Induction Of Immune Responses Research Articles

Effectiveness and Safety of mRNA Vaccines in the Therapy of Glioblastoma

Glioblastoma (GBM) is the most common and most malignant primary brain tumor, presenting significant treatment challenges due to its heterogeneity, invasiveness, and resistance to conventional therapies. Despite aggressive treatment protocols, the prognosis remains poor, with a median survival time of approximately 15 months. Recent advancements in mRNA vaccine technology, particularly the development of lipid nanoparticles (LNPs), have revitalized interest in mRNA-based therapies. These vaccines offer unique advantages, including rapid production, personalization based on tumor-specific mutations, and a strong induction of both humoral and cellular immune responses. mRNA vaccines have demonstrated potential in preclinical models, showing significant tumor regression and improved survival rates. Early-phase clinical trials have indicated that mRNA vaccines are safe and can induce robust immune responses in GBM patients. Combining mRNA vaccines with other immunotherapeutic approaches, such as checkpoint inhibitors, has shown synergistic effects, further enhancing their efficacy. However, challenges such as optimizing delivery systems and overcoming the immunosuppressive tumor microenvironment remain. Future research should focus on addressing these challenges and exploring combination therapies to maximize therapeutic benefits. Large-scale, randomized clinical trials are essential to validate the efficacy and safety of mRNA vaccines in GBM therapy. The potential to reshape the tumor microenvironment and establish long-term immunological memory underscores the transformative potential of mRNA vaccines in cancer immunotherapy.

Colon Cancer Cells Treated with Lacticaseibacillus casei Undergo Apoptosis and Release DAMPs Indicative of Immunogenic Cell Death.

Probiotic bacteria, and especially lactic acid bacteria, have long been known to wield a variety of health-beneficial effects, including antioxidant, antimicrobial, anti-inflammatory, immunomodulatory, and anticancer activities. However, our understanding of the mechanisms involved in these activities remains incomplete. In this study, we wished to investigate the processes that give rise to the anticancer activity of Lacticaseibacillus casei ATCC393 and the possibility that immunogenic cell death of cancer cells can be induced following treatment with this probiotic. In both cell lines that we have examined, we detected notable pro-apoptotic signaling, including the upregulation of death receptors, that culminated in the activation of caspase 3, the endpoint and most characteristic effector molecule of all pro-apoptotic cascades. In addition, we identified damage-associated molecular patterns associated with immunogenic cell death. Calreticulin exposure on the outer cell membrane, HMGB1 translocation outside the nucleus and depletion of intracellular ATP was evident in both cancer cell lines treated with the probiotic, while expression of type I interferons was upregulated in CT26 cells. Our findings suggest that treatment with the probiotic induced apoptosis in cancer cells, mediated by extrinsic death receptor signaling. Moreover, it resulted in the release of molecular signals related with immunogenic cell death and induction of cancer cell-specific adaptive immune responses.

Self-Assembly of Silole-Based Aggregation-Induced Emission Compounds with Green Fluorescent Protein under Physiological Conditions for Traceable and Versatile Drug Delivery.

Biomacromolecules are viewed as promising drugs due to their specific functions in biological processes, biocompatibility, and pharmacological efficacy. Injective administration, chosen to avoid intestinal barriers, may in turn lead to immediate decay in the circulation system, unreliable targeting performance, or the induction of immune responses. For some biomacromolecules, chemically modified proteins have been developed for practical use. Various cargo or carrier systems are under development but have been delayed by technical difficulties. We present self-assembled nanocapsules with diameters ranging from 100 to 500 nm that can be deployed in physiological buffers to enclose various substances present in the buffers at the same time. Our amphiphilic nanocapsule, consisting of silole-core dendrimer products as the hydrophobic part and green fluorescent protein (GFP) derivatives as the hydrophilic part, connects and assembles spontaneously when mixed in solutions while engulfing dissolved or dispersed compounds together in a dose-dependent manner and shows unique optical characteristics because the dendrimer products exhibit aggregation-induced emission. Furthermore, the emission of the dendrimer causes considerable fluorescence resonance energy transfer (FRET) to GFP derivatives upon association. We could easily monitor assemblies by FRET states and particle sizes and have confirmed a stable presence in the buffer for at least a month. Further tracking of nanocapsules by fluorescence confirmed efficient uptake into some cancer cells. Nanocapsules based on GFP variants with or without a cell-surface-specific tag demonstrated that the tag improved the potential for specific targeted delivery. There were also indications that the nanocapsules became unstable after cellular uptake in the intracellular environment. We report here the simple preparation of traceable, stable, and biocompatible self-assembled nanocapsules as the basis for a versatile drug delivery system.

SARS-CoV-2 Variants from Long-Term, Persistently Infected Immunocompromised Patients Have Altered Syncytia Formation, Temperature-Dependent Replication, and Serum Neutralizing Antibody Escape

SARS-CoV-2 infection of immunocompromised individuals often leads to prolonged detection of viral RNA and infectious virus in nasal specimens, presumably due to the lack of induction of an appropriate adaptive immune response. Mutations identified in virus sequences obtained from persistently infected patients bear signatures of immune evasion and have some overlap with sequences present in variants of concern. We characterized virus isolates obtained greater than 100 days after the initial COVID-19 diagnosis from two COVID-19 patients undergoing immunosuppressive cancer therapy, wand compared them to an isolate from the start of the infection. Isolates from an individual who never mounted an antibody response specific to SARS-CoV-2 despite the administration of convalescent plasma showed slight reductions in plaque size and some showed temperature-dependent replication attenuation on human nasal epithelial cell culture compared to the virus that initiated infection. An isolate from another patient—who did mount a SARS-CoV-2 IgM response—showed temperature-dependent changes in plaque size as well as increased syncytia formation and escape from serum-neutralizing antibodies. Our results indicate that not all virus isolates from immunocompromised COVID-19 patients display clear signs of phenotypic change, but increased attention should be paid to monitoring virus evolution in this patient population.

In vivo spatiotemporal characterizing diverse body transportation of optical labeled high immunity aluminium adjuvants with photoacoustic tomography

Vaccine development requires high-resolution, in situ, and visual adjuvant technology. To address this need, this work proposed a novel adjuvant labeling that involved indocyanine green (ICG) and bovine serum albumin (BSA) with self-assembled aluminium adjuvant (Alum), which was called BSA@ICG@Alum. This compound exhibited excellent photoacoustic properties and has been confirmed its safety, biocompatibility, high antigen binding efficiency, and superior induction of immune response. Photoacoustic tomography (PAT) tracked the distribution of Alum in lymph nodes (LNs) and lymphatic vessels in real time after diverse injection modalities. The non-invasive imaging approach revealed that BSA@ICG@Alum was transported to the draining LNs 60 min after intramuscular injection and to distal LNs within 30 min after lymph node injection. In conclusion, PAT enabled real-time three-dimensional and quantitative visualization, thus offering a powerful tool for advancing vaccine design by providing critical insights into adjuvant transport and immune system activation.

Lymph node-targeted STING agonist nanovaccine against chronic HBV infection

Chronic hepatitis B virus (HBV) infection is a global health problem that substantially increases the risk of developing liver disease. The development of a novel strategy to induce anti-HB seroconversion and achieve a long-lasting immune response against chronic HBV infection remains challenging. Here, we found that chronic HBV infection affected the signaling pathway involved in STING-mediated induction of host immune responses in dendritic cells (DCs) and then generated a lymph node-targeted nanovaccine that co-delivered hepatitis B surface antigen (HBsAg) and cyclic diguanylate monophosphate (c-di-GMP) (named the PP-SG nanovaccine). The feasibility and efficiency of the PP-SG nanovaccine for CHB treatment were evaluated in HBV-carrier mice. Serum samples were analyzed for HBsAg, anti-HBs, HBV DNA, and alanine aminotransferase levels, and liver samples were evaluated for HBV DNA and RNA and HBcAg, accompanied by an analysis of HBV-specific cellular and humoral immune responses during PP-SG nanovaccine treatment. The PP-SG nanovaccine increased antigen phagocytosis and DC maturation, efficiently and safely eliminated HBV, achieved a long-lasting immune response against HBV reinjection, and disrupted chronic HBV infection-induced immune tolerance, as characterized by the generation and multifunctionality of HBV-specific CD8+ T and CD4+ T cells and the downregulation of immune checkpoint molecules. HBV-carrier mice immunized with the PP-SG nanovaccine achieved partial anti-HBs seroconversion. The PP-SG nanovaccine can induce sufficient and persistent viral suppression and achieve anti-HBs seroconversion, rendering it a promising vaccine candidate for clinical chronic hepatitis B therapy.

Recombinant outer membrane protein Lipl41 from Leptospira interrogans robust immune responses in mice model.

Leptospirosis is an infectious zoonotic disease that can result in severe complications. It is widespread, especially in hot and humid climates such as the northern region of Iran. The immune responses to leptospirosis are multifaceted. Lipl41 is an outer membrane protein that is expressed during infection and is highly conserved among pathogenic species. This makes it a good candidate for diagnosis and induction of specific immune responses. The aim of the present study was to evaluate immune responses against recombinant Lipl41 in mice. After immunizing of different groups of mice with recombinant Lipl41 (rLipl41), the levels of specific antibodies and cytokine profiles interferon-gamma/interleukin-4 (IFN-γ/IL-4) were measured. The results revealed that rLipl41 showed a significant increase in antibody levels compared with the control groups (P< 0.05). Although the level of IL-4 in the groups that received Lipl41 was similar to that in the other control groups, the IFN-γ levels showed a significant increase (P<0.05). It has been concluded that recombinant Lipl41 protein could strongly stimulate specific immune responses and be considered a potential candidate for vaccine development and diagnostic research.

A genetically engineered therapeutic lectin inhibits human influenza A virus infection and sustains robust virus-specific CD8 T cell expansion.

Native banana lectin (BanLec) is antiviral but highly mitogenic, which limits its therapeutic value. In contrast, the genetically engineered H84T BanLec (H84T) is not mitogenic but remains effective against influenza A virus (IAV) infection in mouse models. However, the potency and effect of H84T on human immune cells and IAV-specific immune responses is undetermined. We found that H84T efficiently inhibited IAV replication in human dendritic cells (DCs) from blood and tonsils, which preserved DC viability and allowed acquisition and presentation of viral antigen. Consequently, H84T-treated DCs initiated effective expansion of IAV-specific CD8 T cells. Furthermore, H84T preserved the capacity of IAV-exposed DCs to present a second non-IAV antigen and induce robust CD8 T cell expansion. This supports H84T as a potent antiviral in humans as it effectively inhibits IAV infection without disrupting DC function, and preserves induction of antigen-specific adaptive immune responses against diverse antigens, which likely is clinically beneficial.

Neoadjuvant lutetium PSMA, the TIME and immune response in high-risk localized prostate cancer.

High-risk localized prostate cancer remains a lethal disease with high rates of recurrence, metastases and death, despite attempts at curative local treatment including surgery. Disease recurrence is thought to be a result of failure of local control and occult micrometastases. Neoadjuvant strategies before surgery have been effective in many cancers, but, to date, none has worked in this setting for prostate cancer. Prostate-specific membrane antigen (PSMA)-based theranostics is an exciting and rapidly evolving field in prostate cancer. The novel intravenous radionuclide therapy, [177Lu]Lu-PSMA-617 (lutetium PSMA) has been shown to be effective in treating men with metastatic castration-resistant prostate cancer, targeting cells expressing PSMA throughout the body. When given in a neoadjuvant setting, lutetium PSMA might also improve long-term oncological outcomes in men with high-risk localized disease. A component of radiotherapy is potentially an immunogenic form of cancer cell death. Lutetium PSMA could cause cancer cell death, resulting in release of tumour antigens and induction of a tumour-specific systemic immune response. This targeted radioligand treatment has the potential to treat local and systemic tumour sites by directly targeting cells that express PSMA, but might also act indirectly via this systemic immune response. In selected patients, lutetium PSMA could potentially be combined with systemic immunotherapies to augment the antitumour T cell response, and this might produce long-lasting immunity in prostate cancer.

Vaccination with ancestral SARS-CoV-2 spike adjuvanted with TLR agonists provides cross-protection against XBB.1

Many different platforms have been used to develop highly protective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans. However, protection has eroded over time due to the emergence of antigenically diverse viral variants, especially the Omicron subvariants. One successful platform for the generation of SARS-CoV-2 vaccines are recombinant spike protein vaccines, of which two are licensed in the United States and Europe. Typically, purified recombinant protein antigens are poorly immunogenic and adjuvants must be included in the formulation. Here, we adjuvanted recombinant ancestral SARS-CoV-2 Wuhan-Hu-1 spike proteins with an emulsion formulation combined with synthetic Toll-like receptor (TLR) 4 and 7/8 agonists. This combination led to the induction of a Th1-skewed immune response that included high titers of antibodies against Wuhan-Hu-1 spike. These serum antibodies included neutralizing and cross-reactive antibodies that recognized the spike from multiple SARS-CoV-2 variants, as well as the receptor binding domain (RBD) from SARS-CoV-1. Despite an absence of robust cross-neutralization, vaccination against Wuhan-Hu-1 spike in the context of TLR-containing emulsions provided complete cross-protection against disease from a lethal challenge with XBB.1 in a stringent K18-hACE2 mouse model. We believe that the combination of recombinant spike antigens with TLR agonist-based emulsion formulations could lead to the development of next-generation SARS-CoV-2 vaccines that provide significant protection from future emerging variants.

Experimental vaccination by single dose sporozoite injection of blood-stage attenuated malaria parasites

Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.

Dose-dependent regulation of immune memory responses against HIV by saponin monophosphoryl lipid A nanoparticle adjuvant.

The induction of durable protective immune responses is the main goal of prophylactic vaccines, and adjuvants play an important role as drivers of such responses. Despite advances in vaccine strategies, a safe and effective HIV vaccine remains a significant challenge. The use of an appropriate adjuvant is crucial to the success of HIV vaccines. Here we assessed the saponin/MPLA nanoparticle (SMNP) adjuvant with an HIV envelope (Env) trimer, evaluating the safety and impact of multiple variables including adjuvant dose (16-fold dose range), immunization route, and adjuvant composition on the establishment of Env-specific memory T and B cell responses (T Mem and B Mem ) and long-lived plasma cells in non-human primates. Robust B Mem were detected in all groups, but a 6-fold increase was observed in the highest SMNP dose group vs. the lowest dose group. Similarly, stronger vaccine responses were induced in the highest SMNP dose for CD40L + OX40 + CD4 T Mem (11-fold), IFNγ + CD4 T Mem (15-fold), IL21 + CD4 T Mem (9-fold), circulating T FH (3.6-fold), bone marrow plasma cells (7-fold), and binding IgG (1.3-fold). Substantial tier-2 neutralizing antibodies were only observed in the higher SMNP dose groups. These investigations highlight the dose-dependent potency of SMNP in non-human primates, which are relevant for human use and next-generation vaccines.

Novel prophylactic and therapeutic multi-epitope vaccine based on Ag85A, Ag85B, ESAT-6, and CFP-10 of Mycobacterium tuberculosis using an immunoinformatics approach.

Current tuberculosis (TB) control strategies face limitations, such as low antibiotic treatment compliance and a rise in multidrug resistance. Furthermore, the lack of a safe and effective vaccine compounds these challenges. The limited efficacy of existing vaccines against TB underscores the urgency for innovative strategies, such as immunoinformatics. Consequently, this study aimed to design a targeted multi-epitope vaccine against TB infection utilizing an immunoinformatics approach. The multi-epitope vaccine targeted Ag85A, Ag85B, ESAT-6, and CFP-10 proteins. The design adopted various immunoinformatics tools for cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and linear B lymphocyte (LBL) epitope prediction, the assessment of vaccine characteristics, structure modeling, population coverage analysis, disulfide engineering, solubility prediction, molecular docking/dynamics with toll-like receptors (TLRs), codon optimization/cloning, and immune simulation. The multi-epitope vaccine, which was assembled using 12 CTL, 25 HTL, and 21 LBL epitopes associated with CpG adjuvants, showed promising characteristics. The immunoinformatics analysis confirmed the antigenicity, immunogenicity, and lack of allergenicity. Physicochemical evaluations indicated that the proteins were stable, thermostable, hydrophilic, and highly soluble. Docking simulations suggested high-affinity binding to TLRs, including TLR2, TLR4, and TLR9. In silico immune simulation predicted strong T cell (cytokine release) and B cell (immunoglobulin release) responses. This immunoinformatics-designed multi-epitope vaccine targeting Ag85A, Ag85B, ESAT-6, and CFP-10 proteins showed promising characteristics in terms of stability, immunogenicity, antigenicity, solubility, and predicted induction of humoral and adaptive immune responses. This suggests its potential as a prophylactic and therapeutic vaccine against TB.

Enhanced Immune Responses in Mice by Combining the Mpox Virus B6R-Protein and Aluminum Hydroxide-CpG Vaccine Adjuvants.

Novel adjuvants and innovative combinations of adjuvants (Adjuvant Systems) have facilitated the development of enhanced and new vaccines against re-emerging and challenging pathogenic microorganisms. Nonetheless, the efficacy of adjuvants is influenced by various factors, and the same adjuvant may generate entirely different immune responses when paired with different antigens. Herein, we combined the MPXV-B6R antigen with BC02, a novel adjuvant with proprietary technology, to assess its capability to induce both cellular and humoral immunity in mouse models. Mice received two intramuscular injections of B6R-BC02, which resulted in the production of MPXV-specific IgG, IgG1, and IgG2a antibodies. Additionally, it elicited strong MPXV-specific Th1-oriented cellular immunity and persistent effector memory B-cell responses. The advantages of BC02 were further validated, including rapid initiation of the immune response, robust recall memory, and sustained immune response induction. Although the potential of immunized mice to produce serum-neutralizing antibodies against the vaccinia virus requires further improvement, the exceptional performance of BC02 as an adjuvant for the MPXV-B6R antigen has been consistently demonstrated.

Retraction for Shepardson et al., "Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent".

Retraction for Shepardson et al., "Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent".

Lactococcus lactis subsp. cremoris YRC3780 modifies function of mesenteric lymph node dendritic cells to modulate the balance of T cell differentiation inducing regulatory T cells.

The intestinal immune system plays a pivotal role in the induction of immune responses against food. In the case of T cell response, dendritic cells (DCs) are especially important. However, the regulation of immune responses to food by intestinal DCs has been poorly described. In this study, we analyzed the effect of Lactococcus lactis subsp. cremoris YRC3780, a lactic acid bacterial strain isolated from kefir, a traditional fermented milk product, on the immune responses induced by antigen presentation by intestinal DCs to T cells as well as the mechanism of action of these immunomodulatory effects. It has been shown that L. cremoris YRC3780 ameliorates the symptoms of pollinosis in both animal and human studies. CD11c+ cells from mesenteric lymph nodes (MLNs) of BALB/c mice were cultured as MLN DCs with L. cremoris YRC3780 and expression of genes inducing regulatory T cells (Tregs) was examined by qPCR. In addition, MLN DCs were cocultured with CD4+ T cells from DO11.10 transgenic mice expressing an ovalbumin (OVA)-specific TCR and the OVA antigen peptide and L. cremoris YRC3780. Induction of Tregs was examined by flow cytometry, gene expression was analyzed by DNA microarray and qPCR, and the production of cytokines was measured by ELISA. MLN DCs from TLR2-deficient mice and components of L. cremoris YRC3780 were used to examine the recognition of YRC3780 by MLN DCs. L. cremoris YRC3780 enhanced the expression of genes involved in Treg induction in MLN DCs and induced Foxp3+CD4+T cells in an MLN DC and CD4+ T-cell co-culture system. The effect on MLN DCs was likely mediated by receptors other than TLR2. Together with microarray analyses of CD4+ T cell gene expression and cytokine ELISA, it was demonstrated that L. cremoris YRC3780 promoted the induction of Th1 and Tregs, and regulated the balance of Th1/Th2 and Treg/Th17 cells involving multiple genes via the antigen-presentation of MLN DCs. Our findings provide insights into the modulation of intestinal immune responses mediated by DCs and the antiallergic effects of lactic acid bacteria.

Optimizing Biocompatibility and Gene Delivery with DMAEA and DMAEAm: A Niacin-Derived Copolymer Approach.

Gene therapy is pivotal in nanomedicine, offering a versatile approach to disease treatment. This study aims to achieve an optimal balance between biocompatibility and efficacy, which is a common challenge in the field. A copolymer library is synthesized, incorporating niacin-derived monomers 2-acrylamidoethyl nicotinate (AAEN) or 2-(acryloyloxy)ethyl nicotinate (AEN) with N,N-(dimethylamino)ethyl acrylamide (DMAEAm) or hydrolysis-labile N,N-(dimethylamino)ethyl acrylate (DMAEA). Evaluation of the polymers' cytotoxicity profiles reveals that an increase in AAEN or DMAEA molar ratios correlates with improved biocompatibility. Remarkably, an increase in AAEN in both DMAEA and DMAEAm copolymers demonstrated enhanced transfection efficiencies of plasmid DNA in HEK293T cells. Additionally, the top-performing polymers demonstrate promising gene expression in challenging-to-transfect cells (THP-1 and Jurkat cells) and show no significant effect on modulating immune response induction in ex vivo treated murine monocytes. Overall, the best performing candidates exhibit an optimal balance between biocompatibility and efficacy, showcasing potential advancements in gene therapy.

Molecular basis of neurodegeneration in a mouse model of Polr3-related disease.

Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of Polr3-related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of Polr3-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic Polr3a mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, cerebral pathology and exocrine pancreatic atrophy. Transcriptome and immunohistochemistry analyses of cerebra during disease progression show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. Earlier in the disease when integrated stress and innate immune responses are minimally induced, mature tRNA sequencing revealed a global reduction in tRNA levels and an altered tRNA profile but no changes in other Pol III transcripts. Thus, changes in the size and/or composition of the tRNA pool have a causal role in disease initiation. Our findings reveal different tissue- and brain region-specific sensitivities to a defect in Pol III transcription.

A General Strategy toward Self‐assembled Nanovaccine Based on Cationic Lentinan to Induce Potent Humoral and Cellular Immune Responses

AbstractAdjuvants play a critical role in the induction of effective immune responses by vaccines. Here, a self‐assembling nanovaccine platform that integrates adjuvant functions into the delivery vehicle is prepared. Cationic Lentinan (CLNT) is mixed with ovalbumin (OVA) to obtain a self‐assembling nanovaccine (CLNTO nanovaccine), which induces the uptake and maturation of bone marrow dendritic cells (BMDCs) via the toll‐like receptors 2/4 (TLR2/4) to produce effective antigen cross‐presentation. CLNTO nanovaccines target lymph nodes (LNs) and induce a robust OVA‐specific immune response via TLR and tumor necrosis factor (TNF) signaling pathways, retinoic acid‐inducible gene I (RIG‐I) receptor, and cytokine‐cytokine receptor interactions. In addition, CLNTO nanovaccines are found that promote the activation of follicular helper T (Tfh) cells and induce the differentiation of germinal center (GC) B cells into memory B cells and plasma cells, thereby enhancing the immune response. Vaccination with CLNTO nanovaccine significantly inhibits the growth of ovalbumin (OVA)‐expressing B16 melanoma cell (B16‐OVA) tumors, indicating its great potential for cancer immunotherapy. Therefore, this study presents a simple, safe, and effective self‐assembling nanovaccine that induces helper T cell 1 (Th1) and helper T cell (Th2) immune responses, making it an effective vaccine delivery system.

E3 Ubiquitin Ligase RNF13 Suppresses TLR Lysosomal Degradation by Promoting LAMP-1 Proteasomal Degradation.

As a highly organized system, endo-lysosomes play a crucial role in maintaining immune homeostasis. However, the mechanisms involved in regulating endo-lysosome progression and subsequent inflammatory responses are not fully understood. By screening 103 E3 ubiquitin ligases in regulating endo-lysosomal acidification, it is discovered that lysosomal RNF13 inhibits lysosome maturation and promotes inflammatory responses mediated by endosomal Toll-like receptors (TLRs) in macrophages. Mechanistically, RNF13 mediates K48-linked polyubiquitination of LAMP-1 at residue K128 for proteasomal degradation. Upon TLRs activation, LAMP-1 promotes lysosomes maturation, which accelerates lysosomal degradation of TLRs and reduces TLR signaling in macrophages. Furthermore, peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis (RA) show increased RNF13 levels and decreased LAMP-1 expression. Accordingly, the immunosuppressive agent hydroxychloroquine (HCQ) can increase the polyubiquitination of RNF13. Taken together, the study establishes a linkage between proteasomal and lysosomal degradation mechanisms for the induction of appropriate innate immune response, and offers a promising approach for the treatment of inflammatory diseases by targeting intracellular TLRs.