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Amorphous High‐Entropy Oxides With High‐Valent Metal and Oxygen‐Vacancy Pairs for Thermally Stable Catalytic Oxidation
ABSTRACT High‐entropy oxides (HEOs) show great promise in heterogeneous catalysis due to their unique structural properties. However, stabilizing the amorphous structure of HEOs under high‐temperature conditions remains challenging. Herein, we propose a thermodynamic synergy‐driven strategy to construct the long‐range disordered structure in HEO, achieving the preservation of defect‐rich sites with high thermal stability. By integrating multiple metal elements with substantial atomic size differences, we construct an amorphous MnFeCoNiCuYZrO x HEO (MYZrO x ‐a), in which the high configurational entropy creates a thermodynamic barrier against amorphous‐to‐crystalline transition. This strategy also demonstrates both universality and scalability for synthesizing thermally stable amorphous HEOs. Combined experimental characterization and theoretical calculations reveal that MYZrO x ‐a retains short‑range disorder and abundant defect sites even after calcination at 600°C. Moreover, the stabilized high‑valence metal–oxygen vacancy (M δ+ –O v ) pairs facilitate the activation of C─H bonds and oxygen species, endowing MYZrO x ‐a with exceptional methane combustion activity and durability, with stable performance exceeding 200 h even under high‑humidity conditions. This work underscores the pivotal role of configurational entropy in designing amorphous HEOs and expands their potential for advanced thermocatalytic applications.
LPS-HDM-Induced Asthma Model: A Translational Platform for Neutrophilic Asthma and Glucocorticoid-Resistant Inflammation 2256839
Abstract Introduction Asthma is a heterogeneous inflammatory airway disease characterized by complex immunopathogenesis. Up to 50% of patients present with a non-Th2-type inflammatory phenotype, characterized by neutrophilic inflammation and poor responsiveness to conventional glucocorticoids. This glucocorticoid-resistant phenotype represents a major unmet clinical need, yet current preclinical models do not capture its underlying mechanisms adequately. Methods To address this gap, we developed a murine model of neutrophilic asthma induced by the combined exposure to lipopolysaccharide (LPS) and house dust mite (HDM), and evaluation the immune cell population in the lung and bronchoalveolar Lavage fluid. Results This LPA-HDM model recapitulates the key hallmark features of non-TH2 asthma, including airway neutrophilia, macrophage infiltration, and airway remodeling. Importantly, the model demonstrates resistance to glucocorticoid (dexamethasone) treatment, mirroring the clinical phenotype of glucocorticoid-refractory asthma. Conclusion The LPS-HDM-induced asthma model provides a robust and reproducible preclinical platform for advancing the mechanistic understanding of neutrophilic asthma and accelerating the development of precision therapies for this challenging patient population. Funding Source n/a Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)
The impact of skin-like CD103+ ILC2s on lung immunity 2258463
Abstract Introduction Proper lung function involves tissue-resident immune cells that participate in homeostasis but also protect against further multiple perturbations. Although the “gut-lung” axis has been described, our study addressed a novel paradigm by which skin ILC2s (skILC2) become educated post-birth during interactions with a commensal hair follicle mite, Demodex, proliferate, exit their tissue of developmental origin, and transit to the lung, termed ex_skILC2s. Dissecting how ex_skILC2s impact the lung microenvironment may reveal novel mechanistic ways to safely promote tissue tolerance to allergens and infectious challenges in preemptive ways that open novel therapeutic strategies for improving lung health. Methods We used a combination of spectral flow cytometry, scRNA-seq, tissue imaging, parabiosis, infectious (Nippostrongylus (Nb), Influenza), and allergic (OVA, alternaria) models to test our hypothesis. Results We show that WT mice infected with Demodex triggered a distinct skin ILC2 subset with a mixed type 2-3 cytokine repertoire, which expands, egresses the skin, enters the blood, and infiltrates into lungs, where they adapt and establish long-term residency. We demonstrate ex_skILC2s in lung are the first group of ILC to be activated upon challenge by the migratory helminth, Nippostrongylus brasiliensis (Nb). In the chronic phase, ex_skILC2s synergize with lung resident ILC2s (nILC2s), newly recruited gut inflammatory ILC2s (iILC2s), and de novo differentiated ILC precursors (ILCPs), to reshape the lung ILC2 landscape. We found that the presence of ex-skILC2s and their distinct activation kinetics play a role in promoting lung tissue repair during the resolution of inflammation after Nb infection. Conclusion Our study highlights that the accumulation of ex_skILC2s complements the natural lung immune cell repertoire in ways that enhance the homeostasis and resilience of the organ to diverse post-birth perturbations. Funding Source n/a Topic Categories Mucosal and Regional Immunology (MUC)
Distinct subsets of tissue-recirculating NK cells revealed by single cell transcriptomic analysis of lymph- and blood-borne cells in sheep 2267560
Abstract Introduction Natural Killer (NK) cells are innate effectors that serve as a first line of defense against viral infections and tumors. NK cells are recruited from blood into tissues early following infection and during ontogeny, and can form tissue-specific resident cells, characterized by organ-specific transcriptional profiles in addition to NK subset specific profiles. However, it is unknown whether circulating NK cells that travel through nonlymphoid or lymphoid tissues and egress via lymph exhibit organ-selectivity. Methods To address this, we used single cell RNA-seq based unbiased transcriptional clustering of sorted circulating NK cells from duodenal efferent lymph, skin afferent lymph, and blood of sheep. Results The data revealed more diversity in mesenteric and skin-circulating relative to blood NK cells. Combined analysis showed unexpected cell heterogeneity with 11 distinct NK cell clusters, which were ubiquitous (similar representation in all sites), skin lymph preferential (>2.4fold enrichment relative to other sites) mesenteric lymph-preferential (>2-fold enrichment), all lymph preferential (>2.7fold) or blood preferential (>78-fold enrichment). When compared with signatures of known human NK cells, most tissues circulating NK clusters were high in tissue circulating score, as expected, and several clusters shared signatures with CD56bright NK cells. Conclusion The data support a model in which NK cells while traveling through tissues acquire functional programming and tissue preferences while remaining circulatory, serving as a specialized mobile layer of host defense. Funding Source NIH Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
Hallmarks of MHC-restricted T cell receptor repertoires 2257786
Abstract Introduction The αβ T cell receptors (TCR) mature in thymus to functionally recognize MHC-ligands, known as MHC-restriction. Thymic selection of T cells serves as the foundation for central tolerance and T cell immunity. Current paradigm stipulates that T cells undergo positive and negative selections through interacting with thymic expressed MHC. How MHC-restriction shapes a TCR repertoire from randomly generated pre-selection repertoire, and hence the hallmark of MHC-restricted T cell repertoire remains unclear. Methods T cells from various MHC-restricted animals, including B6, Balb/c and B10.BR, as well as from MHC-independent animals that are deficient in CD4, CD8 and MHC were isolated and their TCRα and β-chain sequences were obtained using next generation RNA sequencing technology. Results TCR repertoires from various MHC-restricted as well as MHC-independent animals were compared. The results showed that MHC-restricted and MHC-independent TCRs share similar V-gene usages but differ primarily in the composition of CDR3. Thymic selection of MHC-independent TCR is largely unconstrained, but the selection of MHC-specific TCR affects both CDR3 length and specific amino acid usage. MHC-restriction disfavors CDR3 longer than 13 amino acids, removes TCR with cysteines in their CDR3 peptide-binding regions, and limits positively charged and hydrophobic amino acids in CDR3β. Together, these attributes form the hallmarks of MHC-restricted T cell receptor repertoires. Conclusion MHC-expressions impose constraints to both the length and compositions of TCR repertoires. Funding Source National Institutes of Health, intramural research funding Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)
Oral Immunization with Maize-Expressed PEDV S1 Antigen Modulates Mucosal Immunity in Weaned Pigs 2304205
Abstract Introduction Porcine epidemic diarrhea virus (PEDV) is an alphacoronavirus that causes severe enteric disease in swine, leading to high neonatal mortality and growth impairment. Oral vaccines can target gut-associated lymphoid tissue, yet the coordination of mucosal and systemic responses during oral immunization remains poorly characterized. This study assessed a maize-expressed PEDV-S1 oral vaccine by characterizing clinical outcomes, viral shedding and lymphocyte cytokine kinetics following challenge Methods Sixty 3-week-old PEDV-negative pigs were assigned to four groups (n = 15): Control, Vaccine-1, Vaccine-2 (with adjuvant), and Challenge (2x). Vaccine groups received a prime-boost regimen before oral challenge with a non-S INDEL PEDV strain on day 35. Challenge (2x) pigs received two live inoculations. Clinical signs, body weight, and fecal viral RNA were monitored. Necropsies on days 7—45 provided samples for flow cytometry of T, B, γδ-T, NK and regulatory subsets expressing IFN-γ or TNF-α Results Oral vaccination altered disease and immunity. Vaccine-1 pigs showed shorter diarrhea, while Vaccine-2 pigs had mild but longer diarrhea yet greater day-45 body weight than Controls (p < 0.01) and Challenge (2x) (p < 0.05). Viral shedding was highest in Controls (p < 0.01), intermediate in vaccinated pigs and lowest in Challenge (2x) animals after their second exposure. Mesenteric lymph nodes (MLN) profiling showed increased CD4+ T cell activation on day 21 in Challenge (2x) pigs and elevated B cells (CD21+SLA-II-DR+) on day 37 across all antigen-experienced groups. IFN-γ+ CD4+/CD8+ cells were reduced at days 7—21 in antigen-experienced groups, consistent with trafficking from MLN. TNF-α+ subsets remained low whereas γδ-T cells increased from days 21-45 with group-specific patterns. FOXP3+CD25+ T cells remained stable Conclusion Maize-expressed PEDV-S1 oral immunization induced coordinated mucosal and systemic immunity, reduced disease and improved growth supporting its value as a practical tool for swine health Funding Source This project was partially funded through an Iowa State University VPR Seed Grant. Topic Categories Veterinary and Comparative Immunology (VET)
A single cell and spatially resolved atlas of the intestinal innate immune response to infection 2266151
Abstract Introduction Advances in single cell technologies have uncovered novel biology and revealed cellular heterogeneity of complex tissues. However, single cell resolution data for the distal small intestine - a critical site of nutrient absorption and immunological tolerance - are limited, particular during states of infection or inflammation. Methods We generated GUTMAP, a single cell transcriptional atlas of more than 500k cells, from ileum and draining lymph node to address this need and provide a community resource for the study and annotation of intestinal data. Multiple established models of intestinal infection were profiled at acute immunological timepoints to catalogue innate responses to diverse pathogens including SFB, Nippostrongylus brasiliensis, Candida albicans, Yersinia pseudotuberculosis, Cryptosporidium parvum, and murine norovirus. To complement these data and integrate transcriptional responses with tissue pathology, we also carried out single cell spatially resolved transcriptomics. Results Using GUTMAP, we compare between infections and resolve 91 transcriptional cell states in the ileum, including infection-driven and pathogen-specific transcriptional modules. We describe unique enterocyte biology associated with Yersinia infection and demonstrate a spatial link between enterocyte phenotype and the formation of pyogranulomas during infection. We further probe the spatially coordinated cell networks and trafficking during diverse responses to reveal conserved patterns in immune architecture across infection systems. Conclusion GUTMAP is a resource for mucosal immunologists that captures single cell biology of the ileum across diverse infections to answer pivotal questions about innate immune biology. Additionally, GUTMAP acts as resource and bioinformatic tool to aid in the annotation of mucosal data sets and a foundational support for future studies of inflammatory dysregulation in the small intestine. Funding Source NIAID - U01AI095608 Topic Categories Mucosal and Regional Immunology (MUC)
Mitigating Placental Inflammation is Necessary for Improved Fetal Outcomes following Maternal H1N1 Infection 2327794
Abstract Introduction Influenza infection during pregnancy poses significant risks to maternal and fetal health, including increased hospitalization, ICU admission, and mortality, as well as long-term neurodevelopmental deficits in offspring. Maternal H1N1 infection induces COX-1—mediated arachidonic acid pathway activation in the lungs (site of infection) and placenta. Placentas from infected dams show increased infiltration of proinflammatory immune cells, including macrophages and T cells, with elevated frequencies of IFNγ, GZB+, and IL-17+ CD8+ T cells and IFNγ-producing γδ T cells. These markers of placental inflammation were associated with reduced expression of neural growth factors in fetuses from H1N1-infected dams. As H1N1 does not replicate outside the respiratory tract, identifying mechanisms for mitigating placental inflammation will be critical for improved outcomes. Methods To distinguish the contributions of viral replication and maternal immune activation, infected pregnant CD1 dams were treated with oseltamivir and/or low-dose acetylsalicylic acid (LDA), beginning 2 days post-infection and continuing until euthanasia at 6 days post-infection. Results OST reduced lung viral burden and maternal morbidity but had limited impact on placental immune and endocrine dysregulation. In contrast, LDA reduced systemic IFNγ, reduced COX-1 activation, and partially mitigated placental cytokine dysregulation. While all treatments reduced placental IFNγ, only combination therapy simultaneously reduced pulmonary viral replication and normalized placental endocrine and inflammatory profiles, including suppression of GZB+ CD8+ T cells and IFNγ γδ T cells. Combination therapy fully rescued fetal growth, demonstrating that targeting maternal inflammation is required in addition to antiviral therapy to prevent adverse fetal outcomes. Conclusion Given that OST and LDA are approved for use during pregnancy, these findings highlight their combined therapeutic potential for treating influenza infection in pregnancy. Funding Source 5T32AI007417-29 Topic Categories Viral Immunology (VIR)
“Steric‐Locking” Polymer Acceptor Enabled 20.53% Efficiency With Suppressed Energetic Disorder and Enhanced Mechanical Robustness in Green‐Solvent Processed All‐Polymer Solar Cells
ABSTRACT The realization of high‐performance organic photovoltaics via environmentally benign manufacturing is pivotal for sustainable energy. While all‐polymer solar cells (all‐PSCs) offer superior stability and mechanical resilience, achieving high efficiencies in nonhalogenated green solvents remains a formidable challenge. Here, we report a “steric‐locking” strategy for polymer acceptor design that enables a record‐breaking power conversion efficiency of 20.53% (certified 19.79%) in o ‐xylene‐processed all‐PSCs. The introduction of a steric‐locking guest polymer acceptor (PY‐IDT) into the PM6:PYF‐T‐o host matrix profoundly regulates the crystallization kinetics and suppresses the excessive self‐aggregation of the host acceptor. This molecular‐level structural refinement significantly reduces energetic disorder and minimizes non‐radiative voltage loss. Consequently, the suppressed energetic disorder and refined nanostructured domains yielded a concurrent leap in open‐circuit voltage (0.942 V) and fill factor (82.11%). Furthermore, the steric‐locked morphology demonstrates exceptional mechanical robustness, maintaining 92.6% of its initial efficiency after 1000 bending cycles. This work establishes a new efficiency benchmark and provides a universal chemical framework for developing high‐performance, sustainable, and flexible optoelectronics.
Inflammatory Type 2 Conventional Dendritic Cells Induced by Vaccine Adjuvant Promote Antigen Cross-Presentation through Autophagy Inhibition 2305812
Abstract Introduction Cross-presentation (XPT) is pivotal for inducing antigen (Ag)-specific CD8+ T cell responses, which is linked to better therapeutic outcomes. However, in the context of therapeutic vaccination, how to promote T cell cross-priming in vivo remains unclear. This motivates elucidating the mechanisms underlying XPT by specific cross-presenting subsets under physiological conditions. Methods Ag-specific cytotoxic responses in EG7-OVA tumor model upon adjuvanted vaccination with Th1-stimulating adjuvant was assessed for the mechanism underlying cross-priming. The key cross-presenting subsets under adjuvanted vaccination were analyzed by flow cytometry. The potential pathways related to induced XPT were discovered by RNA sequencing (RNA-seq) and pathway analysis and the results were validated by immunoblotting and OT-I XPT assay. Unbiased single-cell RNA-seq was employed to define the counterpart in human immune system (HIS) mice. Results Adjuvanted vaccination elicited a robust Ag-specific anti-tumor response and expanded inflammatory cDC2 (inf-cDC2) in tumor model. In knockout mice studies, inf-cDC2 emerges as the dominant cross-presenting subset during vaccination. RNA-seq analysis highlighted autophagy-related pathways, next confirming that autophagy inhibition drives XPT. Mechanistically, impeding the fusion of autophagosomes and lysosomes in DCs could prime T cells by prolonged XPT. In HIS mice, DC3 was identified as the phenotypic counterpart of inf-cDC2 under vaccination. Adjuvant-induced pathways were highly enriched in autophagy and autophagy inhibition exclusively within DC3 promotes XPT. Conclusion We identified murine inf-cDC2 and human DC3–not cDC1–are the key player in XPT in the context of adjuvanted vaccination and this marked function strongly depends on autophagy blockade. Prioritizing autophagy inhibition, particularly in these DCs, could effectively augment Ag-specific anti-tumor immunity. This bridges the gap between preclinical and clinical investigations in cancer vaccinology. Funding Source n/a Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)
Systemic viral infection diversifies neurodegenerative disease progression 2310089
Abstract Introduction Environmental exposures across the lifespan shape the immune landscape and can influence responses to later challenges. Both innate and adaptive immunity affect the trajectory of neurodegenerative diseases. We have recently shown in mice that microglia slow tauopathy progression by limiting tau spread within the CNS and into the periphery, and that a granzyme K-expressing CD8+ T cell subset engages microglia to reduce microglial distress, restrict tau dissemination, and delay neurological decline in a PD-1/TIGIT-dependent manner. Similar microglia-T cell interactions were observed in human brains with tau-rich lesions associated with age, Alzheimer’s disease, or chronic traumatic encephalopathy. Here, we investigated how systemic viral infection influences disease course in mice expressing mutant human tau. Methods Single cell TCR sequencing, flow cytometry, immunofluorescence, and behavioral assessments were used to define immune changes and disease progression in P301S (Thy1a promoter) mice following systemic infection. Results We found that dual PD-1/TIGIT blockade accelerates neurological dysfunction. In contrast, intravenous LCMV Armstrong infection elicited robust peripheral immune activation yet did not alter the overall rate of decline in P301S mice; instead, it produced a marked increase in variability among individual disease trajectories. We further identified a tauopathy-specific surface marker signature that delineates a subset of Trm-like granzyme K+ CD8+ T cells in the CNS and draining lymph nodes that appears to slow disease progression. The heightened heterogeneity observed after viral infection suggests that systemic immune challenges may perturb this population in unpredictable ways. Conclusion These data demonstrate that tauopathy progression is highly sensitive to systemic immune perturbations, including non-neurotropic viral infections. They underscore the complexity of neurodegenerative disease and highlight how lifelong immunological challenges shape CNS pathology. Funding Source Intramural program at the National Institute of Neurological Disorders & Stroke and the National Institute of Allergy & Infectious Diseases, NIH Defense Health Agency (310286-1.00-65642 and 311661-5.00-66323) Topic Categories Neuroimmunology (NEUR)
The Autoimmune-Associated PTPN22 Variant Promotes Anti-Tumor Immunity in Melanoma 2310217
Abstract Introduction The autoimmune risk allele of PTPN22, 1858C>T, reduces melanoma risk, but the underlying mechanisms are unclear. In humans and mice, PTPN22 encodes the immune regulatory protein Lyp (PEP in mice), expressed almost exclusively in immune cells. We previously showed that mice expressing the equivalent 1858C>T allele, PEP-R619W mice, exhibit reduced B16-OVA melanoma burden. Notably, PEP-R619W mice had more intratumoral CD8 T cells and type I dendritic cells. However, it is unknown if other immune cells shaping the tumor microenvironment, such as CD4 T cells and macrophages, are altered in PEP-R619W tumor-bearing mice. It is also unclear if PEP-R619W immune cells still delay B16-OVA tumor growth in the presence of wildtype (PEP-WT) immune cells. Methods We immunophenotyped the intratumoral immune response of PEP-WT and PEP-R619W mice using single-cell RNA sequencing and flow cytometry. To interrogate how PEP-R619W affects specific immune cell interactions, we generated and used co-culture and tri-culture systems of CD4 T cells, bone marrow-derived macrophages, and B16-OVA cells. Next, we investigated if PEP-R619W immune cells could reduce B16-OVA tumor growth in the presence of PEP-WT cells using PEP-WT: PEP-R619W bone marrow chimeric (BMC) mice. Results PEP-R619W mice have a more pro-inflammatory macrophage population within the tumor. Yet, PEP-R619W macrophages do not activate CD4 T cells differently from PEP-WT macrophages in the absence of tumor cells. Intriguingly, in the presence of tumor cells, PEP-R619W CD4 T cells were more activated and more proliferative- suggesting that PEP-R619W may impact tumor-immune cell interactions. Finally, BMC mice, which have both PEP-WT and PEP-R619W expressing cells had delayed tumor growth compared to PEP-WT mice. Conclusion This study shows that PEP-R619W shifts the macrophage landscape within the tumor and that PEP-R619W may impact tumor-immune cell interactions. Further, we show PEP-R619W cells can still reduce tumor burden when PEP-WT cells are present. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
High-throughput TCR-epitope screening using the Jurkat NFAT Reporter-K562 APC cell system on the Microwell ELISpot Platform 2258594
Abstract Introduction Despite the critical role of T-cell receptors (TCRs) in adaptive immunity, experimental validation of predicted cognate antigens remains a major challenge. Methods For screening TCR-epitope interaction, we developed Jurkat-NFAT-GFP reporter cells expressing TCRs of interest and co-cultured them with K562 antigen-presenting cells (APCs) expressing peptide libraries in a single-chain trimer (peptide—B2M—HLA-A) format. To enhance HLA surface expression, we introduced a G2C mutation in the G4S linker of the single-chain trimer. TCR activation, cell proliferation, and cytotoxicity were monitored using a novel microwell ELISpot assay, where GFP expression signaled functional TCR—peptide—MHC interactions. Cells from GFP+ wells were isolated using CloneXplorer colony picker for NGS to identify cognate epitopes and TCRs. For proof of concept, a library of ∼100 peptides (cancer-associated and viral peptides) were short-listed using the DETECT algorithm and expressed in K562 cells, and tested against Jurkat cells expressing CMV, MART1, p53, and Flu TCRs. Microarrays were used to establish tens of thousands of Jurkat/K562 co-cultures for each TCR construct. Peptide identity was determined by sequencing isolated cells to match the expected TCR specificity. Results For proof of concept, a library of ∼100 peptides (cancer-associated and viral peptides) were short-listed using the DETECT algorithm and expressed in K562 cells, and tested against Jurkat cells expressing CMV, MART1, p53, and Flu TCRs. Microarrays were used to establish tens of thousands of Jurkat/K562 co-cultures for each TCR construct. Peptide identity was determined by sequencing isolated cells to match the expected TCR specificity. Conclusion This end-to-end platform enables high-throughput discovery to screen 1000s of peptides, and functional characterization of TCR—peptide—MHC interactions. It has broad applications in cancer immunotherapy and vaccine development. Funding Source N/A Topic Categories Technological Innovations in Immunology (TECH)
Decoding the Hallmark Features of Modular CAR Domains and Their Impact on CAR T Cell Tumoricidal Activity 2305603
Abstract Introduction Engineering T cells to express a Chimeric Antigen Receptor (CAR) directs potent tumor cytotoxicity, and this cellular immunotherapy has yielded robust success in hematological malignancies. However, in solid tumor models, including neuroblastoma, regression after CAR administration is only transient. The linked domains of CARs determine their activation threshold and can be optimized to overcome efficacy barriers, including exhaustion, persistence, and activation threshold. Yet, as to how each modular domain and its variants influence T cell phenotype and function is poorly understood. Methods We generated a library of 12 constructs that combinatorially link 3 distinct hinge regions (CD8, CD28, or IgG), 2 transmembrane domains (CD8 or CD28), and 2 co-stimulatory regions (41BB or CD28), all frequently used in FDA-approved CARs. We used a scFv targeting the oncofetal antigen GPC2, an antigen with moderate to low expression in neuroblastoma. Expressing these unique CARs in human T cells, we will evaluate differences in T cell cytokine production, killing capacity, phenotype, and persistence using preclinical models of neuroblastoma. These assays will generate a high-dimensional dataset, and we will employ machine learning to identify an in vitro biosignature of CAR T cells that predicts in vivo CAR T cell killing, as well as a favorable phenotype for persistence and effector qualities. Results Preliminary results identified a broad range of CAR T cell cytotoxicity against neuroblastoma lines in vitro, with the transmembrane domain driving the greatest variation in killing, as well as significant interaction effects between domains. Conclusion Overall, we aim to create a model to establish the role of each domain and how they interact to propagate an activation signal, recruit a unique signalosome, and dictate the phenotype and function of CAR T cells. Funding Source NCI Intramural Research Program Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Sex-Dependent Immune Dysregulation and Neurodevelopmental Risk in Maternal Substance Use 2266696
Abstract Introduction Maternal substance use (SU) in pregnancy is associated with adverse neurodevelopmental outcomes in offspring, with males at heightened risk. We investigated how maternal SU impacts maternal and fetal immune responses, and how these alterations may contribute to increased neurodevelopmental risk. Methods Maternal and cord plasma and PBMCs were collected from 68 pregnancies, including 17 SU cases and 51 uncomplicated controls matched for gestational age, maternal BMI, and fetal sex. T cell phenotypes and cytokine production were characterized by flow cytometry. Monocyte function and plasma cytokine and chemokine levels were evaluated. Personalized fetal models of brain immune development were created using microglia-like cells derived from placental macrophages from the same pregnancies, and synaptosome phagocytosis by induced microglia was quantified as a proxy for synaptic pruning behavior. Results Sexually dimorphic alterations in maternal CD4+ T cell frequency were noted in SU, decreased in male pregnancies and increased in female pregnancies compared to sex-matched controls, and cord plasma IL-1β and IFN-γ were significantly reduced in males. Significant impairment in cord blood monocyte function was noted in female SU-exposed pregnancies only. Placenta-derived microglia-like fetal cellular models exhibited decreased synaptosome phagocytosis in males and increased in females. Conclusion Our findings suggest that sex differences in maternal-fetal immune activation in the setting of maternal SU correlate with sex-specific vulnerability to adverse neurodevelopmental outcomes. Funding Source NIH/NIDA: U01DA055353 NIH/NICHD: R01HD113188 MGH ECOR: Patricia and Scott Eston MGH Research Scholar Simons Foundation Autism Research Initiative (SFARI) grant 870754 Topic Categories Immune Mechanisms of Human Disease (HUM)
Multi-omic Signatures of Baseline Immunity Shape Antiviral Responses in Adults and Infants 2327944
Abstract Introduction Infants and young children are vulnerable to influenza and exhibit prolonged viral shedding, but their “baseline” immune state that influences their first infection response is poorly understood. Although often seen as immature, infant immunity quickly changes after birth. We investigated how early-life baseline immune architecture relates to systemic and mucosal antiviral responses. Methods We utilized a systems immunology approach, analyzing 929 samples from a longitudinal cohort of young children with natural infections (IMPRINT) and adults from a controlled infection (CHIM). We integrated proteomics, scRNA-seq and scATAC-seq to map immune states across pre-infection, acute, and convalescent stages. Results Multi-omic analysis revealed that healthy young children possess a “pre-activated” baseline state. Proteomics showed significantly elevated plasma interferons and pro-inflammatory cytokines in children compared to adults, which correlated with a blunted systemic response to influenza infection . Through scRNA-seq, we identified five distinct CD14+ monocyte subclusters. In adults, a higher baseline abundance of interferon-stimulated (ISG+) monocytes predicted better viral control; conversely, in children, a higher baseline abundance of inflammatory monocytes predicted poorer viral control. scATAC-seq supported this divergence, showing that opposing IRF and AP-1 chromatin accessibility programs are associated with these monocyte states. Finally, we identified a systemic—mucosal dichotomy: while children exhibited blunted blood responses, their nasal compartment was hyper-responsive, characterized by strong interferon/cytokine induction and epithelial—myeloid activation. Conclusion Our findings demonstrate that infant immunity is not merely underdeveloped but is a uniquely pre-activated and modularly organized system. By linking baseline epigenetic and transcriptional signatures to mucosal viral burden, this study identifies specific immune architectures that drive influenza susceptibility Funding Source n/a Topic Categories Computational and Systems Immunology (COMP)
Space‐Time Coding Conformal Metasurfaces for Multifrequency Beam Steering and Shaping
ABSTRACT Space‐time coding metasurfaces enable dynamic control of electromagnetic waves by jointly exploiting spatial coding and temporal modulation, unlocking functionalities unattainable with static platforms. While these concepts have been widely explored in planar configurations, their extension to conformal geometries has received comparatively little attention, despite the prevalence of curved platforms in practical applications. Here, space‐time coding conformal metasurfaces are examined as a platform for multifrequency beam steering and shaping on nonplanar structures. A representative cylindrical geometry, characterized by translational invariance of the supporting structure along one direction and mild curvature along the orthogonal transverse coordinate, is adopted as a physically relevant configuration that enables accessible modeling of curvature effects. The proposed design strategy combines semi‐analytical modeling with hybrid synthesis techniques, including evolutionary optimization. The resulting responses are validated through experimental measurements on an X‐band conformal prototype employing a segmented architecture that enables controlled cylindrical bending, showing good agreement with theoretical predictions. These results demonstrate that multifrequency beam steering and shaping can be achieved on curved surfaces, establishing space‐time coding as a viable and scalable approach for dynamic wave manipulation in realistic conformal environments.
The Immune Epitope Database: Revised Receptor Data and Integration with the Adaptive Immune Receptor Repertoire Knowledge Commons 2306862
Abstract Introduction The Immune Epitope Database (IEDB, iedb.org) is a freely available resource that catalogs experimentally defined immune epitopes. Concurrently, the IEDB records ∼190,000 T cell receptors and ∼5,000 antibodies with experimentally verified epitope specificity. Because these receptors have been manually curated from 3,300 references spanning decades, reported data and nomenclature can be inconsistent, posing challenges for computational analyses. To support interoperability and integration with community resources such as the Adaptive Immune Receptor Repertoire Knowledge Commons (AKC), we are revising all immune receptor records to produce resolved, standardized, and analysis-ready receptor data. Methods We developed a computational pipeline that employs IgBLAST for V/D/J gene assignment, ANARCII for identification of Complementarity Determining Regions (CDRs), and tidytcells to standardize author-reported gene names. We furthermore extended tidytcells to validate and standardize CDR3 sequences based on reported V/J gene usage and to support antibody data. Crucially, the pipeline also flags anomalous data for targeted re-curation by expert curators. Results The reprocessed receptor dataset contains V/D/J gene names that are correctly formatted and mapped to existing reference genes, and CDR3 sequences are consistently represented up to their conserved anchor residues. Improved anomaly detection allowed us to identify and correct anomalous receptor records from hundreds of studies. Conclusion These revisions increase data quality and improve interoperability, as exemplified by integration with the AKC. This integration will enable researchers to seamlessly query large-scale repertoires for receptors with experimentally verified specificity in the IEDB, link orphan sequences to known targets, and support cross-repository studies of receptor-epitope pairs and their relationship to health and disease. Funding Source The IEDB is funded by NIAID contract 75N93019C00001. The AIRR Knowledge Commons is supported by a U24 (U24I177622) from the NIAID. Topic Categories Computational and Systems Immunology (COMP)
The histone demethylase KDM5C orchestrates VGLL3 and TLR7 crosstalk to drive female-biased autoimmunity 2310043
Abstract Introduction Female bias in autoimmunity is attributed in part to incomplete X chromosome inactivation of immune genes such as TLR7. However, many female-biased genes dysregulated in autoimmune diseases are autosomal, including VGLL3, a transcriptional co-factor implicated in lupus, systemic sclerosis, and Sjogren’s syndrome. Notably, TLR7 is elevated 4.5-fold in mice overexpressing (OE) Vgll3 that develop lupus-like disease. We sought to define the mechanistic relationship between VGLL3 and TLR7 in female-biased autoimmunity. Methods Vgll3 OE mice were crossed with Tlr7 knock-out (KO) mice, and Vgll3 KO mice were treated with the TLR7 agonist imiquimod. Disease phenotypes were assessed by histology, ELISA for autoantibodies, and RNA-seq. VGLL3 binding at the TLR7 locus was assessed by CUT&RUN. Gene expression datasets from human cells with VGLL3 perturbation were examined for correlated lnRNAs, identifying NEAT1. TLR7-sensing HEKs were stimulated with NEAT1 or extracellular vesicles (EVs) from VGLL3 OE cells. Proximal biotinylation identified upstream regulators of VGLL3. Results Deletion of Tlr7 in Vgll3 OE mice did not prevent skin inflammation or splenomegaly; however, autoantibody production was reduced and inflammatory signature in skin and kidneys was attenuated, with stronger effect in females. Conversely, skin inflammation after imiquimod was diminished in Vgll3 KO mice (vs WT), accompanied by reduction of IFN-stimulated genes. CUT&RUN showed no VGLL3 binding near the TLR7 promoter, indicating indirect regulation. Instead, NEAT1 robustly activated TLR7, as did EVs from VGLL3 OE keratinocytes. KDM5C, an X-linked histone demethylase known to regulate XIST, was identified as an epigenetic regulator of VGLL3. Conclusion VGLL3 amplifies TLR7-driven inflammatory responses through indirect mechanisms involving NEAT1 and EV signaling, forming a feedforward loop that promotes IFN-mediated, sex-biased autoimmunity. Identification of KDM5C as a regulator of VGLL3 links this pathway to X-chromosome biology. Funding Source University of Michigan Skin Research Center, NIH/ NIAID R01 Topic Categories Immune Mechanisms of Human Disease (HUM)
Cannabinoid Modulation of Intestinal and Neuroimmune Dysregulation in Diet-Induced Obesity 2310209
Abstract Introduction Obesity drives systemic inflammation, metabolic dysfunction, and immune dysregulation that contribute to disease. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) exhibit immunomodulatory and metabolic regulatory properties, yet their tissue-specific effects in obesity remain incompletely defined. We previously demonstrated that CBD- and THC-rich cannabis improves insulin sensitivity and rescues proinflammatory macrophage signatures in adipose tissue and liver of obese mice. Similar macrophage alterations in the colon and brain may influence obesity-associated intestinal and neural pathologies; however, these effects have not been reported. To address this gap, we examined the effects of CBD- or THC-rich cannabis on colon and brain macrophages in obese mice and assessed gut microbial populations as drivers of macrophage shifts. Methods Female C57BL/6 mice consumed a low-fat (n = 10) or high-fat diet (HFD; n = 30) for 16 weeks. Obese mice then received placebo, CBD-rich, or THC-rich cannabis for 4 weeks (3×/week; p.o.; n = 10/group). Immune cell composition was assessed by high-dimensional flow cytometry. Fecal DNA underwent 16S rRNA amplicon sequencing using Illumina MiSeq and was analyzed with QIIME. Results In the lamina propria, obesity increased CX3CR1⁻ recruited macrophages and reduced CX3CR1+ macrophages; both effects were rescued by cannabis. Obesity reduced gut microbial diversity and altered community structure, with THC partially restoring lean-like profiles and beneficial taxa. In the brain, obesity increased monocyte-derived macrophages, which were ameliorated by THC alone. Overall, cannabinoids reversed obesity-associated immune and microbial alterations across intestinal and neuroimmune tissues. Conclusion Cannabis reverses obesity-associated immune and microbial dysregulation across intestinal and neuroimmune tissues, supporting cannabinoids as potential modulators of diet-induced immunopathology. Funding Source US National Cancer Institute-funded REMEDY Study Grant U01 CA272977, which is part of the MeDOC Consortium and The Center for Clinical & Translational Research at the University of South Carolina (ClinTrUSC), which is funded as Grant No. P20 GM155896 from Topic Categories Mucosal and Regional Immunology (MUC)