Browse Articles

Interfacial Acid Sites‐Mediated ZnO‐Based Electrocatalysts for Sustainable Dual‐Pathway H ₂ O ₂ Production and Rechargeable Zn‐H ₂ O ₂ Electrochemical Cell

ABSTRACT Facing the challenge of achieving efficient and sustainable hydrogen peroxide (H 2 O 2 ) production, a promising strategy is developing highly selective electrocatalysts with controllable synthesis, structural design and performance optimization. Herein, an interfacial acid sites‐mediated ZnSe/ZnO heterojunction is synthesized for highly selective two‐electron oxygen reduction reaction (ORR) toward H 2 O 2 production. Experimental and theoretical results reveal that surface selenization induced reconstruction, forming a synergistic interface with a built‐in electric field and tailored oxygen vacancies (Ovs), which collaboratively optimize the electronic structure and accelerate reaction kinetics of two‐electron ORR. Moreover, interfacial unsaturated Zn 2+ sites and OVs served as Lewis acids sites to enhance O 2 adsorption and activation, while Br ø nsted acids sites were liable to donate protons to promote *OOH formation. Consequently, a ZnSe/ZnO ‖ ZnO flow cell enabled paired electrolysis for concurrent H 2 O 2 production with a high H 2 O 2 yield of 754.4 M g cat −1 over 12 h. A rechargeable Zn‐H 2 O 2 cell using ZnSe/ZnO cathode delivered a power density of 11.99 mW cm −2 as a self‐sustaining process for simultaneous on‐site H 2 O 2 production and electrical energy generation. This work offers a sustainable route for on‐site H 2 O 2 synthesis with improved energy efficiency, advancing green chemistry and circular economy.

Use of Pillars of Immunology to teach fundamental concepts of immunology to undergraduate students and create excitement for scientific enquiry 2261233

Abstract Introduction The field of immunology is of great interest to undergraduate students. Methods The “Pillar of Immunology” article, “Cutting Edge: Toll-Like Receptor 4 (TLR4)-Deficient Mice are Hyporesponsive to Lipopolysaccharide: Evidence for TLR4 as the Lps Gene Product” by Hoshino, K. et al. (J. Immunol. 1999: 162:3749-3752) was employed to solidify the concept of innate immune cell recognition of pathogen associated molecular patterns by pattern recognition receptors. Results Strengths of the article for teaching included its brevity of four pages with only four figures which was less intimidating to undergraduates unfamiliar with reading scientific manuscripts. The article exposed students to critical experimental immunological techniques including flow cytometry and ELISA and demonstrated the tremendous utility of gene-knockout mice. The demonstration of a loss of function point mutation in the TLR4 locus of C3H/HeJ mice highlighted how single-nucleotide polymorphisms can alter normal physiology, and reinforced concepts of protein synthesis from mRNA expression of genes in DNA. The review, “TLR4: The Winding Road to the Discovery of the LPS Receptor by Murdock and Nunez (J. Immunol. 2016; 197:2561-2562) created excitement for scientific enquiry as it described the quest of the research groups of Shizuo Akira and Bruce Beutler to identify TLR4 as the LPS receptor. Conclusion This “Pillars of Immunology” article and its review were excellent for teaching fundamental concepts of cellular and molecular immunology to senior level undergraduates in a 15-week immunology course. Funding Source n/a Topic Categories Immunology Education and Communication (EDU)

TIRTL-sequencing to interrogate the clonal repertoire of CARpos and CARneg TILs post CAR T-cell therapy for pediatric solid tumors 2259261

Abstract Introduction Post-immunotherapy, tumor infiltrating lymphocytes (TIL) expanded from solid tumors reflect immune responses within the TME. We are investigating B7-H3-CAR T cells for pediatric patients on two early phase clinical trials. CAR T cells expressed a 2nd generation B7-H3.CD28ζ CAR and cell surface 41BB ligand. Loc3CAR (NCT05835687) evaluates intracranial CAR T cells for brain tumors, and 3CAR (NCT04897321) evaluates intravenous CAR T cells after lymphodepleting chemotherapy for solid tumors. Methods Small tumor biopsies from 3 patients were evaluated for TILs: Loc3CAR-19 (ependymoma), 3CAR-17 and 3CAR-18 (synovial sarcoma). We evaluated scalability of the Throughput-Intensive Rapid TCR Library sequencing (TIRTL-seq) to gain insight into the clonal kinetics and paired αβ TCR. CD45/CD3+ sorted cells were dispensed as low as 1 cell per well into a 384-well plate for sequencing. Results Immunophenotyping demonstrated 1% CAR+, 40% CD4+, and 25% CD8+ cells. 60% percent of TILs had an effector memory phenotype. TIRTL-seq identified paired αβ TCR chains in all samples, even when input was limited. Loc3CAR-19 exhibited 1 β chain in 80% of the reads and 2 α chains in 90% of reads, suggesting expansion of a specific TCR pair. In contrast, 3CAR-17 revealed high diversity, with over 86,000 unique chains and over 4,000 inferred αβ pairs. However, we also observed evidence of a clonal expansion in 3CAR-18, where over 12% of cells had the same TCR; in addition, other clonal expansions in this sample shared v and j segment usage, potentially suggesting convergent epitope recognition by distinct TCRs. Conclusion TILs can be expanded from small tumor fragments post-CAR T cell infusion. TIRTL-seq is a scalable platform for αβ TCR-seq for limited cells recovered from cultured TILs. TIRTL-seq analyses suggest TIL clonal expansion and segment usage patterns vary significantly, whereas some show strong clonal expansion and others display high diversity. Funding Source American Lebanese Syrian Associated Charities (ALSAC) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Uncovering cellular programs and regulatory circuits governing cell fate bifurcations using interpretable machine learning 2255655

Abstract Introduction Understanding immune cell fate bifurcations requires deciphering how transcriptional and regulatory programs coordinate dynamic transitions. While deep learning models can capture these differences, they often lack interpretability. To address this, we developed a framework that integrates SLIDE–an interpretable machine learning (ML) method that extracts latent factors (LFs) representing cellular programs–with static and dynamic gene regulatory network (GRN) inference to reveal mechanisms driving immune differentiation. Methods We applied this framework to human B cells differentiating into plasmablasts (PB) or germinal center (GC) cells, and to T cells undergoing terminal (Texterm) or KLR+ cytotoxic (TexKLR) exhaustion. SLIDE identified regulon-level LFs distinguishing each state using scRNA-seq datasets. Static and dynamic state-specific GRNs were reconstructed using CellOracle, and Dictys, benchmarked against SCENIC+. Perturb-seq experiments targeting key TFs (PRDM1, IRF4, IRF8, SPIB, BATF, IKZF1, ETS1) enabled rollback analyses to test SLIDE’s ability to predict early fate bias. Results Using SLIDE, we uncovered strikingly specific and transferable LFs defining both B and T cell states. Cross-referencing these LFs with state-resolved GRN linkages revealed precise, TF-centric regulons that orchestrate lineage bifurcation with higher specificity and biological coherence than SCENIC+. Dynamic GRNs exposed distinct TF waves driving state transitions, while rollback analyses showed that SLIDE–without relying on GRNs–accurately predicted early cell-fate predisposition before transitions occurred, outperforming other methods. Conclusion By coupling interpretable ML with GRNs, this framework reveals mechanistic regulatory circuits governing immune cell differentiation. Moreover, when applied independently of GRNs to TF perturb-seq data, SLIDE could predict cell fate before bifurcation occurs, highlighting its power to identify transcriptional programs that predefine lineage commitment. Funding Source IGVF Consortium Topic Categories Computational and Systems Immunology (COMP)

Sojadodamgangki-tang attenuates allergic lung inflammation by inhibiting T helper 2 cells and Augmenting alveolar macrophages 2307870

Abstract Introduction Sojadodamgangki-tang (SDG) is a traditional East-Asian herbal medicine mainly composed of Pinellia ternate (Thunb.) Makino, Perilla frutescens (L.) Britt and 10 kinds of medicinal herbs. It has been used to treat asthma and mucus secretion including lung and bronchi. Aim of the study The aim of this study was to investigate the anti-inflammatory effects of Sojadodamgangki-tang (SDG) on allergic lung inflammation in vitro and in vivo as well as the underlying mechanisms. Methods We used an ovalbumin (OVA)-induced murine allergic airway inflammation model. Five groups of 8-week-old female BALB/C mice were divided into the following groups: saline control group, the vehicle (allergic) group that received OVA only, groups that received OVA and SDG (200 mg/kg or 400 mg/kg), and a positive control group that received OVA and Dexamethasone (5 mg/kg). In vitro experiments include T helper 2 (TH2) polarization system, murine macrophage cell culture, and human bronchial epithelial cell line (BEAS-2B) culture. Results SDG administration reduced allergic airway inflammatory cell infiltration, especially of eosinophils, mucus production, Th2 cell activation, OVA-specific immunoglobulin E (IgE), and total IgE production. Moreover, the activation of alveolar macrophages, which leads to immune tolerance in the steady state, was promoted by SDG treatment. Interestingly, SDG treatment also reduced the production of alarmin cytokines by the human bronchial epithelial cell line BEAS-2B stimulated with urban particulate matter. Conclusion Our findings indicate that SDG has potential as a therapeutic drug to inhibit Th2 cell activation and promote alveolar macrophage activation. Funding Source 2025-RISE-10-005 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

IL-17A Enhances CD8+ T Cell Metabolism to Restrict West Nile Virus in the Brain 2305958

Abstract Introduction West Nile virus (WNV) is the leading viral agent responsible for human neurological diseases in North America. Currently, there is no approved vaccine or specific treatment available for WNV infection or its neurological complications in humans. Our study suggested that interleukin-17A (IL-17A) plays a crucial role in regulating CD8 T cell cytotoxicity against WNV infection in the brain. In addition, our study has also revealed a novel function of IL-17A in activating the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K-mTOR) signaling pathway in CD8 T cells, leading to increased metabolism of CD8 T cells to cope with the higher energy demand for WNV clearance from the brain in mouse models; however, the underlying molecular mechanism remains unclear. Methods We used IL-17A signaling-deficient mice, RNA sequencing, and liquid chromatography-mass spectrometry (LC-MS/MS) approaches to identify key molecules that regulate the cytotoxicity and metabolism of CD8 T cells to meet the increased energy demand for WNV clearance in the brain. Results Our recent RNA-sequencing analysis suggests that the expression of TMPRSS3 (Transmembrane Serine Protease 3) is significantly reduced in CD8 T cells purified from both WNV-infected and uninfected IL-17 receptor C knockout (Il17rc-/-) mice compared to WT controls. TMPRSS3 has been implicated in cellular processes, including cell viability, apoptosis, and cancer progression, through modulating the PI3K/Akt/mTOR signaling pathway. Conclusion Our results indicate that IL-17A signaling may activate the PI3K-mTOR metabolic pathway via TMPRSS3, thereby exerting immune-therapeutic effects against WNV infection in the brain. Funding Source N/A Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Dual Reporter multiplexing enables simultaneous detection of IgG and IgM antibodies against autoantigens and pathogenic proteins in human samples 2257943

Abstract Introduction Profiling both IgG and IgM antibodies against autoantigens and infectious disease targets provide insight into the immune response and disease progression. IgM antibodies are typically associated with an early immune response, while IgG antibodies are suggestive of more chronic or persistent immune processes. Methods Using the xMAP® INTELLIFLEX® DR-SE system, which features a second reporter channel, we developed a Dual Reporter IgG/IgM Reagent Pack that can be used with any of the MILLIPLEX® serology kits to measure the immune response to various disease-relevant targets, specifically detecting IgG and IgM antibodies on separate channels for each multiplexed antigen bead. The Dual Reporter Reagent Pack was used to profile 88 antigens across 5 existing serology-based MILLIPLEX® kits in apparently healthy and disease serum and plasma samples. Further, to demonstrate the relevance of the Dual Reporter Reagent Pack for vector-borne disease studies, we compared serum and plasma from apparently healthy donors (n = 32) versus individuals with Lyme Disease (n = 8) using a novel multiplex panel containing the Borrelia antigens OspA, OspB, OspC, Flagellin, and VlsE1. Results Our results demonstrated significantly increased binding of both IgG and IgM antibodies to OspC and VlsE1 proteins in Lyme Disease samples. Additionally, IgG binding to the OspB protein was also elevated in Lyme Disease compared to healthy control samples. Conclusion In summary, the Dual Reporter IgG/IgM Reagent Pack enhances the capability for simultaneous profiling of IgG and IgM antibodies, which is applicable to multiple disease states including cancer, neurodegeneration, autoimmune disease, and Lyme Disease. Funding Source n/a Topic Categories Basic Autoimmunity (BA)

Serpin B1 prevents severe pulmonary influenza through specific effects on T cells and NK cells 2334958

Abstract Introduction The murine serpin b1a gene protects against H3N2 influenza A viral induced pathogenicity but the natural protein is intracellular and can be inactivated by ROS. We created a recombinant oxidation resistant murine form of the protein (serpin b1a OxR) and tested its function as a host-directed immunotherapy to prevent influenza induced weight loss and mortality in mice. Methods Three animal studies were performed. 1. A dose response study in H3N2 challenged mice to determine the optimal therapeutic dose of serpin b1a OxR. 2. An MO study to evaluate serpin b1a OxR induced changes in Innate and acquired immune cell responses, cytokines and select plasma analytes and biomarkers associated with H3N2 infection. 3. A study to determine if serpin b1a OxR prevents weight loss and death induced by other influenza type A and B strains (H1N1, B/Brisbane/60/2008 and B/Wisconsin/01/2010). Protein was administered i.p. prior to infection and on a q3d basis thereafter. Results Serpin b1a OxR reduced weight loss significantly and improved recovery and survival in female mice infected with H3N2 and B/Brisbane/60/2008. The protein modulated inflammation early through specific effects on immune cell populations, and suppression of elevated cytokines and markers of inflammation in the lungs and blood of treated animals. Of note, it significantly reduced NK cell count increases in the BALF of treated vs untreated H3N2 infected mice but increased them in the blood. Conclusion Serpin b1a OxR reduces morbidity and mortality induced by some Influenza A and B strains, notably H3N2 and B/Brisbane/60/2008. It also suppressed inflammation as evidenced by reduced proinflammatory cytokines, enzymes and markers of NET formation. Treatment specifically reduces increases in BALF NK cell counts. NK cells contribute to diffuse alveolar injury, impaired gas exchange, and increased susceptibility to secondary bacterial infections in severe influenza. Funding Source CDC, Redd Pharmaceuticals Inc Topic Categories Viral Immunology (VIR)

Revealing NMOSD Molecular Mechanisms in an AQP4-Induced Animal Model 2261163

Abstract Introduction Neuromyelitis optica is a severe autoimmune disease of the central nervous system (CNS), mediated by autoantibody and Th17 responses to Aquaporin-4 (AQP4), a water channel protein highly expressed in astrocyte end feet. Despite its clinical importance, understanding NMOSD pathogenesis remains challenging due to its low incidence and the lack of reliable animal models that recapitulate the human disease. Methods We recently established a robust model by immunizing wild-type (WT) mice with the pathogenic AQP4 201-220 peptide and pertussis toxin. Strong disease only develops when IFN-γ is blocked in WT mice or absent, as in IFN-γ receptor knockout (IFNGRKO) mice, both mimicking key features of human NMOSD. Results Here, we demonstrate that disease is dependent on anti-AQP4 antibodies and antigen-specific T and B cells. To investigate mechanisms of disease progression and whether immune tolerance could be re-established, we compared WT, IFNGRKO, and IFNGRKO mice treated with tolerogenic PLGA nanoparticles encapsulating AQP4 peptide (PLGA(AQP4)) at day 28 post-immunization. Single-cell RNA-sequencing and immune repertoire analysis of CNS and spleen revealed major immune alterations. IFNGRKO mice showed CNS infiltration by clonally expanded CD4+ Th1/Th17 and CD8+ T cells, a strong type I interferon (IFN-I) gene signature (ISGs), and inflammatory reprogramming of microglia toward MHC-II+ states. B cell repertoires were skewed, with reduced diversity, somatic hypermutation, and plasmablast/memory expansion. PLGA(AQP4) treatment reversed these features, reducing T cell infiltration, suppressing ISGs, restoring microglial homeostasis, and limiting B cell clonal expansion and epitope spreading. Conclusion Our findings show that NMOSD is driven by antigen-specific T and B cell responses, amplified by IFN-I and innate CNS dysregulation. PLGA(AQP4) therapy re-establishes tolerance and offers a translational strategy for CNS autoimmunity. Funding Source R01 AI155678 Topic Categories Basic Autoimmunity (BA)

Additive Manufacturing of Ordered Polymer Nanostructures (Adv. Mater. 47/2026)

Exceptional Rare‐Earth Half‐Heusler Thermoelectrics With Sublattice Softening

ABSTRACT Half‐Heusler (HH) compounds are promising thermoelectric (TE) materials, but their intrinsically high lattice thermal conductivity ( κ L ) limits TE performance. Here, we report sublattice softening‐induced intrinsically low κ L and exceptional thermoelectricity in the previously underexplored rare‐earth (RE) containing HHs. Unlike conventional non‐RE HHs, the softened RE‐based lattice framework in RE‐HHs enables vigorous atom vibration within the 4c sublattice, strengthening lattice anharmonicity and phonon damping. This effect can be further amplified when heavier elements occupy the 4c sublattice, effectively suppressing both acoustic and optical phonon propagation and resulting in a pronounced reduction in κ L . Leveraging the low κ L , we identify four RE‐HHs—DyPtSb, Y 0.7 Lu 0.3 PtSb, Sc 0.6 Lu 0.4 PtSb, and Dy 0.7 Y 0.3 PtSb—with peak zT values exceeding 1.0. Notably, Dy 0.7 Y 0.3 PtSb achieves a maximum zT of 1.33 at 875 K. These findings underscore the promising potential of sublattice‐softened RE‐HHs as highly efficient thermoelectrics with broad compositional tunability.

Stem-like and effector peripheral helper T cells orchestrate distinct local immune responses in rheumatoid arthritis 2262732

Abstract Introduction Peripheral helper T (Tph) cells can contribute to the pathogenesis of human autoimmune diseases. Although Tph cells are recognized as the major B-cell helpers in inflamed joints of rheumatoid arthritis (RA), the mechanisms underlying their maintenance, activation, and involvement in tissue inflammation remain poorly understood. Methods We applied multiple sequencing technologies, including scRNA-seq, CITE-seq, scTCR-seq, scBCR-seq and scATAC-seq, on cells from synovial tissue (ST), synovial fluid and peripheral blood from RA patients. ST sections were utilized for spatial transcriptomics data acquisition. In vitro validation experiments, such as T cell-B cell coculture and gene editing, were also performed. Results We recently demonstrated that Tph cells comprise two distinct subsets in RA: stem-like Tph (S-Tph) and effector Tph (E-Tph) cells (Masuo et al., Sci Immunol., 2025). S-Tph cells showed self-renewal capacity and were mainly found within tertiary lymphoid structures (TLSs) together with B cells. By contrast, E-Tph cells expressed various effector molecules capable of activating macrophages. Most E-Tph cells were located outside TLSs and interacted with proinflammatory macrophages. S-Tph cells were able to differentiate into E-Tph cells when cocultured with B cells, while concurrently inducing potent immunoglobulin production by B cells. Extending our T cell analysis, scRNA-seq of B cells revealed the presence of naive, memory, GC-like, ABCs, and ASCs. Among these B cell subsets, the frequency of S-Tph cells in ST correlated most strongly with that of GC-like B cells. Conclusion These findings indicate that interactions between S-Tph and B cells within TLSs of RA synovium are crucial for sustaining Tph population by promoting S-Tph self-renewal and differentiation into E-Tph cells. Our study offers a rationale to target S-Tph cells for the treatment of RA characterized by persistent tissue inflammation with an expectation to reduce global Tph responses and TLS formation. Funding Source Japan Agency for Medical Research and Development grant Topic Categories Immune Mechanisms of Human Disease (HUM)

Cell death executioners driving PANoptosis 2259603

Abstract Introduction Cell death is a key effector mechanism to maintain homeostasis and drive immune activation and host defense. However, excess cell death is linked to inflammation, pathology, and disease. Therefore, balancing the execution of cell death is critical. To control this process, executioner proteins form membrane pores that drive cell lysis and the release of damage-associated molecular patterns (DAMPs) and cytokines. Different executioners have been implicated across cell death pathways. In certain pathways, such as pyroptosis or necroptosis, a single executioner is critical (gasdermin D (GSDMD) and MLKL, respectively). However, in PANoptosis, an innate immune, inflammatory cell death pathway driven by caspases and RIPKs, multiple executioners are activated. Given the increasing recognition of PANoptosis as a key driver of inflammation and pathology in infections and inflammatory conditions, understanding the specific roles of these executioners is critical for identifying therapeutic targets. However, this understanding is currently lacking. Methods We have performed a comprehensive genetic analysis to define the roles of GSDMD, GSDME, and MLKL, the primary pore-forming molecules known to be activated in PANoptosis, in driving cell death in response to a diverse array of pathogen and sterile triggers that are known to induce PANoptosis by activating different innate immune sensors. By utilizing a large number of genetic models, including single, double, and triple knockout systems, to assess the individual and redundant functions of each executioner. Results Our study provides a holistic view of how executioners contribute to PANoptosis in response to diverse stimuli. The executioners can act in a redundant manner to execute PANoptosis. Conclusion These findings demonstrate the potential therapeutic value of targeting executioner molecules for the treatment of diverse infections and inflammatory diseases. 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)

Investigating tracheal repair and remodeling following influenza infection 2261104

Abstract Introduction The airway epithelium forms a critical barrier against inhaled pathogens and toxins, requiring rapid and coordinated repair following injury to maintain barrier integrity. In the distal lung, crosstalk macrophage-epithelial cell crosstalk is essential for alveolar repair after viral infection; however, the role of these interactions the proximal airways like the trachea remains unclear. Using a mouse model of influenza A virus (IAV) infection, we seek to define epithelial repair dynamics and determine the role of macrophages in coordinating tracheal regeneration. In addition to promoting repair, inflammatory responses to tissue injury and infection can lead to maladaptive remodeling, potentially predisposing the airways to disease. We hypothesize that IAV infection triggers macrophage-driven remodeling in the trachea, altering tissue composition and increasing susceptibility to allergic airway disease (AAD). Methods We use a mouse model of IAV infection to define epithelial repair dynamics and determine the role of macrophages in tracheal remodeling. Experiments incorporate transcriptomics, immunofluorescence microscopy, and flow cytometry to assess cellular composition, measure epithelial proliferation, and uncover macrophage—epithelial interactions. To test whether post-IAV remodeling enhances AAD susceptibility, we employ an IAV and allergic airway dual challenge model. Results Preliminary data reveal transcriptional alterations, macrophage accumulation, and expansion of epithelial stem and progenitor populations in the trachea following IAV infection, features consistent with active tissue remodeling. Ongoing work aims to elucidate how macrophages orchestrate epithelial repair and whether post-viral tissue reprogramming promotes AAD susceptibility. Conclusion Defining how macrophages regulate epithelial repair and remodeling in the trachea will advance understanding of immune—epithelial communication and reveal mechanisms linking viral infection to chronic airway disease. Funding Source NIH # R35GM150816, NIH # TL1TR002543 Topic Categories Mucosal and Regional Immunology (MUC)

Narrowband ultraviolet B induces peripheral regulatory T cells to exert antigen-specific immune suppression 2308173

Abstract Introduction Commonly used to treat inflammatory skin diseases, narrowband ultraviolet B (UVB) has been shown to induce antigen-specific immune suppression when combined with alloantigen immunization, but the underlying mechanism remains elusive. Methods We used cytometry by time-of-flight (CyTOF) to analyze the peripheral blood mononuclear cells (PBMCs) from 19 psoriasis patients enrolled in UVB trial. Mouse models of ovalbumin (OVA)-induced skin inflammation and allogeneic skin transplantation were used to investigate the effects of UVB on antigen-specific regulatory T cell (Treg) induction. We applied bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) methods to the analysis of mouse skin Tregs and PBMCs, respectively. Results CyTOF analysis revealed patients’ therapeutic response to be determined by a cluster of CD4+ T cells expressing T cell receptor (TCR)-activated and Treg-associated molecules. In clinical trial and mouse models of skin inflammation and allogeneic skin transplantation, UVB led to immunosuppressive phenotypes through antigen-specific Treg induction. RNA-seq from mouse skin Tregs showed that UVB enhanced gene expression associated with cell stability, cellular location, and cell proliferation. When compiling with human peripheral Tregs analyzed by scRNA-seq, we found similar gene expression patterns involved in Treg differentiation, maintenance, and function. Furthermore, scRNA-seq analysis also demonstrated that UVB inhibited negative regulators of Treg development, thereby promoting CD4+ T differentiation into Tregs, clonal expansion of which was also noted. Conclusion Our findings suggest UVB can induce antigen-specific Tregs in a clinical setting, highlighting its potential for broader immunosuppressive applications. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Extracellular cAMP as a potent immune modulator promotes T cell exhaustion in chronic lymphocytic leukemia 2306108

Abstract Introduction Cyclic adenosine monophosphate (cAMP) is a key intracellular second messenger known to regulate immune responses. However, its presence and functional impact in the extracellular compartment remain poorly understood. Methods We quantified plasm levels of cAMP in Chronic lymphocytic leukemia (CLL) patients. We also used bulk and single-cell RNA sequencing, multiplex cytokine profiling, and functional studies to evaluate immunological properties of extracellular cAMP Results We found that plasma cAMP levels are significantly elevated in CLL patients compared to healthy controls. Notably, we found a positive correlation between plasma cAMP levels with CLL Rai stage. We demonstrate that extracellular cAMP exerts broad immunomodulatory effects on multiple immune cell subsets, including T cells, natural killer cells, B cells, and monocytes. Extracellular cAMP selectively suppressed the expression of key proinflammatory cytokines, such as TNF-α and IFN-γ and activation markers in both CD4+ and CD8+ T cells. Prolonged cAMP inhibitory effects can promote T cell exhaustion as evidenced by the expansion of TIM-3, CD160, and PD-1 expressing T cells. This observation was further supported by a positive correlation between plasma cAMP and the frequency effector memory CD8+CD160+PD-1+ T cells in CLL patients. Transcriptomic analyses revealed downregulation of T cell effector genes and transcription factors critical for lineage differentiation and upregulation of T cell exhaustion score. In monocytes, extracellular cAMP induced a distinct transcriptional program characterized by reduced antigen-presenting functions but enhanced secretion of proinflammatory cytokines and neutrophil-recruiting chemokines. Conclusion Together, our findings reveal that extracellular cAMP is a potent immune regulator and potential biomarker in CLL. Understanding its mechanistic pathways may offer new therapeutic targets for restoring immune regulation in chronic conditions. Funding Source Cancer Research Institute of Northern Alberta Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Regulatory T cells set a dynamic boundary between cellular and humoral immunity based on input signal kinetics 2258109

Abstract Introduction The adaptive immune system defends through two strategies: humoral immunity, mediated by antibodies that require long timescales to achieve high affinity and durable protection, and cellular immunity, mediated by effector T cells that act rapidly to eliminate infected or damaged cells. Because these responses rely on overlapping resources, the immune system faces a fundamental trade-off between establishing humoral or cellular responses. We propose that regulatory T cells (Tregs) dynamically set this balance. Tregs control the availability of interleukin-2 (IL-2), biasing activated T cells toward either T follicular helper (Tfh) fates–which promote germinal center formation–or non-Tfh effectors, favoring cellular immunity. Since Treg consumption of IL-2 scales with T cell activation, cellular immunity is prioritized when threats escalate rapidly and humoral immunity when they progress more gradually. Methods We modeled IL-2 availability and T cell differentiation during immune responses of differing kinetics in silico using a continuous-time Markov chain framework. Predictions were then tested in vivo by varying challenge kinetics and applying high-resolution multiplexed imaging to quantify activated T cell fates, Treg dynamics, and germinal center formation over time. Results The model predicted that 1) expanding challenges favored non-Tfh effector differentiation, whereas transient or prolonged challenges favored Tfh differentiation and germinal center formation, and 2) Tregs controlled this partitioning by scaling IL-2 consumption with total challenge burden. These predictions were validated in vivo by comparing immunization strategies. Conclusion Our findings provide evidence that Tregs dynamically tune Tfh versus non-Tfh effector differentiation according to the kinetics of the immune challenge. This framework introduces a new paradigm for how Tregs govern trade-offs between cellular and humoral immunity, with broad implications for vaccination, cancer, and autoimmunity. Funding Source This material is based upon work supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM087237, by the Ragon Institute under a Strategic Initiative grant, by Massachusetts General Hospital, and by the Massachusetts Institute of Technology. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

A novel LNP/mRNA-based STING immunotherapy approach for chronic HBV infection 2334947

Abstract Introduction Chronic hepatitis B virus (HBV) infection remains a major global health burden. Current antiviral therapies suppress viral replication but fail to eliminate cccDNA or substantially reduce HBsAg, making functional cure rare. Innate immune control of HBV is limited by poor engagement of the STING pathway in hepatocytes due to low endogenous expression and inefficient agonist delivery. We developed a universal STING mimic (uniSTING) delivered via lipid nanoparticles encoding uniSTING mRNA, which drives formation of endomembrane-independent STING polymers and preferential activation of the IRF3/type I interferon axis while minimizing NF-κB signaling. Methods HBV-positive cells were treated with LNP/uniSTING, followed by assessment of type I interferon and interferon-stimulated genes (ISG) induction. In vivo, HBV carrier mice were administered LNP/uniSTING, and serum HBV viremia were monitored alongside HBV-specific innate and adaptive immune responses. Results uniSTING elicited strong IFN-I responses in HBV negative cells. In the HepAD38 cell line where HBV transcription from the integrated HBV genome is suppressed by doxycycline to produce HBV predominantly from HBV cccDNA, uniSTING induced robust IFN-β and ISGs expression, whereas in the Dox- condition, characterized by high-level HBV replication, uniSTING-induced IFN-β and ISG responses were attenuated. In vivo, administration of LNP/uniSTING to naive mice induced robust IFN-β production and ISG expression. In chronic HBV carrier mice, repeated administration of LNP/uniSTING resulted in sustained reductions in serum HBV DNA and HBsAg levels, accompanied by induction of anti-HBs IgG responses. Conclusion These findings demonstrate that uniSTING can break HBV immune tolerance and elicit a functional anti-HBs antibody response in vivo. Collectively, this work highlights uniSTING as a promising immunotherapeutic strategy for chronic HBV infection by simultaneously activating innate antiviral pathways and promoting protective humoral immunity. Funding Source NIH R01 AI181664 Topic Categories Viral Immunology (VIR)

Local Antigen Encounter and a Type I IFN-IL-15 Axis Cooperatively Program Cytotoxic CD4 Differentiation and Tissue Residency 2261140

Abstract Introduction Cytotoxic CD4 T cells (ThCTL) are a distinct tissue-resident effector subset driving MHC-II- restricted cytotoxicity against pathogens and tumors. They become especially important when pathogens evade immune clearance by downregulating MHC-I. Methods We used a model of influenza infection to define the requirements for differentiation of early CD4 effectors into ThCTL, in the lung, post influenza infection. Results Differentiation into lung ThCTL requires effectors to recognize cognate antigen/MHC-II, locally in the lung, at 6-8 days post-infection (dpi). Various antigen presenting cell subsets can drive ThCTL differentiation but CD28 co-stimulation is not needed and may even attenuate it, which contrasts to T follicular helper (TFH) differentiation. Sustained antigen-independent signals from infection are also crucial throughout the effector phase. We find that infection-induced type I IFN induces IL-15 production, which is essential for supporting development of lung tissue-resident ThCTL. Preliminary data suggest that this represents a stage in the progression of ThCTL effectors into lung CD4 tissue-resident memory (TRM) cells which can provide long-term memory against respiratory infections. While local antigen presentation and IL-15 are traditionally linked to the development of TRM, our findings show that this programming is initiated at this effector checkpoint, determining their fate as TRM. Conclusion This requirement for antigen and infection signals at 6-8 dpi aligns with an effector checkpoint controlling the fate decisions for CD4 memory, TFH and ThCTL. We therefore suggest that vaccines deliver localized antigen and infection-associated signals during this window, to induce the development of protective immunity. Our findings propose a paradigm wherein stringent requirements at this effector checkpoint guard against unnecessary cytotoxic responses if the pathogen has been cleared but ensure the development of potent tissue-restricted immunity if it is still a threat. Funding Source American Lung Association Catalyst Award, R21AI175883 Topic Categories Mucosal and Regional Immunology (MUC)

Zwitterionic Interlayer‐Directed Submicrometer Self‐Assembly for Efficient Vacuum‐Deposited Near‐Infrared Perovskite LEDs

ABSTRACT Vacuum‐deposited perovskite emitters provide precise control over thickness and composition, making them inherently compatible with established organic light‐emitting diode evaporation infrastructure. However, vacuum deposition suffers from limited crystallization control compared with solution processing, which usually results in suboptimal device performance. The external quantum efficiency (EQE) of near‐infrared vacuum‐deposited perovskite LEDs remains approximately 10%. In particular, vacuum‐deposited 3D perovskites typically undergo rapid nucleation and poor crystal growth, leading to defect‐rich films with low photoluminescence quantum efficiencies (PLQEs). Although various passivation strategies have been explored to mitigate defect densities, the underlying growth processes and crystallization mechanisms under vacuum‐deposition conditions remain insufficiently understood. Here we demonstrate an interlayer‐directed crystallization strategy in a sequential vacuum deposition process, where a zwitterionic interlayer, 5‐aminovaleric acid (5AVA), directs the self‐assembly of perovskite precursors into oriented submicron‐scale domains. This approach produces high‐quality perovskite films with significantly enhanced PLQE and improved morphology. Perovskite light‐emitting diode (PeLED) fabricated via this route achieves a record EQE of 16.6% with a high radiance of 224 W sr − 1 m − 2 . These findings establish interlayer‐directed crystallization as a promising strategy for efficient vacuum deposited PeLEDs, showing potential in industrial evaporation technologies.