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2D In‐Plane Molecular Superlattice Heterojunctions for High‐Performance Ambipolar Electronics and Low‐Dose X‐Ray Sensing
ABSTRACT Two‐dimensional in‐plane molecular superlattice heterojunctions, where distinct semiconducting components are integrated laterally within a single crystalline plane, offer an ideal architecture for controlling charge separation and transport in optoelectronic devices. However, realizing such structures with molecular‐level precision, long‐range periodicity, and sharp interfaces in organic semiconductors remains a major challenge. Here, the first 2D organic heterojunction featuring long‐range, in‐plane donor–acceptor superlattice via cocrystal engineering is presented. By employing phase‐separated molecular design for the donor (TIPS‐PEN) and acceptor (PDI‐FCN), strong in‐plane cohesion is decoupled from out‐of‐plane steric repulsion, inducing a periodic –D–A–D– arrangement within the crystal plane. The resulting high‐density, lattice‐defined heterointerfaces facilitate exciton dissociation, directional charge transport, and efficient extraction. The ultrathin crystal enables effective gate‐field control, yielding ambipolar OFETs with exceptional on/off ratios of 10 8 (holes) and 10 7 (electrons). Capitalizing on the narrow bandgap and the ordered 2D heterointerface, this material demonstrates outstanding high‐energy photon conversion efficiency. As an X‐ray detector, it exhibits high sensitivity of 4.21 × 10 4 µC Gy −1 cm −2 and low detection limit 5.73 nGy s −1 , enabling clear imaging at 14.77 nGy s −1 ultralow dose rate. This work provides new ideas for constructing 2D multicomponent organic heterostructures and unlocks potential for next‐generation flexible electronics and low‐dose radiation sensing.
Enhancement of Regenerative Activity Subsequent to SenoVax(TM) Senolytic Immunotherapy Cholesterol controls the pore-forming activity of mammalian gasdermins 2260188
Abstract Introduction Pyroptosis is a lytic form of cell death that requires pore formation by members of the gasdermin family of proteins. Gasdermin domains are liberated from their carboxy-terminal autoinhibitory domains to release an amino-terminal pore forming fragment that executes pyroptosis. A number of host- and pathogen-derived proteases are described that mediate this conversion during pyroptosis. Gasdermin D (GSDMD) is the most well characterized member of the gasdermin family in mediating IL-1 family cytokine release and pyroptosis downstream of inflammasome signaling. Methods Through a screen designed to find host regulators of NT-GSDMD pore forming activity, Results we discovered endosome adaptors including Rabgef1, control NT-GSDMD pore formation at the plasma membrane. Deficiency in Rabgef1 causes cholesterol accumulation in membranes within macrophages and defects in NT-GSDMD pore formation. Depletion of cholesterol through several orthogonal means rescues pyroptosis in endosome adaptor deficient macrophages. Mechanistic analysis revealed that Rabgef1 and cholesterol content is a general regulator for the gasdermin family of pore forming domains. Prior studies have illustrated that cholesterol content of the plasma membrane is adaptable to prevent bacterial intoxication and viral entry. Conclusion Our results suggest that these same cholesterol adaptations that endow a cell with resistance to initial pathogen encounter also poise the host to commit to pyroptosis. We posit that the combination of metabolic sensitization with active gasdermin fragments represent a novel modality in innate immune-inspired cell death immunotherapy. We accomplish this with proof-of-concept synergistic death induction through engineered cell models or synthetic killer mRNAs to enforce gasdermin fragment expression combined with regimens to deplete cellular cholesterol. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
“Do not eat me’’: LILRB4 signaling as a novel macrophage immunotherapy in lung cancer 2254327
Abstract Introduction Lung cancer is the leading cause of cancer-related deaths. Although current T cell-targeting immunotherapies have improved patient survival, the efficacy is still low. Today, macrophage-mediated immune escape via “do not eat me” signaling is brought to light. The leukocyte immunoglobulin-like receptors (LILRs) are new targets for cancer immunotherapy aimed at tumor-associated macrophages (TAMs). Methods TAMs from lung cancer patients were FACS-sorted and processed for RNA sequencing. Opal multiplex staining on patient microarrays was used to investigate the cellular expression of LILRB4 in the tumor microenvironment. Peripheral blood mononuclear cells (PBMCs) were differentiated into macrophages and co-cultured with cancer cells to obtain in vitro TAMs. qPCRs and Western blotting were performed to evaluate the expression levels of LILRs on TAMs. The functional effect of LILRB4 knockdown TAMs (KD) on cancer cells was studied by flow cytometry. RNA-seq was conducted to elucidate how LILRB4 regulates phagocytosis in TAMs. Further LILRB4 blockage was applied on the ex vivo model of human precision-cut lung slices (PCLS) and in in vivo lung cancer models. Results A comprehensive analysis of the expression profiles of LILRs revealed that among LILRs, LILRB4 is highly expressed in TAMs. In vitro, TAMs-specific blockage of LILRB4 had no effect on cancer cell proliferation and apoptosis, but significantly increased their phagocytosis. RNA sequencing identified differential expressed genes in LILRB4 KD TAMs, which indicate that silencing of LILRB4 inhibits cell cycle progression of TAMs. This result was confirmed by flow cytometry and correlated with reduced phagocytic activity in the G2/M phase. In addition, blocking LILRB4 ex vivo and in vivo reduced tumor growth and differentially affected the immune cell composition. Conclusion Taken together, our data suggest that LILRB4 may play a role in macrophage-specific immune evasion in lung cancer and is a promising target for lung cancer immunotherapy. Funding Source Institute for Lung Health Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Regulation of neutrophil activity by novel potato-derived peptide 2261086
Abstract Introduction Neutrophils, key effectors of innate immunity, respond through phagocytosis, degranulation, and release of neutrophil extracellular traps (NETs). While essential for host immunity, extensive dysregulated NETs can lead to chronic inflammation and tissue injury. Despite their pathological relevance in multiple chronic illnesses, effective therapeutic strategies for targeting NET-associated inflammation remain understudied. Methods In this study, we investigated the effects of previously identified TNKPVI, a biostable potato-derived peptide, on Lipopolysaccharide (LPS)-activated human neutrophils and macrophages. The levels of key inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin (IL-6), and interleukin-8 (IL-8) were quantified using ELISA. We also evaluated the effect of TNKPVI on reactive oxygen species (ROS), and nuclear factor erythroid 2—related factor 2 (Nrf2). Lastly, the peptides’ role on neutrophil extracellular traps (NET) formation was examined using immunofluorescence microscopy. Results Our results showed that TNKPVI significantly reduced the levels of inflammatory cytokines; IL-6, IL-8, and TNF-α in LPS-activated neutrophils and macrophages. Moreover, TNKPVI increased Nrf2 expression while suppressing intracellular ROS in LPS-induced human neutrophils. Microscopic examination followed by immunofluorescence staining showed reduced extracellular DNA colocalized with neutrophil elastase, a signature of NETs in PMA-activated neutrophils. Conclusion These findings suggest that TNKPVI exhibits potent anti-inflammatory and antioxidant properties by attenuating ROS production, activating NRF2 pathways, and inhibiting NET formation. Collectively, these results support TNKPVI as a potential therapeutic candidate for NET-associated inflammatory disorders. Funding Source n/a Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)
Synergistic Activation of TLR Adaptors MyD88 and TRIF Induces Inflammatory Cell Death in Infection 2260795
Abstract Introduction Severe infections often cause life-threatening inflammation, multi-organ failure, and death. During infection, pathogens carry multiple pathogen-associated molecular patterns (PAMPs) such as LPS, flagellin, nucleic acids, and lipoproteins which activate more than one pattern-recognition receptor (PRR). These PRRs trigger cytokine secretion and inflammatory cell death to control pathogen load; however, a dysregulated immune response can lead to excessive inflammation and lethality. While earlier studies have primarily focused on single PAMP responses, cells in vivo are exposed to multiple microbial ligands simultaneously. Methods Primary bone marrow-derived macrophages (BMDMs) were stimulated with PAMPs, and real-time imaging of cell death was performed using the IncuCyte system. Microarray analysis was conducted to examine differential gene expression. Results We found that specific PAMP combinations induce lytic cell death, while other combinations do not. Toll-like receptors (TLRs) and their adaptor molecules, MyD88 and TRIF, functioned as upstream regulators that activated inflammatory cell death. In addition, signaling through the interferon-α/β receptor (IFNAR) and interferon regulatory factor 1 (IRF1) was essential for the induction of inflammatory cell death. We also performed microarray analysis to understand the upregulated and downregulated genes in PAMP combinations compared with the untreated control. Through this analysis, we identified significant differences in specific molecules, and we performed genetic, functional validation to show that these molecules directly modulated the induction of inflammatory cell death. Conclusion These findings identify key mediators of lytic cell death and suggest that targeting these pathways can be used to mitigate inflammation and lethality during infections. Funding Source This research was supported by NIH grants AI101935, AI124346, AI160179, AR056296, and CA253095 and the American Lebanese Syrian Associated Charities to Dr. Kanneganti. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
IRF1 tunes the IRF4—IRF8 axis to drive effector B-cell fates in autoimmunity and inflammaging 2258675
Abstract Introduction Interferon regulatory factor 1 (IRF1) links IFNs and TLR signals to lymphocyte programs, yet its role in B cells and systemic lupus erythematosus (SLE), a disease driven by IFN-induced dysregulated B cell responses, is unclear. Methods Results We show that human SLE B cells have higher IRF1 mRNA levels and increased chromatin accessibility at IRF1 binding motifs compared to healthy donor B cells. In keeping with this, enforced IRF1 expression in human B cells induced a core effector gene module (TBX21, STAT1, IRF4), increased proliferation and enhanced antibody-secreting cell (ASC) differentiation. Consistent with this, global or B cell—intrinsic Irf1 deletion in aging B6 and lupus-prone Yaa.Fcγr2b—/— mice contracted ASCs and age-associated B cells (ABCs), while expanding germinal-center (GCB) and memory B cell (Bmem) pools. These shifts resulted in lower autoAb production, attenuated glomerular immune-complex deposition, reduced renal pathology and extended survival. Mechanistically, IRF1 regulated the transcriptome and epigenome of B cells to drive inflammatory ASC, ABC and effector Bmem programs enriched for expression of IFN-stimulated genes, proliferation, and secretory/stress modules that are required for pathogenic B cell identity. Loss of Irf1 prevented activation of these programs and redirected B-cell programs toward a resting-like memory fate, in part by controlling the balance of Irf4 and Irf8 expression in ASC-precursors. Multimodal integrated regulatory potential modeling following probabilistic in silico deletion of TF binding regions revealed that IRF1 regulates Irf4 by tuning the chromatin accessibility surrounding the Irf4 gene. Consistent with the multi-omics data, Irf1-deficient B cells exhibited a lower IRF4/IRF8 ratio and failed to proliferate and differentiate into ASCs in vitro. Conclusion Thus, IRF1 serve as a rheostat that controls the balance of IRF4 and IRF8 to regulate B cell differentiation programs. Funding Source NIH (R01 AI110508 & R01AI153365) Topic Categories Basic Autoimmunity (BA)
Early-life Fungal Colonization Reveals Stage-specific Immune Regulation in the Oral Mucosa 2241171
Abstract Introduction Neonates possess a developing immune system, which is different from adults as a result of initially living in a semi-allogeneic sterile environment to then being exposed to a microbial-rich surrounding, rendering newborns highly susceptible to infections. Following microbial exposure, the mucosal immune system of neonates goes through successive, non-redundant phases that support the developmental needs of the infant to establish immune homeostasis. However, it remains unknown how neonates prevent fungal outgrowth during colonization, representing a critical gap in knowledge. Methods To address this, we developed a novel mouse model of neonatal commensal Candida albicans colonization that results in persistent fungal presence. Single cell RNA sequencing was utilized to obtain a comprehensive view of gene expression dynamics. Results Early during colonization, proinflammatory cytokines were downregulated with increased porpotion of CD25+ Foxp3+ Treg and CD25+ Foxp3- T cells, likely to mitigate excessive immune activation and promote tolerance. Unexpectedly, CCL11 levels were elevated during early fungal persistence. Neutralization of CCL11 reduced oral fungal burden, suggesting a role in mediating tolerance. Later during colonization, IL-22-mediated immunity and associated tissue remodeling plays a critical role in controlling fungal burden and preventing fungal invasion. Furthermore, single-cell RNA sequencing revealed dynamic shifts in immune cell subpopulations over time. Conclusion In summary, neonatal fungal colonization elicits dynamic immune responses that contribute to maintaining homeostasis at the oral mucosal barrier. Funding Source NIAID R21AI187999 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)
Chronic lung exposure to Saccharopolyspora rectivirgula leads to a pulmonary fibrotic pattern in mice 2257218
Abstract Introduction Hypersensitivity pneumonitis (HP) is an immune-mediated pulmonary disorder resulting from repeated exposure to environmental agents, such as Saccharopolyspora rectivirgula (SR) antigens, responsible for Farmer’s lung. This disease progresses from acute alveolar inflammation to a chronic stage characterized by the development of pulmonary fibrosis in humans. The only effective treatment to date is avoidance of antigen exposure, which is difficult to achieve for workers. An acute mouse model of HP in response to SR is already widely used in the field; however, evidences of fibrosis and the development of pulmonary function alterations in a chronic model of HP remain lacking, undermining our ability to develop relevant therapies for patients. The objective of this study is to develop a chronic and fibrotic mouse model of HP induced by SR antigens with better relevance to human HP pathophysiology. Methods Mice were exposed intranasally to SR antigens for three consecutive days per week, followed by a four-day rest period. This cycle was repeated for 6, 8, 10 and 12 weeks. Pulmonary function was analysed with the FlexiVent system, followed by broncho-alveolar lavage (BAL) and lung tissue collection. Samples were analyzed with flow cytometry to characterize inflammatory cell populations. Results Chronic exposure led to increased alveoli and tissue CD4 and CD8 T cells, alveolar macrophages and neutrophils infiltration in time. Functional data analyses revealed decreased inspiratory capacity and static compliance with a tendency towards increased elastance between 8-12 weeks of exposure (compared to unexposed mice), all indicative of a fibrotic respiratory pattern. The presence of fibrosis will be further confirmed via histological and gene expression analyses. Conclusion Chronic exposure to SR leads to chronic inflammation and a fibrotic pulmonary function pattern. This model is of utmost importance for understanding fibrosis-associated mechanisms and evaluating potential therapeutic strategies for HP. Funding Source Canadian Institutes of Health Research (CIHR) Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)
Feed‐Draw Printing Enables Monolithically Integrated Flexible Sensors With High Interfacial Toughness and Wide Linear Range
ABSTRACT Flexible sensors are essential for wearable electronics and robotic perception, yet their practical deployment is fundamentally constrained by the compromise between sensing sensitivity and mechanical durability, as well as the deficiency in achieving robust integration with other functional components. Here, we report a monolithic microcone capacitive sensor (MMCS) fabricated via a feed‐draw printing (FDP) strategy, which enables the direct fabrication of programmable microcone morphologies and in situ co‐curing across dielectric and electrode layers. This strategy generates continuous, covalently interlinked interfaces with interfacial toughness of up to 1 547 J m −2 , representing 3.97 times that of existing microcone counterparts. As a result, the MMCS exhibits outstanding durability, maintaining stable performance over 200 000 loading cycles. Meanwhile, the programmable microcone morphology offers on‐demand sensitivity tuning (reaching 0.29 kPa −1 ), achieving a low limit of detection of 1 Pa and a wide measurement range from 0 to 450 kPa. Furthermore, the MMCS is monolithically printed into wearable bands for sports analytics, and within magnetic soft grippers for grasping perception. This work establishes a generalizable route for covalently bonded, sensitivity‐enhanced, and functionally integrated soft sensors, paving the way for high‐performance practical wearable and robotic interfaces.
Lattice‐Matched 2D Template Enables Efficient Cesium Tin Halide Perovskite Solar Cells
ABSTRACT Cesium tin iodide (CsSnI 3 ) has emerged as a promising inorganic light‐absorber for lead‐free perovskite solar cells (PSCs) due to its ideal bandgap of 1.3 eV and intrinsic thermal stability. However, its application is limited by random crystallization and spontaneous δ‐CsSnI 3 phase transition, causing substantial photovoltaic performance losses. Here, we employ lattice‐matched 2D perovskite templates to induce the oriented growth of 3D perovskites, enabling phase‐pure 2D/3D perovskite heterostructures for efficient and durable CsSnI 3 ‐based PSCs. Compared to their alkyl counterparts, 2D perovskites adopting aromatic spacer cations introduce additional interlayer π – π stacking to inhibit octahedral tilting and minimize their lattice spacing mismatch with 3D CsSnI 3 . This improved crystallographic compatibility promotes oriented growth of 2D/3D heterostructures along the (110) plane, regulating the crystallization kinetics and creating an additional energy barrier that suppresses δ‐CsSnI 3 phase formation. As a result, the optimized CsSnI 3 ‐based PSCs deliver a champion power conversion efficiency (PCE) of 15.27% with a high open‐circuit voltage of 0.90 V. Benefiting from reduced trap states and eliminated δ‐CsSnI 3 phase impurities, the target devices exhibit markedly improved operational stability, retaining over 95% of their initial PCE after 1280 h at maximum power point tracking under continuous one‐sun illumination in nitrogen without encapsulation.
Robust T Cell Activation Kills Tumors Regardless of T Cell Specificity 2260126
Abstract Introduction Solid tumors are populated with functional, non-circulating virus-specific CD8+ T cells, primed for rapid response to re-infection. Immunosurveillance by these memory T cells is evident across multiple tissues and solid tumors. Activation of these bystander cells triggers clearance of poorly immunogenic tumors in mice and is phenocopied in human tumor explants through unknown mechanisms — putatively involving the adjuvanting of tumor-specific T cell responses — providing the basis for a Phase I immunotherapy trial termed peptide alarm therapy (PAT). Methods To define mechanisms of PAT mediated tumor clearance in murine models, we used single-cell multi-omics, targeted immune cell depletions, and genetic manipulations. We mapped how viral peptides influence antiviral T cell states and by what axes they signal to activate the innate and adaptive immune system to mount an effective response against malignant cells. We validated our multi-omic approach via in vivo studies to measure treatment efficacy in the context of key immune cell depletion and pathway inhibitions. Results We initially hypothesized that tumors were cleared in an antigen-specific manner; however, PAT cured without conventional recognition-dependent mechanisms and in the absence of any tumor-specific TCRab T cell. Mechanistically, robust T cell activation recruited immune cells, utilized innate leukocytes, and triggered a tumoricidal combination of effector molecules and panoptotic pathways, resulting in tumor-specific clearance independent of conventional T cell mechanisms. IFN-γ, TNF, and NO induced caspase-dependent death, recapitulating melanoma cures in mice or human melanoma cell death in vitro. Gene expression signatures of immune and tumor cell types involved in this panoptotic pathway were predictive of survival among human melanoma patients. Conclusion Thus, triggering productive T cell activation within tumors can be sufficient for immunotherapy, without needing to induce or rescue cancer-specific responses. Funding Source F30CA253992, R01CA238439, DP1238659 Topic Categories Computational and Systems Immunology (COMP)
Enhancing antibody delivery to the brain using antiviral immune response 2256145
Abstract Introduction Glioblastoma (GBM) is the most aggressive primary brain tumor in adults with an incident rate of 12,000 cases in the United States every year. Current treatment options for these patients include surgical resection, radiation, and chemotherapy. Despite these conventional treatments, patients have a dismal prognosis mostly due to the inability to deliver therapeutic agents across the blood-brain barrier. In recent years, the use of oncolytic picornavirus has been employed as a novel virotherapy for GBM. We hypothesized that we could enhance antibody delivery to the brain through harnessing the immune response associated with this oncolytic virus. Prior work from our lab has shown that CD8 T cell engagement with MHC class I on brain endothelium induces CNS vascular permeability which is dependent on perforin. We therefore asked if picornavirus antigen specific CD8 T cells could enhance antibody delivery to the brain. Methods To test this, we evaluated the potential of activating MHC class I restricted CD8 T cells in vivo through intravenous administration of their cognate picornavirus antigens. Results We determined that this approach enhanced delivery of antibody to brain parenchyma. Importantly, antibody delivery to the brain was still enhanced when CD8 T cells lacked perforin expression which significantly reduced the toxicity of this combination approach. Conclusion These findings demonstrate that theCD8 T cell response towards virotherapy can be harnessed to promote delivery of therapeutic antibody to the brain. Funding Source NCI — R01 CA 94953 NINDS — R01 NS122174 NINDS —R01 NS103212 Mayo Clinic Graduate School of Biomedical sciences Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Kindlin-3 splicing variants mark stress granulopoiesis 2261219
Abstract Introduction Mutations in the FERMT3 gene cause Leukocyte Adhesion Deficiency type III (LAD-III), a rare immunodeficiency characterized by recurrent infections. FERMT3 encodes kindlin-3, a protein essential for integrin activation, and a longer splice variant that differs by the insertion of four amino acids–Ile-Pro-Arg-Arg (IPRR)–within the pleckstrin homology (PH) domain (kindlin-3-IPRR). The expression pattern and function of the IPRR-containing isoform in neutrophil adhesion remain unclear. Methods Kindlin-3 knockout HL-60 cells and mouse hematopoietic stem cells (HSCs) were reconstituted with kindlin-3 short or kindlin-3-IPRR long isoforms by viral transduction. β2 integrin activation was assessed by an antibody reporter binding assay. Cell adhesion was measured in a flow chamber under flow or static conditions. FERMT3 splicing patterns in neutrophils from healthy donors and patients undergoing stress myelopoiesis induced by granulocyte colony-stimulating factor (G-CSF) or HSC transplantation were analyzed using RNA sequencing datasets. Results Kindlin-3-IPRR is functional in activating β2 integrins and supporting neutrophil adhesion. The IPRR insertion promotes kindlin-3 association with the plasma membrane. Analysis of RNA sequencing data reveals that the long kindlin-3-IPRR isoform is enriched in both hematopoietic stem cells and mature polymorphonuclear neutrophils (PMNs), suggesting a critical role in these populations. Kindlin-3-IPRR rescued the adhesion defect of kindlin-3 KO mouse HSCs. Notably, G-CSF treatment markedly increased expression of the long isoform in normal-density neutrophils (NDNs), whereas G-CSF—induced low-density neutrophils (LDNs) exhibited upregulated levels of the short isoform. Conclusion These findings suggest that stress conditions differentially regulate kindlin-3 isoform expression in human neutrophils. The kindlin-3-IPRR isoform is functional and may be necessary for NDN mobilization in response to G-CSF and could serve as a molecular signature of stress myelopoiesis. Funding Source NIH R01HL174533 Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)
Beyond Memorization: Active and Adult Learning Strategies in Undergraduate Immunology 2241521
Abstract Introduction Learning immunology can be intimidating for undergraduates, but engaging directly with real-world examples can make complex concepts easier to grasp. This study examines an undergraduate immunology course at the University of North Dakota School of Medicine & Health Sciences, designed using adult learning principles and active learning strategies. In this course, students spend about a third of class in interactive lectures and the remainder in collaborative activities such as clinical case studies and problem-solving exercises. Instead of relying on traditional exams, student understanding is measured through weekly quizzes and participation in case studies and other learning activities, encouraging them to apply concepts rather than just memorize facts. Methods A mixed-methods approach was designed to measure student gains in content knowledge and perceptions of learning with these pedagogical methods. Data collection occurs at three points throughout the semester, including pre/post assessments and surveys to explore student engagement, perceptions, and motivation. Results 53 students completed a 50-question pre-quiz to gauge baseline understanding. Scores ranged widely, from 10 to 32 out of 50, indicating that many students began the course with only partial familiarity with core immunology concepts. Initial data collection (pre-test and initial perceptions survey) has been completed, and additional data from mid-semester and final surveys will be gathered to track student learning and perceptions over time. Conclusion We anticipate that students may initially perceive the course as less “intellectually demanding” without high-stakes exams, we expect that evidence from assessments and surveys will show gains in conceptual understanding and an appreciation of the material’s relevance to real-world contexts. Findings from this study will provide practical guidance for instructors interested in student-centered approaches that balance intellectual rigor with engagement and application. Funding Source Internal Scholarship of teaching and learning support Topic Categories Immunology Education and Communication (EDU)
RORα governs CD8+ T cell memory subset specification and offers a therapeutic node for antiviral immunity 2259080
Abstract Introduction The establishment of immunological memory is crucial for durable antiviral immunity and underlies effective vaccine design in enhancing memory responses. The retinoic acid receptor—related orphan receptor α(RORα), a ligand-regulated transcription factor of the nuclear receptor superfamily, has been implicated in CD8+ T cell immunity, yet its role remains poorly defined. Methods To investigate this, we integrated genomic approaches with both genetic and pharmacologic perturbations of RORα to examine its role in CD8+ T cell development during antiviral responses. Results RORα-deficient mice infected with acute lymphocytic choriomeningitis virus (LCMV) exhibited fewer virus-specific CD8+ T cells and higher splenic viral titers at day 5 post-infection than wild-type controls. Despite reduced numbers, RORα-deficient CD8+ T cells showed enhanced cytotoxic potential, indicating that RORα modulates effector programming rather than overall functional capacity. RORα deficiency also led to increased migration and redistribution of CD8+ T cells into non-lymphoid compartments, particularly the liver and adipose tissues, and promoted the development of memory precursors (MP), peripheral memory (TPM), and tissue-resident memory (TRM) populations. Single-cell RNA-seq and ATAC-seq revealed enrichment of transcriptional and chromatin programs linked to MP and TRM gene signatures, including elevated expression of Tcf7 and Runx family members, alongside reduced accessibility at loci governing terminal effector differentiation. Pharmacologic inhibition of RORα with the RORα-selective inverse agonist, SR3335, recapitulated the knockout phenotype, favoring memory CD8+ T cell differentiation over terminal effectors. Conclusion Collectively, our data reveal distinct programming of CD8 T effector versus memory populations attributable to RORα activity. As a ligand-regulated transcription factor, RORα may be a promising target to enhance CD8+ T cell memory responses for improved vaccines and cell-based immunotherapies. Funding Source N/A Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)
Shared B cell receptor repertoire signatures across autoimmune diseases from integrated public datasets 2309774
Abstract Introduction Autoimmune disorders arise from aberrant adaptive immune responses against self tissues and affect millions worldwide. B cells play a central role in many autoimmune diseases, as autoantibody production can directly drive disease pathogenesis. Each B cell expresses a unique B cell receptor (BCR), whose secreted form is an antibody. B cell tolerance is established during B cell development by eliminating or silencing cells with self-reactive BCRs before they reach maturity. However, this process is impaired in several autoimmune diseases. Thus, high-throughput profiling of the BCR repertoire can potentially reveal disease-associated alterations in BCR composition. Although many studies have sequenced BCR repertoires in autoimmune conditions, integrative analyses across diseases remain limited due to heterogeneous protocols and inconsistent metadata. Here, we conducted a large-scale meta-analysis of public BCR sequencing datasets to identify shared repertoire signatures of autoimmunity across multiple diseases. Methods We utilized nf-core/airrflow, an automated data analysis workflow we previously developed to homogeneously process BCR sequencing data using the Immcantation framework. Relevant clinical metadata were curated and harmonized from the original studies. The standardized analysis workflow enables extension of this meta-analysis to additional public datasets as they become available. Results We integrated BCR repertoires from 736 individuals with myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, and healthy controls from 13 publicly available studies. Across diseases, we evaluated repertoire features previously implicated in autoimmunity, including BCR heavy chain CDR3 length, CDR3 physicochemical properties, and IGHV gene usage. Conclusion This study demonstrates the feasibility and value of harmonised re-analysis of public BCR repertoire datasets, resulting in a unified resource for the study of BCR repertoires across autoimmune diseases. Funding Source This work is funded by the R01 supplement 3R01AI114780-09S1 to KCO, SHK and GG, and R01AI114780 to KCO. Topic Categories Basic Autoimmunity (BA)
Weight gain and loss increase adipose dendritic cell proportions and antigen presentation 2257389
Abstract Introduction Weight cycling is a growing health concern that has been shown to worsen risk of diabetes beyond that of obesity. Dendritic cells (DCs) play a causal role in obesity-associated inflammation and metabolic disease. However, their role in weight cycling-associated disease is not known. Previous data from single-cell sequencing showed some subsets of DCs and genes associated with antigen presentation increase with weight gain and weight loss. Our central hypothesis is that changes to DC antigen presentation may affect diabetes risk with weight regain. Here, we aimed to confirm our sequencing data and test the hypothesis that antigen presentation increases in DCs with weight cycling. Methods Mice were put on nutrient-matched low-fat or high-fat diets to elicit lean, obese, weight loss, and weight-cycled groups. Adipose tissue immune cells were isolated for flow cytometry. Results Adipose tissue conventional DC1, H2-Db, H2-IA/IE, and CD40 did not increase across groups. Monocyte-derived DC and type 2 conventional DC increased upon weight gain and weight loss. Similarly, protein expression of MHC Ib (Qa2 and CD1d) and CD86 molecules increased upon weight gain and weight loss. Conclusion The result points towards a potential role for non-classical antigen presentation and potential crosstalk to CD8, NKT, and NK cells. Interestingly, previous single-cell sequencing data also suggests that these populations increase similarly with weight gain and weight loss. Future studies will understand the functional role of DCs in weight cycling Funding Source Texas Chapter of the American College of Sports Medicine (TACSM) Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)
Interfacial Differentiated Recoordination Trigger Asymmetric Bi (δ <sup>+</sup> )—Bi (δ <sup>−</sup> ) Regions for Robust CO <sub>2</sub> Photosynthesis to CH <sub>3</sub> COOH
ABSTRACT Direct solar‐driven conversion of CO 2 and H 2 O into high‐value‐added C 2 products, such as acetic acid, represents a critical frontier challenge in artificial photosynthesis. However, its efficiency is primarily constrained by sluggish photogenerated charge migration and the dynamics limitations for C‐C coupling. This paper reports a “disorder‐induced reconstruction” strategy that utilizes the inherent local disorder of covalent organic frameworks (COFs) to induce the construction of asymmetric active centers on the surface of Bi 24 O 31 Br 10 (BOB), inducing atomic‐scale reconstruction and spontaneously forming extended regions with asymmetric Bi(δ+)‐Bi(δ‐) bimetallic sites. Without the use of sacrificial agents or noble metal co‐catalysts, the resulting catalyst exhibits excellent performance in the conversion of CO 2 to acetate, with a yield as high as 1.03 mmol g −1 h −1 and a selectivity of 97.63%. The apparent quantum efficiencies of catalyst can reach 13.75% and 8.33% at 380 and 400 nm, respectively. This work reveals a previously unknown mechanism for reconstructing inorganic surfaces into asymmetric active structural units using local disorder in organic modifiers, providing a paradigm for the design of next‐generation photocatalysts.
Exploring Human NK Cell Function and Activation by Endothelium via P-STAT5 and HuR regulation 2254028
Abstract Introduction Natural killer (NK) cells circulate in the blood in a poised but inactive state and can be further primed by activating signals to acquire enhanced cytotoxicity and secretion of pro-inflammatory cytokines such as IFN-γ, and TNF-α. We hypothesize that NK cells can be primed by migration through endothelial cells (ECs) as they enter graft or tumor tissue. Methods Nk cell isolation, Flow cytometry. Trans-endothelial migation assay. Results We observed that isolated human blood NK cells will undergo trans-endothelial migration (TEM) through IL-1β-activated but not resting EC monolayers over 60 minutes. Human peripheral blood NK cells showed a rapid rise of P-STAT5 in 20-30 minutes and elevated synthesis of TNF-α and Granzyme B after 4-5 days of coculture. IL-15-induced increases of P-STAT5 was inhibited by an anti—IL-15 antibody. Furthermore, we are exploring whether the increased TNF-α and IFN-γ synthesis is inhibited by a pharmacological blocker of HuR binding to their mRNAs. Conclusion Elucidating key molecular interactions at the endothelial interface that govern NK cell behavior has potential implications for therapeutic modulation. Funding Source n/a Topic Categories Transplantation Immunology (TRAN)
Identification of antigen-experienced human anti-HER2-specific B cells from peripheral blood 2256237
Abstract Introduction HER2 is a clinically validated oncogenic receptor and therapeutic antibody target; however, the natural occurrence and maturation of anti-HER2 antibodies in non-cancer individuals remain poorly characterized. Methods Peripheral blood mononuclear cells (PBMCs) from seven people with HIV with pre-diabetes and four people without HIV with diabetes were stained with fluorescently tagged double-barcoded HER2 ectodomain, and controls were stained with fluorescently tagged barcoded CMV gB (pre- and post-fusion). Anti-CD14, CD3, IgG, and CD19 antibodies were also included in the panel. Antigen-positive IgG+ B cells were sorted for paired B-cell receptor (BCR) and antigen barcode sequencing. The Linking B-cell Receptor to Antigen specificity through sequencing (LIBRA-seq) score for each antigen in the screening library was computed based on the unique molecular identifiers (UMIs) for the respective antigen barcode. Selected HER2-assigned antibodies were recombinantly expressed and assessed by ELISA. Results We profiled B cells from 160 million PBMCs, isolated 1,910 antigen- and IgG-positive B cells, obtained 936 paired heavy—light sequences, and retained 126 high-quality sequences. From donors without HIV, we had 29 million PBMCs from which we isolated 521, obtained 94 pairs, and retained 7. Antibody isotype profiles were IgG-skewed in PLWH, whereas HIV-negative donors showed more IgM. After filtering IgG sequences with strong read support (UMI &gt; 10), we identified 13 antibody clones that bound HER2 (or HER2 plus CMV gB). Of these, 11/13 were from PLWH (10 IgG1, 1 IgG3), and 2/13 were from HIV-negative donors (both IgG2). All thirteen recombinant antibodies bound to HER2 with different strengths, compared to negative controls. Conclusion LIBRA-seq mapping of BCRs in non-cancer donors identified naturally occurring, antigen-experienced human anti-HER2 antibodies, showcasing its potential as a powerful tool for immune profiling and BCR sequencing with promising diagnostic and therapeutic applications. Funding Source Vanderbilt Institute for Clinical and Translational Research (VICTR) Topic Categories Immune Mechanisms of Human Disease (HUM)