Despite rapid waning of IgG after vaccination, disease incidence among young children in this setting remains low, suggesting that lower thresholds of antibody, or other markers of immunity (eg, memory B cells), may be needed to assess population protection among children who have aged past infancy. Gavi, the Vaccine Alliance; Wellcome Trust. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) is the first oncogenic virus described in human. EBV infects more than 90% of the human population worldwide, but most EBV infections are asymptomatic. After the primary infection, the virus persists lifelong in the memory B cells of the infected individuals. Under certain conditions the virus can cause several human cancers, that include lymphoproliferative disorders such as Burkitt and Hodgkin lymphomas and non-lymphoid malignancies such as 100% of nasopharyngeal carcinoma and 10% of gastric cancers. Each year, about 200,000 EBV-related cancers emerge, hence accounting for at least 1% of worldwide cancers. Like all gammaherpesviruses, EBV has evolved a strategy to escape the host immune system. This strategy is mainly based on the tight control of the expression of its Epstein-Barr nuclear antigen-1 (EBNA1) protein, the EBV-encoded genome maintenance protein. Indeed, EBNA1 is essential for viral genome replication and maintenance but, at the same time, is also highly antigenic and T cells raised against EBNA1 exist in infected individuals. For this reason, EBNA1 is considered as the Achilles heel of EBV and the virus has seemingly evolved a strategy that employs the binding of nucleolin, a host cell factor, to RNA G-quadruplex (rG4) within EBNA1 mRNA to limit its expression to the minimal level required for function while minimizing immune recognition. This review recapitulates in a historical way the knowledge accumulated on EBNA1 immune evasion and discusses how this rG4-dependent mechanism can be exploited as an intervention point to unveil EBV-related cancers to the immune system. [Display omitted] [ABSTRACT FROM AUTHOR]

Chronic hepatitis B is a global public health problem, and coinfection with hepatitis delta virus (HDV) worsens disease outcome. Here, we describe a hepatitis B virus (HBV) surface antigen (HBsAg)-targeting monoclonal antibody (mAb) with the potential to treat chronic hepatitis B and chronic hepatitis D. HBsAg-specific mAbs were isolated from memory B cells of HBV vaccinated individuals. In vitro neutralization was determined against HBV and HDV enveloped with HBsAg representing eight HBV genotypes. Human liver-chimeric mice were treated twice weekly with a candidate mAb starting 3 weeks post HBV inoculation (spreading phase) or during stable HBV or HBV/HDV coinfection (chronic phase). From a panel of human anti-HBs mAbs, VIR-3434 was selected and engineered for pre-clinical development. VIR-3434 targets a conserved, conformational epitope within the antigenic loop of HBsAg and neutralized HBV and HDV infection with higher potency than hepatitis B immunoglobulins in vitro. Neutralization was pan-genotypic against strains representative of HBV genotypes A-H. In the spreading phase of HBV infection in human liver-chimeric mice, a parental mAb of VIR-3434 (HBC34) prevented HBV dissemination and the increase in intrahepatic HBV RNA and covalently closed circular DNA. In the chronic phase of HBV infection or co-infection with HDV, HBC34 treatment decreased circulating HBsAg by >1 log and HDV RNA by >2 logs. The potently neutralizing anti-HBs mAb VIR-3434 reduces circulating HBsAg and HBV/HDV viremia in human liver-chimeric mice. VIR-3434 is currently in clinical development for treatment of patients with chronic hepatitis B or D. Chronic infection with hepatitis B virus and co-infection with hepatitis D virus place approximately 290 million individuals worldwide at risk of severe liver disease and cancer. Available treatments result in low rates of functional cure or require lifelong therapy that does not eliminate the risk of liver disease. We isolated and characterized a potent human antibody that neutralizes hepatitis B and D viruses and reduces infection in a mouse model. This antibody could provide a new treatment for patients with chronic hepatitis B and D. [Display omitted] • Identification of a human mAb VIR-3434 that potently neutralizes HBV and HDV. • VIR-3434 targets a conserved, conformational epitope of the HBsAg antigenic loop. • VIR-3434 treatment blocks intrahepatic HBV spread in human liver-chimeric mice. • VIR-3434 treatment reduces circulating HBsAg and HDV RNA in co-infected mice. • Data have enabled clinical development of VIR-3434 against chronic hepatitis B/D. [ABSTRACT FROM AUTHOR]

• Effective vaccines could reduce the rates of systemic Salmonella infection. • CD4 TRM are required for complete protection against iNTS in mice. • Previous vaccine failure could be due to an inability to induce CD4 TRM. Salmonella infections cause a wide range of intestinal and systemic disease that affects global human health. While some vaccines are available, they do not mitigate the impact of Salmonella on endemic areas. Research using Salmonella mouse models has revealed the important role of CD4 T cells and antibody in the development of protective immunity against Salmonella infection. Recent work points to a critical role for hepatic tissue-resident memory lymphocytes in naturally acquired immunity to systemic infection. Thus, understanding the genesis and function of this Salmonella -specific population is an important objective and is the primary focus of this review. Greater understanding of how these memory lymphocytes contribute to bacterial elimination could suggest new approaches to vaccination against an important human pathogen. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae is increasingly resistant to antibiotics, and new therapies to prevent or treat K. pneumoniae infections are urgently needed. The mammalian adaptive immune response to K. pneumoniae infection has not been fully defined, but significant advances have been made in the past 5 years. T cells are instrumental in lung immunity to K. pneumoniae. Tissue-resident memory T cells (T RM cells), derived from type 17 T helper (Th17) cells and maintained by interleukin (IL)-7 signals, help to control repeat K. pneumoniae infection in the lung. Various monoclonal antibody (mAb) studies have demonstrated that some antibodies can protect against various K. pneumoniae infections. Many mAbs promote bacterial killing through opsonophagocytosis. Several exciting K. pneumoniae vaccine candidates or alternative therapies have shown promising results in animal models, but remain to be translated to humans. For many years the host adaptive immune response to K. pneumoniae was a relative black box. However, with the recent emergence of multidrug-resistant and hypervirulent strains of K. pneumoniae , this pathogen has been thrust into the research spotlight. Numerous laboratories are currently investigating host immune responses to K. pneumoniae with the ultimate goal of developing new prophylactics and therapeutics. Several promising vaccine candidates have been identified in preclinical studies that now require translation to human therapy. Klebsiella pneumoniae is among the most common antibiotic-resistant pathogens causing nosocomial infections. Additionally, it is a leading cause of neonatal sepsis and childhood mortality across the globe. Despite its clinical importance, we are only beginning to understand how the mammalian adaptive immune system responds to this pathogen. Further, many studies investigating potential K. pneumoniae vaccine candidates or alternative therapies have been launched in recent years. Here, we review the current state of knowledge on the adaptive immune response to K. pneumoniae infections and progress towards developing vaccines and other therapies to combat these infections. [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) are among the most common infections in humans. Current challenges include increasing antimicrobial resistance, frequent recurrence, and lack of vaccines or adjunctive immunotherapies. Recent work, mostly in preclinical models, has unveiled new paradigms in urinary tract immune defenses. These include advances in understanding how myeloid cells modulate UTI susceptibility and outcomes, and a new phagocytic role for collecting duct intercalated cells. Advances in our mechanistic understanding of the host–pathogen conversation can help shape future immunomodulatory therapies for UTIs. Epithelial remodeling within the bladder after uropathogenic Escherichia coli (UPEC) infection underlies increased susceptibility to recurrent UTI. During cystitis, specific populations of bladder tissue-resident macrophages and memory T cells mediate complex responses to acute and recurrent UTI. A sex-dependent defect in neutrophil maturation within the kidney contributes to the increased severity of pyelonephritis seen in androgen-exposed hosts. Complement factor C5a, acting through its receptors C5aR1 and C5aR2, enhances renal proinflammatory responses and promotes UPEC colonization of the renal tubular space. Intercalated cells within the renal collecting duct represent nonprofessional phagocytes, taking up uropathogenic bacteria and secreting antimicrobial peptides. Recent advances in preclinical modeling of urinary tract infections (UTIs) have enabled the identification of key facets of the host response that influence pathogen clearance and tissue damage. Here, we review new insights into the functions of neutrophils, macrophages, and antimicrobial peptides in innate control of uropathogens and in mammalian infection-related tissue injury and repair. We also discuss novel functions for renal epithelial cells in innate antimicrobial defense. In addition, epigenetic modifications during bacterial cystitis have been implicated in bladder remodeling, conveying susceptibility to recurrent UTI. In total, contemporary work in this arena has better defined host processes that shape UTI susceptibility and severity and might inform the development of novel preventive and therapeutic approaches for acute and recurrent UTI. [ABSTRACT FROM AUTHOR]

Echinococcosis is a highly prevalent global zoonosis, and vaccines are required. The commercial vaccine based on a protein-based subunit (EG95), however, is limited by its insufficient cellular immunity, a short protection period, and limited prevention against novel mutant strains. Herein, we applied bioinformatics to develop a DNA vaccine (pEG95-IL2) expressing both multi-epitope-based antigens (EG95-PT1/2/3) and an IL-2 adjuvant to regulate T cell differentiation and memory cell response. EG95-PT1/2/3 was screened with hierarchical structure prediction from the epitope conformation of B cells with high confidence across various species to guarantee immunogenicity. Importantly, cationic arginine-rich lipid nanoparticles (RNP) were utilized as a delivery vehicle to form lipoplexes that had a transfection efficiency of nearly two orders of magnitude greater than that of commercial reagents (Lipofectamine 2000 and polyethyleneimine) with both immune and nonimmune cells (DC2.4 and L929 cells, respectively). RNP/pEG95-IL2 lipoplexes displayed a robust and long-term antigen expression, as well as adjuvant effects during the immunization. Consequently, intramuscular injection of RNP/pEG95-IL2 elicited similar humoral immune responses and significantly greater cellular responses in mice when compared with those of the commercial vaccine. In addition, the inoculation protocol of RNP/pEG95-IL2 with sequential booster further strengthens cellular immunity in comparison with the homologous booster. Those findings provide a promising strategy for improving plasmid vaccine efficacy. [Display omitted] • Multi-epitope-based DNA vaccine (RNP/pEG95-IL2) was developed by bioinformatics technology. • RNP/pEG95-IL2 elicited stronger cellular immune responses compared to the commercial vaccine. • The SB strategy of DNA vaccine produced greater immune responses than HB. • RNP benefited high and long-lasting expression of DNA antigens. • RNP accelerated BMDCs maturation and cytokine production as an immune adjuvant. [ABSTRACT FROM AUTHOR]

• EBV and genetic risk together may drive T-bet+ B cells in autoimmune disease • Genetic risk profiles likely determine how EBV shapes T-bet+ B-cell programs • There is a need for more selective therapies targeting pathogenic T-bet+ B cells. B cells expressing the transcription factor T-bet are found to have a protective role in viral infections, but are also considered major players in the onset of different types of autoimmune diseases. Currently, the exact mechanisms driving such 'atypical' memory B cells to contribute to protective immunity or autoimmunity are unclear. In addition to general autoimmune-related factors including sex and age, the ways T-bet+ B cells instigate autoimmune diseases may be determined by the close interplay between genetic risk variants and Epstein–Barr virus (EBV). The impact of EBV on T-bet+ B cells likely relies on the type of risk variants associated with each autoimmune disease, which may affect their differentiation, migratory routes and effector function. In this hypothesis-driven review, we discuss the lines of evidence pointing to such genetic and/or EBV-mediated influence on T-bet+ B cells in a range of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). We provide examples of how genetic risk variants can be linked to certain signaling pathways and are differentially affected by EBV to shape T-bet+ B-cells. Finally, we propose options to improve current treatment of B cell-related autoimmune diseases by more selective targeting of pathways that are critical for pathogenic T-bet+ B - cell formation. [ABSTRACT FROM AUTHOR]

Despite the growing interest in the role of regulatory B cells (Bregs) in autoimmunity, their distinct role and function in kidney transplant outcomes remain elusive. Here, we retrospectively analyzed the proportion of Bregs, transitional Bregs (tBregs) and memory Bregs (mBregs) and their capacity to produce IL-10 in non-rejected (NR) versus rejected (RJ) kidney transplant recipients. In the NR group, we observed a significant increase in the proportion of mBregs (CD19+CD24hiCD27+) but no difference in tBregs (CD19+CD24hiCD38+), as compared to the RJ group. We also observed a significant increase in IL-10-producing mBregs (CD19+CD24hiCD27+IL-10+) in the NR group. As our group and others have previously reported a potential role of the human leukocyte antigen G (HLA-G) in human renal allograft survival, notably through IL-10, we then investigated possible crosstalk between HLA-G and IL-10+ mBregs. Our ex vivo data suggest a role of HLA-G in enhancing IL-10+ mBreg expansion upon stimulation, which further decreased CD3+ T cell proliferation capability. Using RNA-sequencing (RNA-seq), we identified potential key signaling pathways involved in HLA-G-driven IL-10+ mBreg expansion, such as the MAPK, TNF and chemokine signaling pathways. Together, our study highlights a novel HLA-G-mediated IL-10-producing mBreg pathway that may serve as a therapeutic target to improve kidney allograft survival. [ABSTRACT FROM AUTHOR]

Countermeasures against Zika virus (ZIKV) epidemics are urgently needed. In this study we generated a ZIKV virus-like particle (VLP) based vaccine candidate and assessed the immunogenicity of these particles in mice. The ZIKV-VLPs were morphologically similar to ZIKV by electron microscopy and were recognized by anti-Flavivirus neutralising antibodies. We observed that a single dose of unadjuvanted ZIKV-VLPs, or inactivated ZIKV, generated an immune response that lasted over 6 months, but did not neutralize ZIKV infection of cells in vitro. However, when we co-administered the ZIKV VLPs with either Aluminium hydroxide (Alhydrogel®; Alum), AddaVax or Pam 2 Cys we observed that Alum was the most effective in a single dose regime, since it not only produced antibodies that neutralized the virus, but also generated a greater number of antigen-specific memory B cells. We additionally observed that the generation of the neutralising antibodies persisted for up to 6 months. Our results suggest that a single dose ZIKV VLPs could be a suitable single dose vaccine candidate for use in outbreak settings. [ABSTRACT FROM AUTHOR]

Data-driven mathematical modeling predicted that central memory CD8+ T cell precursors proliferate more slowly than terminally differentiating effector CD8+ T cell; this prediction has now been confirmed in several experimental studies in mice. The new data are explained by an early branching model; T cell blasts give rise to slowly dividing precursors of re-expandable memory cells and rapidly dividing effectors. The effector differentiation pathway is selectively vulnerable to pyrimidine starvation. Measuring the division histories of memory cells suggests that memory can develop both from comparatively quiescent and extensively divided precursors; we posit that recall responses may primarily emerge from quiescent memory cells. The iteration of murine infection experiments and mathematical modeling of recent data shows that precursors of re-expandable CD8+ T cell memory cells form early during an acute immune response to infection. Differential regulation of memory formation and effector response might be exploitable for improving vaccination and immunotherapy. In acute immune responses to infection, memory T cells develop that can spawn recall responses. This process has not been observable directly in vivo. Here we highlight the utility of mathematical inference to derive quantitatively testable models of mammalian CD8+ T cell memory development from complex experimental data. Previous inference studies suggested that precursors of memory T cells arise early during the immune response. Recent work has both validated a crucial prediction of this T cell diversification model and refined the model. While multiple developmental routes to distinct memory subsets might exist, a branch point occurs early in proliferating T cell blasts, from which separate differentiation pathways emerge for slowly dividing precursors of re-expandable memory cells and rapidly dividing effectors. [ABSTRACT FROM AUTHOR]

• The IG genes are highly polymorphic, but this variation is not covered in current GWAS. • Definition of IG germline gene diversity in different human population groups is a prioritized topic. • Convergent Ab responses indicate preferential IG gene usage. • Technology platforms to untangle IG genotype-function associations are increasingly available. Immunoglobulin (IG) genes, encoding B cell receptors (BCRs), are fundamental components of the mammalian immune system, which evolved to recognize the diverse antigenic universe present in nature. To handle these myriad inputs, BCRs are generated through combinatorial recombination of a set of highly polymorphic germline genes, resulting in a vast repertoire of antigen receptors that initiate responses to pathogens and regulate commensals. Following antigen recognition and B cell activation, memory B cells and plasma cells form, allowing for the development of anamnestic antibody (Ab) responses. How inherited variation in IG genes impacts host traits, disease susceptibility, and Ab recall responses is a topic of great interest. Here, we consider approaches to translate emerging knowledge about IG genetic diversity and expressed repertoires to inform our understanding of Ab function in health and disease etiology. As our understanding of IG genetics grows, so will our need for tools to decipher preferences for IG gene or allele usage in different contexts, to better understand antibody responses at the population level. [ABSTRACT FROM AUTHOR]

Maternal pertussis immunization using Tdap vaccine is recommended in many countries to protect newborns from severe post-natal infection. Immunological changes during pregnancy may influence the response to vaccines. The quality of IgG and memory B cell responses to Tdap immunization in pregnant women has not yet been described. The impact of pregnancy on the response to Tdap vaccination was assessed by comparing humoral immune responses in 42 pregnant and 39 non-pregnant women. The levels of serum pertussis antigens and tetanus toxoid-specific IgG, IgG subclasses, IgG Fc-mediated effector functions, as well as memory B cell frequencies were assessed before and at several time points after vaccination. Tdap immunization induced similar levels of pertussis and tetanus-specific IgG and IgG subclasses in pregnant and non-pregnant women. Pregnant women produced IgG promoting complement deposition, and neutrophils and macrophages phagocytosis at levels comparable to non-pregnant women. They were also able to expand pertussis and tetanus-specific memory B cells at similar frequencies as non-pregnant women, suggesting equivalent "boostability". Higher levels of vaccine-specific IgG, IgG subclasses, and IgG Fc-mediated effector functions were detected in cord blood as compared to maternal blood, indicating efficient transport across the placenta. This study demonstrates that pregnancy does not affect the quality of effector IgG and memory B cell responses to Tdap immunization and that polyfunctional IgG are efficiently transferred across the placenta. ClinicalTrials.Gov (NCT03519373). [ABSTRACT FROM AUTHOR]

Introduction: The pathogenesis and progression mechanism of Immunoglobulin A nephropathy (IgAN) is not fully understood. There is a lack of panoramic analysis of IgAN immune cell infiltration and algorithms that are more efficient and accurate for screening key pathogenic genes. Methods: RNA sequencing (RNA-seq) data sets on IgAN were downloaded from the Gene Expression Omnibus (GEO) database, including GSE93798, GSE35489, and GSE115857. The RNA-seq data set of kidney tissue as control samples were downloaded from the Genotype-Tissue Expression (GTEx) database. Three machine learning algorithms--weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO), and support vector machine--were used to identify the key pathogenic gene sets of the IgAN disease. The ssGSEA method was applied to calculate the immune cell infiltration (ICI) of IgAN samples, whereas the Spearman test was used for correlation analysis. The receiver operator characteristic curve (ROC) was used to evaluate the diagnostic efficacy of key genes. The correlation between the key genes and ICI was analyzed using the Spearman test. Results: A total of 177 genes were screened out as differentially expressed genes (DEGs) for IgAN, including 135 up-regulated genes and 42 down-regulated genes. The DEGs were significantly enriched in the inflammatory- or immune-related pathways (gene sets). Activating transcription factor 3 (AFT3), C-X-C Motif Chemokine Ligand 6 (CXCL6), and v-fos FBJ murine osteosarcoma viral oncogene homolog B (FOSB) were identified using WGCNA, support vector machine, and LASSO algorithms. These three genes revealed good diagnostic efficacy in the training and test cohorts. The CXCL6 expression positively correlated with activated B cells and memory B cells. Conclusion: ATF3, FOSB, and CXCL6 genes were identified as potential biomarkers of IgAN. These three genes exhibited good diagnostic efficacy for IgAN. We described the landscape of immune cell infiltration for IgAN. Activated B cells and memory B cells were more highly expressed in the IgAN samples than in the control samples. CXCL6 seems crucial to the pathogenesis of IgAN and may induce IgAN by enriching immune cells. Our study may contribute to developing CXCL6 inhibitors that target B cells for IgAN therapy. [ABSTRACT FROM AUTHOR]

Initiating from multipotent progenitors, the lineages extrapolated from hematopoietic stem cells are determined by transcription factors specific to each of them. The commitment factors assist in the differentiation of progenitor cells into terminally differentiated cells. B lymphocytes constitute a population of cells that expresses clonally diverse cell surface immunoglobulin (Ig) receptors specific to antigenic epitopes. B cells are a significant facet of the adaptive immune system. The secreted antibodies corresponding to the B cell recognize the antigens via the B cell receptor (BCR). Following antigen recognition, the B cell is activated and thereafter undergoes clonal expansion and proliferation to become memory B cells. The essence of'cellular reprogramming' has aided in reliably altering the cells to desired tissue type. The potential of reprogramming has been harnessed to decipher and find solutions for various genetically inherited diseases and degenerative disorders. B lymphocytes can be reprogrammed to their initial naive state from where they get differentiated into any lineage or cell type similar to a pluripotent stem cell which can be accomplished by the deletion of master regulators of the B cell lineage. B cells can be reprogrammed into pluripotent stem cells and also can undergo transdifferentiation at the midway of cell differentiation to other cell types. Mandated expression of C/EBP in specialized B cells corresponds to their fast and effective reprogramming into macrophages, reversing the cell fate of these lymphocytes and allowing them to differentiate freshly into other types of cells. The co-expression of C/EBPα and OKSM (Oct4, Sox2, Klf4, c-Myc) amplified the reprogramming efficiency of B lymphocytes. Various human somatic cells including the immune cells are compliant to reprogramming which paves a path for opportunities like autologous tissue grafts, blood transfusion, and cancer immunotherapy. The ability to reprogram B cells offers an unprecedented opportunity for developing a therapeutic approach for several human diseases. Here, we will focus on all the proteins and transcription factors responsible for the developmental commitment of B lymphocytes and how it is harnessed in various applications. [ABSTRACT FROM AUTHOR]