Neoself-antigen presentation in SLE: Mordred’s coronation in Arthur’s absence
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CXCL16 knockout inhibit asthma airway inflammation by suppressing H2-DM molecular mediated antigen presentation
The inflammatory microenvironment influences dendritic cell-mediated antigen presentation to regulate asthma Th2 inflammation. The scavenger receptor is expressed on DCs and regulates antigen presentation and T priming. However, whether the transmembrane scavenger receptor (SR-PSOX/CXCL16) regulates the phenotype and antigen presentation function of DCs remains unclear. We found that CXCL16 is mainly expressed on DCs in the lung tissues of asthma patients and asthma mice. CXCL16 knockout led to the suppression of airway inflammation, mucus overproduction, and airway hyperresponsiveness in Aspergillus-induced asthma. In addition, the adoptive transfer of Aspergillus-pulsed DCs shows the CXCL16+ DCs exerted a promoting role in airway inflammation, the CXCL16− DCs inhibit airway inflammation. Additionally, RNA sequencing and flow cytometry data revealed that CXCL16 knockout inhibits airway inflammation by suppressing the antigen processing and presentation function of DCs, which was mediated by MHC II chaperone H2-DM. Furthermore, we found CXCL16 knockout suppressed dendritic cells differentiated forward to cDC2b subtype which is mainly charged with antigen presentation to T cell. In conclusion, we found that CXCL16 downregulated the capacity of DC antigen processing and presentation to suppress airway inflammation by reducing H2-DM expression which mediated DC differentiation. The study suggested that inhibition of CXCL16 can be a potential therapy for asthma.
An active representation learning method for reaction yield prediction with small-scale data
Reaction optimization plays an essential role in chemical research and industrial production. To explore a large reaction system, a practical issue is how to reduce the heavy experimental load for finding the high-yield conditions. In this paper, we present an efficient machine learning tool called “RS-Coreset”, where the key idea is to take advantage of deep representation learning techniques to guide an interactive procedure for representing the full reaction space. Our proposed tool only uses small-scale data, say 2.5% to 5% of the instances, to predict the yields of the reaction space. We validate the performance on three public datasets and achieve state-of-the-art results. Moreover, we apply this tool to assist the realistic exploration of the Lewis base-boryl radicals enabled dechlorinative coupling reactions in our lab. The tool can help us to effectively predict the yields and even discover several feasible reaction combinations that were overlooked in previous articles.
A lentiviral vector expressing a dendritic cell-targeting multimer induces mucosal anti-mycobacterial CD4+ T-cell immunity
Most viral vectors, including the potently immunogenic lentiviral vectors (LVs), only poorly direct antigens to the MHC-II endosomal pathway and elicit CD4+ T cells. We developed a new generation of LVs encoding antigen-bearing monomers of collectins substituted at their C-terminal domain with the CD40 ligand ectodomain to target and activate antigen-presenting cells. Host cells transduced with such optimized LVs secreted soluble collectin-antigen polymers with the potential to be endocytosed in vivo and reach the MHC-II pathway. In the murine tuberculosis model, such LVs induced efficient MHC-II antigenic presentation and triggered both CD8+ and CD4+ T cells at the systemic and mucosal levels. They also conferred a significant booster effect, consistent with the importance of CD4+ T cells for protection against Mycobacterium tuberculosis. Given the pivotal role of CD4+ T cells in orchestrating innate and adaptive immunity, this strategy could have a broad range of applications in the vaccinology field.
Syk inhibitor attenuates lupus in FcγRIIb−/− mice through the Inhibition of DNA extracellular traps from macrophages and neutrophils via p38MAPK-dependent pathway
Spleen tyrosine kinase (Syk), an important hub of immune signaling, is activated by several signalings in active lupus which could be interfered by Syk inhibitor but is still not completely evaluated in innate immune cells associated with lupus activity. Hence, a Syk inhibitor (fostamatinib; R788) was tested in vivo using Fc gamma receptor-deficient (FcγRIIb−/−) lupus mice and in vitro (macrophages and neutrophils). After 4 weeks of oral Syk inhibitor, 40 week-old FcγRIIb−/− mice (a full-blown lupus model) demonstrated less prominent lupus parameters (serum anti-dsDNA, proteinuria, and glomerulonephritis), systemic inflammation, as evaluated by serum TNFa, IL-6, and citrullinated histone H3 (CitH3), gut permeability defect, as indicated by serum FITC dextran assay, serum lipopolysaccharide (LPS), and serum (1 → 3)-β-D-glucan (BG), extracellular traps (ETs) and immune complex deposition in spleens and kidneys (immunofluorescent staining of CitH3 and immunoglobulin G) than FcγRIIb−/− mice with placebo. Due to the spontaneous elevation of LPS and BG in serum, LPS plus BG (LPS + BG) was used to activate macrophages and neutrophils. After LPS + BG stimulation, FcγRIIb−/− macrophages and neutrophils demonstrated predominant abundance of phosphorylated Syk (Western blotting), and the pro-inflammatory responses (CD86 flow cytometry analysis, supernatant cytokines, ETs immunofluorescent, and flow cytometry-based apoptosis). With RNA sequencing analysis and western blotting, the Syk-p38MAPK-dependent pathway was suggested as downregulating several inflammatory pathways in LPS + BG-activated FcγRIIb−/− macrophages and neutrophils. Although both inhibitors against Syk and p38MAPK attenuated macrophage and neutrophil inflammatory responses against LPS + WGP, the apoptosis inhibition by p38MAPK inhibitor was not observed. These results suggested that Syk inhibitor (fostamatinib) improved the severity of lupus caused by FcγRIIb defect partly through Syk-p38MAPK anti-inflammation that inhibited both ET formation and cytokine production from innate immune cells.
The guided fire from within: intratumoral administration of mRNA-based vaccines to mobilize memory immunity and direct immune responses against pathogen to target solid tumors
We investigated a novel cancer immunotherapy strategy that effectively suppresses tumor growth in multiple solid tumor models and significantly extends the lifespan of tumor-bearing mice by introducing pathogen antigens into tumors via mRNA-lipid nanoparticles. The pre-existing immunity against the pathogen antigen can significantly enhance the efficacy of this approach. In mice previously immunized with BNT162b2, an mRNA-based COVID-19 vaccine encoding the spike protein of the SARS-CoV-2 virus, intratumoral injections of the same vaccine efficiently tagged the tumor cells with mRNA-expressed spike protein. This action rapidly mobilized the pre-existing memory immunity against SARS-CoV-2 to kill the cancer cells displaying the spike protein, while concurrently reprogramming the tumor microenvironment (TME) by attracting immune cells. The partial elimination of tumor cells in a normalized TME further triggered extensive tumor antigen-specific T cell responses through antigen spreading, eventually resulting in potent and systemic tumor-targeting immune responses. Moreover, combining BNT162b2 treatment with anti-PD-L1 therapy yielded a more substantial therapeutic impact, even in “cold tumor” types that are typically less responsive to treatment. Given that the majority of the global population has acquired memory immunity against various pathogens through infection or vaccination, we believe that, in addition to utilizing the widely held immune memory against SARS-CoV-2 via COVID-19 vaccine, mRNA vaccines against other pathogens, such as Hepatitis B Virus (HBV), Common Human Coronaviruses (HCoVs), and the influenza virus, could be rapidly transitioned into clinical use and holds great promise in treating different types of cancer. The extensive selection of pathogen antigens expands therapeutic opportunities and may also overcome potential drug resistance.
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