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Pseudomonas instigates neutrophil accumulation in adipose tissue and insulin resistance in obesity 2309070
Abstract Introduction Obesity is a global pandemic, with over 75% of the U.S. population classified as overweight or obese. Adipose tissue inflammation is a major driver of metabolic complications associated with obesity. Previous studies have shown that obesity promotes neutrophil recruitment to visceral adipose tissue (VAT), which correlates with increased intestinal permeability and insulin resistance. The microbiome in obese VAT differs from that in lean VAT and is shaped by high-fat diet consumption. Whether specific microbes drive VAT neutrophil accumulation to cause obesity-related complications remains unknown. Methods To address this question, we developed a mouse model in which fecal microbiota from obese human donors were administered to mice pretreated with antibiotics and an antifungal (avatar mice). Using three-dimensional whole-mount imaging of VAT, 16S sequencing, flow cytometry, and molecular analyses, we investigated gut microbiome-driven mechanisms underlying VAT inflammation. Results Our study revealed that: (1) Proteobacteria were enriched in the VAT of mice gavaged with fecal microbiota from obese humans; (2) oral gavage with Pseudomonas aeruginosa (PAO1), a member of the Proteobacteria phylum, led to its detection in VAT and caused an increase in VAT neutrophils and Cxcr2 expression in the avatar mice; (3) the increase in VAT neutrophils was strictly dependent on PAO1, as heat-killed PAO1, other bacteria, or PAO1 mutants lacking essential structural components (e.g., flagella or O-antigen) were unable to recapitulate the obese phenotype; and (4) gavage with PAO1 was sufficient to trigger insulin resistance in recipient avatar mice. Conclusion Together, these findings reveal potential mechanisms by which bacteria in the human intestinal microbiome trigger adipose tissue inflammation and metabolic dysfunction in obesity. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)
TH17 responses elicited by a BcfA-containing vaccine protects against B. bronchiseptica disease and respiratory tract bacterial burden in mice 2257134
Abstract Introduction Bordetella bronchiseptica (Bb) is a respiratory pathogen of farm and companion animals. Current vaccines do not prevent transmission. Improved vaccines are needed to address this problem. We tested an intranasal subunit vaccine containing Bordetella colonization factor A (BcfA), filamentous hemagglutinin (FHA), and pertactin (Prn) as antigens. BcfA, an outer membrane protein with dual antigen and adjuvant functions, promotes a protective TH1/TH17 immune response critical for clearance of Bordetella species. Methods Mice were primed and boosted intranasally with BcfA/FHA/Prn. Immune responses were evaluated 2 weeks post boost by flow cytometry and ELISAs. Immunized animals were challenged with the laboratory Bb strain RB50, and phagocytes and CFUs were analyzed at days 4, 7, 14, and 28 post-challenge. Respiratory function was evaluated using noninvasive whole-body plethysmography. Results The vaccine elicited mucosal CD4+IL-17+ tissue resident memory T cells and systemic and mucosal IgG and IgA responses. Unimmunized challenged mice showed increased coughing and impaired lung function while BcfA/FHA/Prn immunized mice were protected from respiratory disease and showed reduced bacterial burden in the lungs and nose. Conclusion These findings demonstrate that an intranasal subunit vaccine containing BcfA/FHA/Prn elicits mucosal and systemic immunity and has the potential to provide sustained protection against Bb infection and disease and reduce colonization and subsequent transmission. Funding Source RO1AI153829 Topic Categories Vaccines and Immunotherapy (VAC)
Meta-inflammation Enhances Migration and Invasion of Prostate Cancer Cells via S100A4 Signaling 2267403
Abstract Introduction Prostate cancer is one of the most commonly diagnosed cancers in American men and a leading cause of cancer-related death, largely due to incurable metastatic disease. Obesity has been linked to increase the risk of developing aggressive and fatal prostate cancer, in part through chronic low-grade inflammation, or meta-inflammation. Within the tumor microenvironment, macrophage-derived inflammatory mediators promote cancer progression. Tumor-associated macrophages are key drivers of this process. This study aimed to investigate the molecular and cellular mechanisms linking meta-inflammation to prostate cancer cell migration and invasion. Methods An in vitro co-culture model that mimics the macrophage-to-adipocyte ratio observed in obese adipose tissue was established using human adipocytes (from donors with BMI ≥30) and U937 macrophage-like cells. Three conditions were tested: unstimulated, acute inflammation (10 ng/mL LPS for 24 h), and chronic inflammation (adipocytes pretreated with 10 ng/mL LPS for 24 h followed by 24 h in basal media). This low-dose LPS protocol mimics the metabolic endotoxemia commonly seen in obesity. Conditioned media from each condition were used to stimulate DU145 human prostate cancer cells. Results Transwell migration, invasion, and wound-healing assays showed that DU145 cells treated with conditioned media from acute and chronic inflammatory co-cultures displayed significantly increased migration and invasion compared with controls. Western blotting and immunofluorescence revealed upregulated S100A4, a protein associated with inflammation and cancer progression. Conclusion These findings suggest that obesity-associated meta-inflammation enhances prostate cancer cell migration and invasion, shedding light on mechanisms through which chronic inflammatory signaling may promote metastatic progression. Funding Source n/a Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)
Synergistic Control of Radiative Decay and Exciton Splitting Dynamics for Efficient Organic Solar Cells Processed by Non‐Halogenated Solvent
ABSTRACT The commercialization of organic solar cells (OSCs) is strongly essential by the use of non‐halogenated solvents, which unfortunately suffers from inferior photovoltaic performance. To raise the efficiency, expanding the donor/acceptor interfacial distance can elevate charge transfer (CT) state energy and enhance CT/local excitation (LE) hybridization to boost the radiative decay dynamics ( k r ) and further upgrade open‐circuit voltage ( V oc ). However, this morphological modulation inadvertently induces excessive phase separation, which impairs exciton dissociation and subsequently reduces short‐circuit current density ( J sc ). Herein, we rationally designed a novel trimer, T‐IOI, as the third component to tackle this circumstance, where the ameliorated miscibility with the acceptor phase can impede large crystalline aggregate clusters with the assist of steric hindrance effect. Moreover, its extended and folded configuration broadens donor/acceptor interfaces, which can elevate CT energy, strengthen CT/LE hybridization and further raise k r metric. Consequently, the photovoltaic performance of the corresponding small‐area (0.06 cm 2 ) device is significantly enhanced from 18.8% to 20.5% upon optimal incorporation ratio of T‐IOI. Furthermore, large‐area devices (1 cm 2 ) are successfully fabricated with a remarkable PCE of 19.0%, which not only surpasses that of the binary control device (15.6%) but also maintains excellent reproducibility alongside accelerated operational stability (T 80 : 830 h).
Unsupervised clustering identifies a CD161+ MAIT-like T cell population associated with anti—PD-1 response and immune-related toxicity in melanoma 2309523
Abstract Introduction Manual gating has been the standard for cytometry analysis but does not scale well to high-parameter panels. Unsupervised clustering enables unbiased profiling of immune cells without biaxial constraints. We developed an unsupervised clustering pipeline and applied it to 29 melanoma patients treated with anti—PD-1 therapy to identify immune populations associated with response and toxicity. Methods Peripheral Blood Mononuclear Cell (PBMC) samples from 29 melanoma patients (70 samples) treated with anti—PD-1 therapy provided by the Huntsman Cancer Institute were analyzed using a 43-marker mass cytometry panel. Cells were clustered using a self-organizing map to iteratively group cells with similar marker expression. Cluster identities were assigned using cosine similarity to manually gated reference populations, followed by expert quality control using cluster-versus-marker heatmaps and marker-specific UMAP expression overlays. Results Unsupervised clustering identified a distinct CD161+ memory mucosal-associated invariant T (MAIT)-like T cell population that was not captured by standard T cell subset and functional marker gating. This subset showed heterogeneous CD8 expression, low CD45RA, variable CD27, and high CD161, consistent with a memory-like MAIT phenotype. The frequency of this population was significantly higher in responders to anti—PD-1 therapy and increased during on-treatment timepoints in patients who developed immune-related adverse events, linking this subset to both therapeutic response and immune-mediated toxicity. Conclusion Unsupervised clustering of high-dimensional cytometry enables identification of immune populations that manual gating misses. Discovery of a CD161+ memory MAIT-like T cell population associated with both anti—PD-1 response and immune-related adverse events suggests overlapping immune mechanisms linking efficacy and toxicity. Unsupervised analysis reduces the risk of missing outcome-associated biomarkers in immunotherapy. Funding Source Teiko Topic Categories Computational and Systems Immunology (COMP)
Loss of the Vitamin D Receptor Exacerbates Influenza Severity Through Dysregulated Immunity and Elevated Parathyroid Hormone 2249087
Abstract Introduction Respiratory infections caused by influenza viruses remain a global health burden, with disease severity in part determined by host immune responses. Immune cells have vitamin D receptors (VDR) and vitamin D has been shown to regulate host immunity to infection. Methods Wild-type (WT) and VDR knockout (KO) mice were infected with mouse-adapted influenza A/H1N1 (A/California/04/2009(H1N1pdm09)). Some WT mice also received exogenous PTH. Clinical scores and lung histology assessed disease severity, whereas viral load, immune cell responses, and cytokine levels in the lungs were quantified by viral titration assay, qPCR, ELISA, and flow cytometry. Results WT mice cleared virus efficiently with non-lethal disease, whereas VDR KO mice had 22% mortality, delayed viral clearance, and exacerbated lung pathology. These outcomes were accompanied by heightened type I and II interferon responses, increased infiltration of myeloid cells and CD4+ T cells but less natural killer (NK) cells into the lungs. Vitamin D deficiency and VDR KO result in very high parathyroid hormone (PTH) levels. WT mice were treated with PTH to determine the effects of PTH on host immunity to influenza virus infection. Influenza virus infection in PTH treated WT mice resulted in more severe clinical scores, higher viral burden, and amplified IFN-γ responses compared to WT mice. Conclusion Vitamin D deficiency and high PTH combine to create a hyperinflammatory environment with excessive interferon production, delayed viral clearance, and tissue injury. The work highlights a novel paradigm in which the vitamin D-PTH axis governs host resistance to influenza virus disease by controlling the amount of inflammation and the amount of virus in the lung. The data suggest that a low cost vitamin D supplement would improve vitamin D status, and limit PTH-driven immune dysregulation protecting the lung against influenza virus infection. Funding Source This work was supported by the National Institutes of Health (NIH) grants R01AT005378 to M.T.C., T32GM154124 to M.T and T32DK120509 to N.E.F. And USDA National Institute of Food and Agriculture and Hatch Appropriations Projects #PEN04963 Accession #700657 Topic Categories Viral Immunology (VIR)
Functional Dynamics of Cytotoxic CD4+ T cells in Acute and Chronic Viral Infections 2259913
Abstract Introduction Classically CD4+ T cells are recognized for their helper functions in coordinating adaptive immunity; however recent studies have identified a unique subset of antigen experienced CD4+ T cells which acquire cytotoxic potential evidenced by their ability to eliminate MHC II+ targets in vivo. Though these cytotoxic CD4+ T cells (CD4 CTLs) play a crucial role in various chronic viral infections and cancers, the regulation of their function and in vivo target specificity remain unclear. Methods To study CD4 CTL dynamics, we used a well established mice model of acute (Armstrong) and chronic (Clone 13) LCMV infection. Results We demonstrate that both acute and chronic LCMV infections rapidly induce a subset of granzyme B and perforin-expressing Th1 cells with in vivo cytotoxic function. These cells are detectable as early as 48 hrs post-infection, and their killing activity is in part perforin-dependent. Intriguingly, in contrast to the sustained cytotoxic activity seen in acute infection, chronic infection triggers a progressive decline in CD4 CTL killing ability in vivo, that is restored upon PD-L1 blockade. The early killing activity suggested that these cells might regulate antigen presentation during infection. Using a 1:1 Wildtype:MHC II-/- bone marrow chimera model we show that MHC II-/- DCs (which are immune to CD4 CTL killing but susceptible to CD8 T cell and NK cell killing) undergo initial immune-mediated killing similar to WT DCs by 60 hours post LCMV-infection. However, by Day 9 of chronic LCMV infection a higher proportion of MHC II-/- CD8α+ DCs were LCMV-infected compared to wildtype CD8α+ DCs in the same mice, suggesting that CD4 CTLs play a role in limiting viral infection in this specific DC subset during chronic viral infection. Conclusion In conclusion, our study provides new insights into the dynamics of CD4 CTLs during acute and chronic viral infections, and begins to define their specific target cells in vivo. Funding Source Showalter Trust Foundation award, the Indiana CTSI and funds from IUSCCC and IU CCEH Topic Categories Viral Immunology (VIR)
ICAM-1 Adhesion Molecules Facilitate Immune Cell Docking at the Cribriform Plate Perineural Microenvironment in Aging 2258099
Abstract Introduction With aging, the immune system releases pro-inflammatory factors causing chronic inflammation or “inflammaging”. Within the aged central nervous system (CNS), myeloid cell populations increase due to inflammation-induced myelopoiesis within skull bone marrow compartments. Decreased waste removal through CNS lymphatics worsens inflammation and immune cell buildup, leaving the CNS prone to neurodegenerative disorders. This highlights the need to study CNS drainage sites like the cribriform plate (CP). The CP is a sieve-like structure within the ethmoid bone that holds olfactory bulbs and nerves passing from the CNS to the nasal epithelium. The CP also enables cerebrospinal fluid and waste drainage into nasal lymphatics and olfactory nerves. Previously, our lab has identified that the CP perineural regions contain an immune microenvironment that changes during neuroinflammation. We have shown that CP bone channels connect the bone marrow to olfactory nerve bundles, facilitating immune cell migration into the perineural space. It is unknown how immune cells dock within the perineural niche, and how the perineural microenvironment differs with age. Methods Utilizing immunohistochemistry, flow cytometry, and 3D Light sheet fluorescent microscopy Results we show that (1) the aged perineural immune environment has an increase in CD11b+ myeloid cells. (2) ICAM1 (CD54) adhesion molecule expression, area, and mean fluorescent intensity increases with age, and identified ICAM-1 as the docking protein located perineurally on TUBB3+ olfactory nerve bundles at the CP in elderly mice and humans. We propose that the accumulation of myeloid cells contributes to nerve damage in aging. We study markers of death (caspase-3) and gliosis (GFAP) within the olfactory nerve bundles to test this hypothesis. Conclusion These findings help elucidate the role of ICAM-1 within olfactory nerves and highlights potential therapeutic use of localized ICAM-1 drug therapy to preserve CNS drainage and olfactory nerve health. Funding Source N/A Topic Categories Neuroimmunology (NEUR)
Role of polyunsaturated fatty acids in regulating innate immune antiviral and inflammatory response during respiratory syncytial virus infection 2309103
Abstract Introduction Respiratory syncytial virus (RSV) infection causes of hyper-inflammatory lung diseases such as pneumonia and bronchiolitis in infants and neonates. RSV infection elicits strong innate immune inflammatory responses in macrophages by activating inflammasome pathway, which is involved in generating mature form of pro-inflammatory cytokines such interleukin-1β (IL-1β) and IL-18. However, the role of non-protein factors driving this response during infection remain poorly defined. Dihomo-γ-linolenic acid (DGLA , C20:3), an ω-6 polyunsaturated fatty acid, has recently emerged as an immunomodulatory lipid, but its role during viral infection, particularly RSV infection, has not been investigated. Methods Human THP-1 macrophages infected with recombinant RSV expressing mKate2 (mKate2-RSV) were treated with DGLA, oleic acid (18:1), and linoleic acid (18:2). RSV infection status was analyzed by measuring mKate2 expression by western blotting. Inflammasome activation was evaluated by measuring production of IL-1β and cleavage of pre-IL-1β to mature IL-1β (p17) by inflammasome/caspase-1 pathway. Results DGLA treatment significantly reduced RSV infection in macrophages. Simultaneously, DGLA triggered release of IL-1β and its mature cleaved p17 form even from uninfected macrophages. Notably, RSV-infected macrophages treated with DGLA showed enhanced IL-1β release compared with untreated infected cells. This effect was specific to DGLA, as no similar increase of IL-1β release was observed following treatment with linoleic acid or oleic acid. Conclusion These findings have identified DGLA as a potent regulator of RSV infectivity and inflammasome activation during RSV infection. DGLA-mediated enhancement of IL-1β maturation and release along with DGLA’s effect in reducing RSV infection highlights a previously unrecognized role for ω-6 fatty acid signaling in innate immune response against RSV. The mechanism by which DGLA mediates antiviral response and inflammasome activation will be discussed. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
nELISA high-throughput proteomic profiling of RADIOHEAD: insights from the largest plasma study of patients receiving checkpoint inhibitor therapy 2257210
Abstract Introduction Proteomics holds great promise for cancer immunotherapy, with intensive efforts being exerted for early disease identification, patients selection, and adverse event prediction. Despite this potential, the high cost and low throughput of existing tools to profile circulating proteins render such studies prohibitively slow and costly. Methods The Nomic platform, based on highly multiplexed immunoassay nELISA® technology, enables profiling of 1000 proteins at high throughput and low cost. Here, we leverage the Nomic platform to quantify ∼600 circulating proteins across ∼3000 samples from the RADIOHEAD cohort, a prospective study of 1070 immunotherapy naive pan-tumor patients on standard of care immune checkpoint inhibitor (ICI) therapy regimens. Results As previously reported, PD-1/PD-L1 inhibitors resulted in increased circulating levels of sPD-1/sPD-L1, and as well as several chemokines (CXCL9, CXCL10). We also identified 216 proteins associated with response to treatment, including established markers such as IL-6, and novel ones including Syndecan-1. Leveraging the longitudinal nature of the RADIOHEAD cohort, we used a window of 60 days prior to the onset of immune-related adverse events (irAEs) to identify 151 markers predicting their onset. Surprisingly, many of the markers most strongly associated with irAEs were cell surface receptors that were cleaved and released in circulation, including several immune receptors that are targets for immunotherapies in development. While PD-1 or PD-L1 cleavage is likely beneficial, other therapies require cell surface localization of their target to mediate cell killing, such as CAR Ts or ADCs. Conclusion We will discuss the implications of these findings for the development of immunotherapy combinations, as well as the potential role for circulating receptors in controlling irAE risk. Funding Source n/a Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Pulmonary immunomodulation by nitroalkenes: implications for asthma-associated inflammation 2267798
Abstract Introduction Allergic asthma remains a global health concern, due to its increasing prevalence and limited treatment options. This highlights the urgent need for new mechanistic understanding and alternative therapeutic approaches. In allergic asthma, hematopoietic cells including dendritic cells, eosinophils, and T helper subsets drive exaggerated inflammatory responses that sustain cytokine production and immune activation. Prolonged interactions between immune and structural cells induce epithelial reprogramming and epithelial-mesenchymal transition (EMT), leading to airway remodeling, matrix deposition, fibrosis, and ultimately irreversible airway obstruction. This causes transient inflammation into chronic disease. Nitroalkenes have emerged as bioactive lipid mediators with strong immunoregulatory potential capable of tempering airway inflammation. While prior studies have reported their protective effects in allergic airway disease, the cellular and molecular pathways responsible remain insufficiently understood. Methods The present study investigates how nitroalkenes influence immune cell recruitment and cytokine-mediated disruption of structural cell homeostasis in allergic asthma. Using a murine model of allergic airway disease (AAD), wild-type mice were given nitroalkenes orally, and pulmonary function was assessed by FlexiVent. Results Nitroalkene administration significantly improved lung function and decreased bronchoalveolar lavage (BAL) protein content and inflammatory cell count compared to controls, indicating lung-protective effects. However, the specific immune cell populations responsible for these improvements remain to be clarified. Conclusion Elucidating these mechanisms will reveal key regulatory nodes through which nitroalkenes restore airway equilibrium and suppress fibrotic remodeling, offering a promising direction for developing novel therapeutics against chronic, treatment-resistant asthma. Funding Source n/a Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)
Feasibility and Immunological Impact of Reusing Wild-Type C57BL/6 Mice in Systemic and Cutaneous Anaphylaxis Models 2309549
Abstract Introduction The reuse of laboratory animals across compatible immunological procedures offers a strategy to reduce animal numbers in line with the 3Rs principles. However, data on the physiological and immune effects of consecutive allergic or anaphylactic challenges remain limited. This study evaluated the feasibility and immunological impact of reusing C57BL/6 mice previously exposed to systemic anaphylaxis for a second moderate-severity challenge, either systemic or cutaneous. Methods Twenty-four 7-week-old male mice received an intravenous injection of compound 48/80 to induce systemic anaphylaxis (Run 1). Body temperature, hematological and cytokines were monitored at baseline, after Run 1, and on Day 5 before reuse. Seven days later (Run 2) mice underwent either a second systemic challenge or a cutaneous anaphylaxis via intradermal ear injection with mast cells agonists, combined with Evans Blue to monitor vascular permeability. Results During Run 1, transient hypothermia peaked 20—30 min post-induction, with full recovery within 80 min. In Run 2, the temperature drop was milder, and no mouse fell below 34 °C. Neutrophils transiently increased after Run 1 and returned to baseline, while lymphocytes showed the opposite trend. Cytokine concentrations increased after the first systemic challenge, returned to baseline and remained stable after the second exposure. Cutaneous responses and Evans Blue extravasation were comparable to single-use animals, confirming preserved immune and vascular responsiveness. No major modulation of other hematological parameters , and no behavioral distress were observed. Conclusion These findings demonstrate that mice can be safely reused for a second systemic or cutaneous anaphylaxis procedure after 5—7-days,with no exacerbation of immune or physiological responses, supporting ethical and scientific validity of controlled animal reuse in preclinical allergy research. Funding Source n/a Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)
Burn Baby Burn: Leveraging Fatty Acid Oxidation to Improve CD8+ T cell Efficacy Against Ovarian Cancer 2250461
Abstract Introduction CD8+ T cell differentiation upon activation is heavily influenced by type and availability of local nutrients. However, when nutrients are limited such as in a tumor microenvironment (TME), it has a strong negative impact on cytotoxic T cell survival and differentiation. In the metabolically hostile TME, quick progression of CD8+ T cell exhaustion paired with the immune evasion mechanisms of cancer cells results in a subdued immune response and poor prognosis. This is particularly problematic in ovarian cancer, a prominent and highly fatal gynecologic malignancy characterized by tumor development within fat deposits such as the omentum. We hypothesize that using PPARα agonist Fenofibrate (FF) can increase T cell usage of local fats to drive them towards a memory phenotype, promoting survival in the TME and enhance antitumor properties. As memory T cell populations can persist for longer durations, selecting for this phenotype may generate better CD8+ T cell function and tumor control. This project characterizes how augmentation of fat burning metabolism can increase the potential of CD8+ T cells as a therapy protecting against ovarian cancer. Methods CD8+ T Cells were treated with FF to transcriptionally enhance metabolic machinery required to support increased fatty acid oxidation (FAO). Impact on T cell metabolism and cytotoxic capacity under in vitro conditions mimicking the TME were evaluated by flow cytometry and Seahorse Mitostress Test. T cell survival, function and protection were tested in vivo, and T cells were isolated and analyzed ex vivo via flow cytometry. Results T cells treated with FF show enhanced memory phenotype and fat uptake, reduced terminal exhaustion, and higher spare respiratory capacity compared to untreated controls in vitro. Ongoing studies are investigating the presence of these trends in vivo. Conclusion Our data suggests Fenofibrate may enhance success of adoptive cell transfer therapy by improving the survival and function of CD8+ T cells in the ovarian TME. Funding Source NIH (NIAID) RO1 grant: CA257954 Dartmouth TQCR Training Grant: T32CA260626 BioMT Core Facilities: NIH NIGMS grant P20-GM113132. The Norris Cotton Cancer Center Grant: 5P30CA023108. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Helminth infection induces neuroimmune remodeling and clinical remission in a mouse model of multiple sclerosis 2260051
Abstract Introduction The central nervous system (CNS) is under constant immunosurveillance and is influenced by immune-related effector molecules, including type 2-associated cytokines, which have been shown to support healthy CNS function in a variety of contexts. Long-lasting type 2 immunity elicited by intestinal helminth infections can modify immune responses and wound repair locally and in peripheral tissues, but direct effects of helminth infection on the CNS are poorly understood. Here, we explore whether naturally evoked type 2 immune responses can modify neuroimmune interactions for therapeutic gain in a mouse model of multiple sclerosis. Methods Trichinella spiralis (Ts) is a helminth that infects both mice and humans, enabling identification of translationally relevant pathways of helminth-induced immunomodulation. Following Ts infection, mice were induced with experimental autoimmune encephalomyelitis (EAE) as a model of autoimmune neuroinflammation, and evaluated clinically, histologically, and immunologically with a particular focus on immune modulation within the CNS. Results Chronic infection with Ts remodelled the neuroimmune landscape, including establishment of a robust population of CNS-resident T helper (Th)2 cells and transient activation of microglia. Upon EAE induction, demyelination and infiltration of inflammatory Th17s into the CNS were reduced and resulted in clinical remission of EAE symptoms. Clinical remission was Stat6-dependent, relied on formation of CNS-resident immune populations, and could be promoted by adoptive transfer of Th2 cells in the absence of overt infection, highlighting the potential for helminth-primed Th2s to prevent neuroinflammation. Clinical remission and reduction of CNS-infiltrating Th17s could be induced therapeutically in relapsing-remitting EAE, suggesting therapeutic potential for helminth-mediated immunomodulation. Conclusion These findings highlight the potential for harnessing type 2 immunity to modify outcomes of neuroinflammation and neurodegeneration. Funding Source MS Canada, Canadian Institutes for Health Research, Research Corporation for Science Advancement, National Institutes of Health, Praespero Autoimmune Research Fund, Rutgers Busch Biomedical Grant Program Topic Categories Neuroimmunology (NEUR)
The Scavenger Receptor/Fatty Acid Translocase CD36 Promotes Optimal Expansion and Activation of CD11c+ T-bet+ B Cells 2258145
Abstract Introduction B cells expressing the pro-inflammatory transcription factor T-bet have been implicated in a variety of disease states, including obesity, aging, and autoimmunity. The dependence of this subset on innate signaling via TLR7/9 agonism in the presence of IFNg and IL-21 has been well characterized. However, less is known about the metabolic requirements that may sustain this population during chronic inflammation. Our laboratory has observed that CD11c+ T-bet+ B cells from murine tissues express high levels of the scavenger receptor/fatty acid translocase CD36, suggesting a critical role for this receptor in T-bet+ B cell differentiation and/or function. Methods To investigate the role of CD36 in this subset, a B cell-specific CD36 knockout was generated using Cre-Lox recombination. Splenic B cells from control or knockout mice were stimulated in vitro with the TLR7 agonist R848, oxLDL, or both. Flow cytometry was used to assess B cell expression of T-bet, CD36, CD86, and MHC-II. Reactive oxygen species (ROS) were also measured using CellROX Green. In vivo, expansion of splenic CD11c+ T-bet+ B cells was evaluated following R848 administration or high-fat diet (HFD) feeding. Results We found that in vitro, R848 drives T-bet and CD36 expression in B cells, resulting in intracellular accumulation of neutral lipids. B cells lacking CD36 had reduced levels of CD86, but not MHC-II, after stimulation with oxLDL, R848, or their combination. Cellular ROS levels, however, were not impacted by CD36 deletion in any stimulation condition. In vivo, deletion of CD36 from B cells was also found to significantly and selectively limit the expansion of splenic CD11c+ T-bet+ B cells following administration of R848, or after HFD. Conclusion Taken together, these findings implicate CD36 as a metabolic regulator of T-bet+ B cell differentiation and activation. Further work will delineate how CD36 integrates lipid uptake with immune signaling to shape T-bet+ B cell responses during chronic inflammation. Funding Source National Institutes of Health grant K12 GM111726. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)
Targeting IRF5 with selective covalent oral small molecules attenuates Type I IFN and pro-inflammatory cytokine secretion in human PBMCs and in mice 2309520
Abstract Introduction Interferon regulatory factor 5 (IRF5) is an undrugged transcription factor strongly associated with autoimmune diseases including systemic lupus erythematosus (SLE), Sjögren’s syndrome, and rheumatoid arthritis. In those diseases IRF5 is dysregulated, causing proinflammatory cytokine and Type I interferon (IFN) secretion, exacerbating inflammation. Knockout of IRF5 suggests its loss protects from inflammatory arthritis, colitis, and SLE, positioning IRF5 as a highly attractive target for dampening pathological inflammation. This study reports the discovery of IRF5 inhibitors to control autoimmune disease. Methods A novel, cell-based DNA-encoded library platform–OmniDEL–was used to screen for IRF5 inhibitors. Compounds were characterized in acutely stimulated THP-1 cells, human peripheral blood mononuclear cells (PBMCs), human monocytes, and mouse models. A TLR7/8 agonist, R848, was used to stimulate cells and trigger secretion of Type I IFNs and cytokines, which were quantitated by ELISA. High content imaging assessed IRF5 nuclear translocation. Results OmniDEL produced IRF5 hits from cell lysates. Off-DNA initial hits confirmed covalent engagement by mass spectrometry, exhibited selectivity for IRF5 vs family members, and inhibited PBMC cytokine responses. In a dose dependent manner, initial hits and improved compounds inhibited IRF5 nuclear translocation in monocytes, and inhibited cytokine secretion –including IL-6, TNFα, IL-12, and IL-1β–in monocytes and PBMCs. Upon R848 stimulation, compelling inhibition was observed in normal mice and in mice with a humanized immune system. No toxicity was observed in mice dosed twice daily at high levels for up to 7 days. Conclusion This study describes the discovery and proof-of-concept of the first covalent IRF5 small molecule inhibitors. These data support advancement towards DC nomination and clinical development with the goal of developing a best-in-class oral therapy for the treatment of autoimmune and other serious inflammatory diseases. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)
Why do we need a New Bloom’s Taxonomy for Gen Z? 2257384
Abstract Introduction Gen Z has grown up in a digital-first world where multitasking, quick information processing, and visual learning are every day. Traditional Bloom’s Taxonomy–though important–was developed before the digital age and may not fully capture the cognitive shifts caused by constant connectivity and multimedia use. Today’s learners need skills that extend beyond the original taxonomy. Competitive skills like digital literacy, media evaluation, coding, design thinking, and collaborative problem-solving are now crucial. A revised taxonomy could better account for these 21st-century skills. Methods We at Chicago State University used appropriate surveillance methods, such as direct observation, digital monitoring, biometric sensors, and self-reporting tools. Ensured ethical practices by obtaining informed consent, protecting privacy, and maintaining transparency. Used tools such as LMS analytics, screen-monitoring software, and video analysis platforms to collect data. Analyzed the data using qualitative or quantitative methods. Results Our research shows that Gen Z often learns in non-linear, self-guided ways using YouTube, social media, and interactive platforms. The hierarchical structure of Bloom’s (from remembering to creating) may not accurately reflect the fluid, iterative process in which Gen Z acquires and applies knowledge. Emotional intelligence, empathy, and global citizenship are becoming more important in education. A modern taxonomy might need to explicitly include the domains of effectiveness and social impact to better align with Gen Z’s values and the broader goals of holistic education. Conclusion Instead of abandoning Bloom’s Taxonomy, a reimagined or expanded version could retain its core strengths while incorporating new elements relevant to today’s learners. Some scholars have already proposed models like Digital Bloom’s Taxonomy or Heick’s Taxonomy of Learning, which adapt the original framework for contemporary contexts. Funding Source n/a Topic Categories Immunology Education and Communication (EDU)
Multimodal analysis resolves GNG4 as a distinguishing feature of activated germinal center-resident T follicular helper cells in humans 2258382
Abstract Introduction CD4 T follicular helper (Tfh) cells coordinate humoral immune responses within germinal centers (GC) of lymphoid tissues. Although Tfh are known to play critical roles in vaccination and autoimmunity, gene expression programs that define distinct Tfh states in humans remain unclear. Further, the precise molecular programs spatially engaged by Tfh within the GC compartment are undefined. Such ambiguity has limited translational efforts to monitor or target specific GC Tfh states for clinical benefit. Methods Here, we delineated CD4 T cell heterogeneity in human tonsils and blood using paired spectral flow cytometry and a trimodal single-cell sequencing platform to define protein, transcriptional, and epigenetic features of distinct Tfh states. To identify features that are anatomically restricted to GC-resident Tfh, we performed spatial transcriptomics on human tonsils. Finally, we tested our findings by reanalyzing longitudinal human lymph node samples following vaccination. Results Tfh with an activated GC-like phenotype were highly enriched in chromatin accessibility, transcripts, and protein expression of GNG4 (encoding G protein subunit gamma 4). Integrated analyses of Tfh epigenomic and transcriptional states implicated NFATC1 in GNG4 induction during Tfh activation. In spatial transcriptomic analysis of tonsils, GNG4 expression distinguished activated Tfh states within spatially resolved GC rather than nonGC anatomic compartments, outperforming conventionally GC-associated features of Tfh such as BCL6, TOX2, and B3GAT1. Finally, we found that GNG4 was specifically induced in Tfh in vivo and increased over time in a reanalysis of previously published BNT162b2 mRNA and quadrivalent influenza vaccination data. Conclusion Together, these data identify GNG4 as a distinguishing feature of activated GC Tfh states in humans. In ongoing work, we will investigate the role of GNG4 in Tfh function, with implications for GC responses in human health and disease. Funding Source Sam Barnett Dubensky was supported by the NIH Medical Scientist Training Program T32 (GM007170). This research was supported by the Doris Duke Foundation (2021190) and NIH (K08AI136660) (to Laura A. Vella); the Parker Institute for Cancer Immunotherapy and V Foundation for Cancer Research, co-sponsoring a Parker Bridge Fellow Award (to Derek A. Oldridge); the NIAID (AI179680) and Jeffery Modell Foundation (to Neil Romberg); as well as the Burroughs Wellcome Fund and CHOP Research Institute (to Sarah E. Henrickson). Topic Categories Immune Mechanisms of Human Disease (HUM)
Tailored Surface Microenvironment of Molecular Nanophotocatalysts for Boosting Photocatalytic Hydrogen Evolution
ABSTRACT Organic photocatalysts are an attractive platform for solar‐to‐chemical energy conversion, but their performance is often constrained by bulk aggregation, poor light penetration, and rapid exciton recombination. Although surfactant‐assisted nanostructuring can help alleviate aggregation, surfactants are generally treated as passive stabilizers with little direct influence on photocatalytic function. Here we show that surfactants can actively engineer the interfacial microenvironment of organic nanophotocatalysts, leading to substantially enhanced photocatalytic hydrogen evolution. A donor–acceptor small molecule, CNP90, is co‐assembled with either hydrophilic polyethylene glycol (PEG) or amphiphilic Tween surfactants (Tween 20, T20; Tween 80, T80) via nanoprecipitation to afford a series of tailored nanophotocatalysts. Although all surfactants improve colloidal stability, T20/CNP90 exhibits markedly enhanced photoluminescence quantum yield and charge generation, leading to a more than 16‐fold increase in the hydrogen evolution rate to 520.17 mmol g −1 h −1 , among the highest values reported for organic photocatalysts. Spectroscopic studies combined with molecular dynamics simulations reveal that T20 constructs an amphiphilic interfacial microenvironment around CNP90, comprising a hydrophobic inner shell that suppresses nonradiative recombination and a hydrophilic outer corona that promotes water access to catalytic sites. These insights establish surfactant‐driven microenvironment engineering as a powerful, low‐cost, and generalizable paradigm for maximizing the performance of organic photocatalysts.
Xenotransfusion of Triple-Knockout Porcine Red Blood Cells: Effects of hCD55/hCD39 Expression and Anti-CD154 Therapy in Non-Human Primates 2234209
Abstract Introduction Global aging and emerging infectious diseases threaten the stability of blood supplies, underscoring xenotransfusion as a potential alternative. Triple-gene knockout (TKO) pig red blood cells (pRBCs), which lack α-Gal, Neu5Gc, and SDa, can avoid acute hemolysis but exhibit shorter survival than allogeneic RBCs. We investigated the roles of complement activation and antibody induction in the clearance of pRBCs in non-human primates (NHPs). Methods Blood from O-type TKO pigs and TKO pigs expressing human CD55 and CD39 (TKO/hCD55.hCD39) was used for pRBC preparation. After 25% blood volume withdrawal, NHPs received one of the following: TKO pRBCs alone (TKO_XTf, N = 8), TKO pRBCs with PG-405 [anti-CD154(Fab)-NTIG-IL-10; 30 mg/kg IV] followed by repeat administration of PG-405 3 days later (TKO_XTf_aCD154, N = 4), or TKO/hCD55.hCD39 pRBCs (TKO/hCD55.hCD39_XTf, N = 4). Hematologic, biochemical, cytokine, complement, and antibody responses were evaluated at multiple time points. Results No acute hemolytic reactions or other severe adverse events were observed in any group, and transfusion promptly restored vital signs compromised by blood loss. In the TKO/hCD55.hCD39_XTf group, the post-transfusion rise in plasma factor Bb was delayed compared with other groups. In the TKO_XTf_aCD154 group, the rapid increase in anti-pRBC antibodies post-transfusion was markedly suppressed. Although both complement activation and antibody induction were effectively inhibited, the hematologic benefits of transfusion persisted for more than 24 hours but were lost within 72 hours across all groups, providing no significant survival advantage over TKO_XTf controls. Conclusion Complement and antibody inhibition alone are insufficient to prevent clearance of pRBCs in xenotransfusion, indicating the need for additional strategies. Further studies are required to elucidate the molecular pathways mediating interactions between splenic macrophages and pRBCs, which likely play a critical role in clearance. (Grant No. 22-CM-EC-18) Funding Source the Defense Acquisition Program Administration and the Ministry of Trade, Industry, and Energy of the Korean Government (grant no. 22-CM-EC-18) Topic Categories Translational and Interventional Immunology (TI)