Browse Articles

The Establishment and Decay of Co-Stimulation Blockade Induced Tolerance to Semi-Allogenic Heart Grafts 2257765

Abstract Introduction Preventing graft rejection in transplant recipients relies on broadly immunosuppressive drugs with negative side effects that reduce patient adherence. Thus, achieving tolerance through transient immunomodulatory therapies is the aspirational goal in clinical transplantation. In mouse models, transient co-stimulation blockade (CoB) targeting CD28:CD80/86 or CD154:CD40/CD11b interactions can induce but not maintain long-term graft acceptance. We characterized the mechanisms leading to decay in donor-specific (DS) T cell hyporesponsiveness in a mouse model of CoB-induced heart transplant tolerance. Methods Utilizing a murine semi-allogeneic (2W1S-OVA.BALB/c x C57BL/6) heart transplant in C57BL/6 recipients, we examined DS CD4+ and CD8+ T cells in recipients receiving a tolerance-inducing treatment of anti-CD154 in conjunction with donor splenocytes (TolRx). Controls were naive or untreated C57BL/6 recipients that acutely rejected their allografts. Full spectrum flow cytometry and single-cell RNA sequencing (scRNA-Seq) were used to characterize DS T cells isolated from the recipient spleen. Results Early stable tolerance was associated with phenotypically low-avidity, naive-like DS CD4+ and CD8+ T cells, and increased numbers of DS Foxp3+ regulatory T cells (Tregs). scRNA-Seq confirmed phenotypic findings and revealed extensive transcriptional changes in DS Tregs that led to the emergence of 2 subsets of Tregs, namely Foxp3 high and effector IL-10 high. Erosion of tolerance was associated with Treg expansion and the emergence of high-avidity, effector-like DS T cells that were phenotypically similar to acute rejection. Conclusion Our findings indicate that CoB induced tolerance results in a DS T cell response dominated by Tregs, as well as phenotypically naive conventional CD4+ T and CD8+ T cells. Erosion of tolerance was associated with activation and expansion of DS T cells. Experiments are ongoing to test if this late activation is due to loss in the regulatory function of DS Tregs. Funding Source Funding from NIAID - 5P01AI097113-13 and NHLBI- 5T32HL007605-40 Topic Categories Transplantation Immunology (TRAN)

Adipocyte PDL1 suppresses immune checkpoint blockade (ICB) therapy through promoting MDSC-mediated IFNγ suppression 2226486

Abstract Introduction Adipocytes are a key component of the tumor microenvironment (TME), but their contributions to ICB response remain relatively understudied. Methods Using an adipocyte rich, PDL1+ mouse melanoma model (NCH1), we found that while αPDL1 treated NCH1 tumors in wild-type (WT) mice, αPDL1 response in adipocyte-PDL1KO mice was significantly improved. αPDL1 in adipocyte-PDL1KO mice, versus WT mice, enhanced IFNγ production in CD4+ T and CD8+ T cells, while decreasing MDSC prevalence in the TME. Results Mechanistically, MDSC depletion in WT mice improved αPDL1 response and restored IFNγ production to levels similar to adipocyte-PDL1KO. In a complementary approach, we pharmacologically inhibited adipocyte PDL1 expression with the PPARγ inhibitor GW9662, as PDL1+ adipocytes differentiate from PDL1- pre-adipocytes through PPARγ. GW9662+αPDL1 phenocopied adipocyte-PDL1KO in controlling NCH1 growth and induced immune memory that protected against secondary melanoma rechallenge, with an establishment of polyfunctional CD69+CD103+ tissue resident memory T-cells. For rapid clinical translation, we tested imatinib, an orally bioavailable FDA-approved drug that inhibits PPARγ. It improved improve αPDL1 response in the AT3 breast cancer model. Surprisingly, though, imatinib inhibited adipocyte differentiation in vitro but did not suppress their PDL1 expression, suggesting unknown complexity in adipocyte differentiation. Conclusion Taken together, these results support the role of adipocyte PDL1 in promoting MDSCs in the TME that suppress IFNγ production and support the development of clinical strategies that deplete adipocyte PDL1 to improve ICB responses. Funding Source R01CA279566 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Curcumin and Berberine as Potential Therapeutic Agents Targeting ACSL4-Mediated Ferroptosis in Glioblastoma 2258063

Abstract Introduction Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-resistant brain cancers. Despite advances in surgery and chemoradiation, long-term survival remains poor, underscoring the need for novel therapeutic approaches. Natural bioactive compounds such as curcumin and berberine have shown promise as anticancer agents through their ability to modulate oxidative stress and programmed cell death. ACSL4, a lipid-metabolizing enzyme essential for ferroptosis, has emerged as a molecular target that regulates glioblastoma cell survival. This study investigates whether curcumin and berberine can trigger ACSL4-associated ferroptotic cell death in GBM, offering a potential translational pathway for therapeutic development. Methods U87MG glioblastoma cells were cultured and treated with curcumin or berberine. Cell viability was measured using standard assays, and ongoing work includes assessing ACSL4 expression and markers of ferroptosis to clarify drug-specific mechanisms. Co-treatment experiments are being performed to evaluate whether combining curcumin and berberine enhances therapeutic efficacy. Results Curcumin treatment reduced GBM cell viability, suggesting cytotoxic activity consistent with ferroptotic cell death. Preliminary studies indicate that berberine produces a complementary reduction in viability, and combined treatment may produce additive effects. Further analysis of ACSL4 expression and lipid peroxidation is underway to confirm whether both compounds act through ferroptosis-associated mechanisms. Conclusion These findings support the potential of curcumin and berberine as therapeutic agents for glioblastoma through targeting ACSL4-mediated ferroptosis. Continued mechanistic analysis will help establish whether these natural compounds can be developed as adjunctive treatments for resistant brain tumors. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)

Prime-Target neoantigen vaccination strategy enhances neoantigen-specific T cell immunity at the tumor microenvironment in murine cold tumor models 2256928

Abstract Introduction Despite their great promise in cancer treatment, the clinical efficacy of therapeutic cancer vaccines against solid tumors remains limited because of the immunosuppressive cold tumor microenvironment (TME), which suppresses anti-tumor T-cell activity. To overcome this, we propose a novel “Prime-Target” neoantigen vaccination strategy (referred to as P/T vaccination) that combines subcutaneous (SQ) and intra-tumor (IT) neopeptide vaccinations with a potent adjuvant combination of K3 CpG plus c-di-AMP (K3/c-di-AMP). This strategy first primes systemic neopeptide-specific T cell responses and then targets cold tumors by recruiting neopeptide-specific T cells into TME. Methods Murine cold tumors that are resistant to immunotherapy such as mesothelioma (AE17) and pancreatic adenocarcinoma (KPC-4662) were vaccinated with SQ priming followed by IT boosting using corresponding neopeptides plus K3/c-di-AMP. Tumor growth and survival were assessed. Immune responses in the tumors were analyzed by flow cytometry and single-cell RNA/TCR sequencing. Results P/T vaccination markedly suppressed tumor growth and prolonged survival. These therapeutic effects require intratumoral delivery of the full neopeptide vaccine, as neither IT adjuvants nor neopeptides alone after SQ vaccination, confer protection. Mechanistically, P/T vaccination recruits massive novel TCR clones of neoantigen-specific CD4+ Th1 cells and effector CD8+ T cells into the tumor, while markedly increasing effector T cell/Treg ratios and reducing M2 macrophages within the TME. Conclusion The Prime-Target neoantigen vaccination elicits potent systemic anti-tumor T cell immunity and directs it to the tumor. This dramatically alters the TME, remodeling it towards an effector phenotype that is more favorable for tumor control. This novel approach provides a mechanistic framework for optimizing neoantigen vaccination strategies against immunosuppressive cold solid tumors. Funding Source the Department of Immunology of the Erasmus MC, the Dutch Cancer Society (KWF Grant 12837), International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo (Project number K22-3063 and K25-3190) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Enhanced Antitumor Immunity by a Peptide Improving Mitochondrial Quality in Dendritic Cells 2258813

Abstract Introduction Cancer is one of the leading causes of death worldwide and poses significant challenges in treatment. Although conventional immunotherapy mainly focuses on CD8+ T cells to eliminate cancer, targeting other immune cells is emerging as a strategy to overcome its limited efficacy. Dendritic cells (DCs), key regulators of antitumor T cell responses, rely on mitochondria to maintain their immunological function. However, within the tumor microenvironment, DCs exhibit functional impairment associated with mitochondrial dysfunction. Recent evidence highlights the therapeutic potential of regulating mitochondrial quality in immune cells; yet this approach remains largely unexplored in DCs. Therefore, we developed a mitochondria-modulating peptide (MMP) to enhance mitochondria function in DCs and antitumor immunity. Methods Vehicle- or MMP-treated BMDCs were analyzed in vitro using qRT-PCR, Seahorse assay, ELISA, and flow cytometry. BMDCs were then co-cultured with T cells in the presence of polarizing cytokines to assess DC-mediated effects on T cells. For in vivo study, B16F10 cells were injected subcutaneously into mice, followed by intraperitoneal MMP administration. Tumor-infiltrating lymphocytes were analyzed by flow cytometry. Results Treatment with MMP restored the mitochondrial function of BMDCs in vitro. Moreover, MMP-treated DCs exhibited antitumoral characteristics, including increased antigen uptake, reduced expression of PD-L1 and iNOS, and decreased pro-tumor cytokines production. Consistent with these changes, co-culture of T cells resulted in increased Th1 differentiation, reduced Foxp3+ Treg differentiation, and enhanced proliferation and cytotoxicity of CD8+ T cells. In vivo, MMP administration suppressed tumor progression in the B16F10 melanoma model. Conclusion Improving mitochondrial quality in DCs using a peptide-drug reinvigorates antitumor immune responses. These results suggest that targeting mitochondrial activity in DCs can be a promising strategy for cancer treatment. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

The Epstein-Barr virus-induced gene 2—Cholesterol 25-hydroxylase axis is essential for the recruitment of mast cell progenitors 2260869

Abstract Introduction Basophils, eosinophils, and mast cells (MCs) are granulocytes that expand in the airways during type 2 inflammation (T2I)-associated diseases, where they are thought to play a major role in disease pathobiology. While the chemotactic signals recruiting basophils and eosinophils to inflamed tissues are well characterized, the signals directing MC progenitor (MCp) recruitment remain unknown. Methods We conducted single-cell RNA sequencing on flow-sorted MCps and pulmonary endothelial cells, cross-referencing MCp chemokine receptor and endothelial ligand expression to define a series of candidate signals. In addition, we adapted an approach in which mice were intravenously injected with FITC-labeled anti-CD45 to distinguish immune cells within the vasculature from those within the lung parenchyma, thereby tracking the dynamics of MCp recruitment following HDM challenge. Results Mouse MCps displayed high expression of Gpr183, encoding the Epstein-Barr virus-induced gene 2 (EBI2), while pulmonary endothelial cells highly expressed cholesterol 25-hydroxylase (Ch25h), the enzyme responsible for generating EBI2 ligands. These transcriptional profiles were validated in publicly available human scRNA-seq datasets. In wild-type mice, MCps rapidly entered and matured within the lung parenchyma following allergen exposure. In contrast, MCp recruitment to the lung parenchyma was abolished in both Vav1Cre; EBI2FL/FL (Mice with hematopoietic cell—specific deletion of EBI2) mice and Ch25h-/- mice. Conclusion Our findings suggest a key role for the EBI2-Ch25h axis in directing MCp recruitment during T2I. Funding Source NIAID Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

Programmable Multiphasic Condensates Formed via Evaporation–Induced Phase Separation of Minimal Peptide Model

ABSTRACT Biomolecular self‐assembly is ubiquitous in nature, encompassing both ordered and disordered structures to create sophisticated superstructures essential for complex biological functions. Protein and peptide condensates formed via liquid–liquid phase separation (LLPS) are characterize by disordered assembly, gaining significant interest due to their crucial role in physiological events and potential applications from drug delivery to biosensing. Short peptides with ordered structures have been widely explored as building blocks for nanoarchitectured materials, but they lack the disordered features that endow biological systems with flexibility and adaptability. Here we introduce a minimalistic peptide sticker‐and‐spacer model that forms biomolecular condensates with core–shell structure through phase separation and spontaneous evaporation. The design allows to derive the guidelines for programming condensate's architecture from homogeneous to multiphasic state via the selection of sticker and spacer. Furthermore, we demonstrate control over compartmentalization driven by intrinsic redox chemistry and post‐assembly modification. The condensates efficiently encapsulate and protect small‐molecule payloads and function as microreactors. The evaporation‐induced spontaneous phase separation results in solidified condensates enriched with redox‐active tyrosine, which serve as novel nano‐bioreactors, promoting selective biomineralization and formation of uniform metal–peptide nanohybrids. Therefore, our study provides a framework for the artificial design of protocells mimetic multicompartmental condensates endowed with on‐demand functionality.

Isotope-edited ESEEM: A new method for probing copper binding sites in neurodegenerative proteins

Reliable and calibrated diabetic retinopathy grading from Gaussian-filtered fundus images using attention and gated state-space feature mixing

Trogocytosis as a Cellular method for Identification of Antigen specific T cells in Adoptive Cellular Therapy 2265839

Abstract Introduction Our group previously demonstrated that our polyclonal adoptive cellular therapy platform significantly increased overall survival in mice in brain cancer models. The T cells transferred into our mice are cocultured with tumor specific RNA primed dendritic cells. Although this method is successful at isolating and expanding activated and antigen specific T cells, not all of the cells being transferred are tumor specific. We have designed a cellular method for identifying T cells that are antigen specific by harnessing the power of trogocytosis, the process of transferring membrane fragments from antigen presenting cells to lymphocytes. Methods We generate primary T cells from mice splenocytes and coculture them with electroporated bone marrow derived dendritic cells. These cells are then stained and sorted with flow cytometry based on their dye uptake to separate into a trog+ and a trog- population. We phenotyped these T cells using flow cytometry to assess activation status, proliferation status, and cytotoxic markers. We analyzed tumor-specific T cell activation using a restimulation challenge and measuring IFNy with an Elisa kit. PCR microarray analysis was done to assess differences in gene expression between the trog+ and trog- cells Results We observed that there were changes in the phenotype between the trog+ and trog- populations. The trog+ cells expressed much higher levels of IFNy expression levels compared to the trog- cells when challenged with the tumor it was primed against. PCR microarray showed significant upregulation of multiple activation, proliferation, differentiation, and polarization markers in the trog+ group. Conclusion Our results indicate this assay has the ability to generate activated, antigen specific T cells. These isolated T cells have the potential to increase the efficacy of our ACT treatment as well as becoming a discovery platform for the identification of personalized tumor mutations thus enhancing future strategies of targeted cellular cancer treatments. Funding Source NA Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Pelvic and Inguinal Lymphadenopathy in a Murine Model of Lyme Disease: Is LD-Gynecological Pathology Immune-Mediated? 2257953

Abstract Introduction Lyme disease (LD) has been linked to gynecological complications including endometriosis, and uterine fibroids. Epidemiological data suggest increased incidence of these conditions among previously infected individuals, yet mechanisms remain unclear. We hypothesized that systemic infection induces persistent reproductive tract pathology and local immune activation, measurable through longitudinal imaging. Methods Female mice were intradermally infected with Bb. Weekly in vivo imaging (IVIS and MRI) monitored bacterial burden, uterine morphology, and lymph node changes. Blood, urine, and vaginal fluid were collected at serial timepoints for microbiological and immunological analyses. An AI-based segmentation pipeline quantified tissue structures. Histopathology of the reproductive tract and pelvic lymph nodes characterized structural and immune alterations. Results Infected mice developed uterine cysts and morphological changes by 10 weeks post-infection. IVIS confirmed Bb colonization of the vagina and bladder, while MRI best captured organ abnormalities. Iliacus medialis and inguinal lymph nodes exhibited sustained enlargement beyond 12 weeks. Flow cytometry at 15 weeks revealed pronounced B-cell proliferation without an increase in antibody-secreting or CD4+ T cells. Pelvic lymphadenopathy reflected persistent infection rather than bacterial load. Combined antibiotic treatment fully resolved infection and reversed lymphadenopathy. Conclusion Bb infection induces progressive uterine pathology and chronic pelvic lymphadenopathy, highlighting the link between infection and immune dysregulation in gynecological disease. MRI with AI-driven analysis provides a powerful platform for tracking disease progression. Persistent lymphoid activation occurs independently of bacterial burden but is reversible with combined antibiotic therapy, offering insights into mechanisms and therapeutic targets in LD-associated gynecopathology. Funding Source Private Foundation Fellowship Topic Categories Mucosal and Regional Immunology (MUC)

Discovery of a FcgRIIb agonist antibody for treatment of autoimmune and inflammatory diseases 2240137

Abstract Introduction Within the family of receptors that bind the Fc portion of IgG (FcgR), FcgRIIb is the only member that functions as an inhibitory receptor. Co-ligation of FcgRIIb with activating receptors induces inhibitory signaling from FcgRIIb that negatively regulates the activation signal. Mice deficient in FcgRIIb have enhanced antibody response, increased IgE induced anaphylactic reactions, hypersensitivity to collagen-induced arthritis, and spontaneous development of lupus-like symptoms. Therapeutic targeting of FcgRIIb has proven challenging due to the 96% sequence identity of the extracellular portions of FcgRIIa, an activating FcgR, and FcgRIIb. Discovering antibodies to FcgRIIb that do not also bind and activate FcgRIIa, which results in an unwanted production of pro-inflammatory cytokines, has been difficult. Furthermore, accelerated clearance has been associated with the use of high affinity antibodies to FcgRIIb. Methods To identify novel FcgRIIb selective antibodies, we employed naïve semi-synthetic libraries. Clone selection was performed by phage/yeast display and validated in scFV-Fc format. Interestingly, we observed that none of our FcgRIIb-selective clones were able to induce SHIP-1 recruitment in a cell-based assay. We then hypothesized that geometry of FcgRIIb binding might play a role in promoting agonism and converted scFVs to full-length antibodies. Results Converted FcgRIIb clones in the format of antibodies were now capable of initiating downstream signaling from FcgRIIb, highlighting the importance of the geometry in agonizing FcgRIIb. Conclusion One of the identified FcgRIIb agonist antibodies does not block immune complex binding, has a favorable PK profile, and reduces antigen specific antibody responses in a KLH immunization model. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Biomechanical stiffness is essential for CD8+ T cell activation and proliferation 2258840

Abstract Introduction The cytoskeleton maintains cellular shape and structure, and serves as a biomechanical regulator of cellular responses. Although CD8+ T cell activation is well characterized, the roles of mechanotransduction and cytoskeletal stiffness remain unclear. Understanding how these biomechanical properties affect CD8+ T cell activation and function could provide new insight into immune regulation. Methods We examined CD8+ T cells from a Protein Tyrosine Phosphatase Non-Receptor Type 21 knockout (Ptpn21⁻/⁻, KO) mouse model, previously reported to exhibit a disorganized actin cytoskeleton in hematopoietic stem cells. Intrinsic biomechanical properties were quantified using atomic force microscopy (AFM) with Hertzian modeling. Functional consequences of altered stiffness were evaluated by flow cytometry, comparing KO and wild-type (WT) mice after in vitro stimulation and in vivo adoptive transfer of CD8+OT-I T cells into B16-OVA tumor-bearing recipients. Results AFM revealed that Ptpn21⁻/⁻ CD8+ T cells were mechanically softer with a reduced elastic modulus. This softening was functionally significant to CD8+ T cell behavior. KO cells showed reduced activation upon CD3/CD28 bead stimulation, while responses to soluble OVA peptide remained comparable, indicating defective mechanotransduction. Calcium-flux assays demonstrated reduced store-operated Ca²+ entry, and AFM showed prolonged relaxation time, together suggesting impaired mechanotransduction during early TCR signaling. In vivo, the percentage of KO CD8+ T cells circulating in the spleen, lymph nodes, and peripheral blood was significantly lower than that of WT cells in a competitive adoptive transfer model, and the residual KO cells were less activated and proliferative. Conclusion In conclusion, our findings demonstrate that cytoskeletal softening in Ptpn21⁻/⁻ CD8+ T cells impairs mechanotransduction, resulting in weakened T cell activation and reduced proliferation within a tumor-bearing environment. Funding Source HL162725, HL130995, CA282579 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Gut microbial composition modulates food-specific CD4+ T cells in food allergy 2256989

Abstract Introduction The growing food allergy epidemic is thought to be related to changing environmental factors, particularly changes in the gut microbiome. While prior work has demonstrated that food allergy can be modulated by gut microbes, little is known about how food allergen-specific CD4+ T cells are affected by gut microbial composition. Here, we report that food allergy severity differs between mice obtained from two different specific pathogen-free vendors (Jackson Labs [Jax] and Taconic Biosciences [Tac]) along with differences in food-allergen specific Treg cells in the small intestine. Methods Mice were sensitized to ovalbumin (OVA) via intraperitoneal injection of OVA with alum. Two weeks later, animals were challenged with 3-7 gavages of OVA. Animals were observed for development of diarrhea within 60 minutes following challenge. Body temperature was tracked before and after gavage. Lymphocytes were isolated from small intestine lamina propria (SI LP) and stained with OVA peptide:MHCII tetramers or for markers of mucosal mast cells (MMC). Intestinal permeability was measured in naive Tac and Jax animals using FITC-dextran uptake assay. In co-housing experiments, mice were co-housed for 4 weeks prior to OVA sensitization. Results Mice from Tac developed diarrhea and anaphylaxis after fewer allergen exposures than mice from Jax. We also found that Tac mice have significantly fewer allergen-specific regulatory T cells in SI LP compared to mice from Jax. In addition, Tac mice had a greater abundance of MMCs and increased intestinal permeability. This increased food allergy severity phenotype was transferable via co-housing, which corresponded to a shift in Jax microbial communities towards those found in Tac mice. Conclusion Our findings demonstrate for the first time that food allergen-specific Treg cells can be modulated by gut microbial community composition, which in turn is correlated to food allergy severity. Altered intestinal permeability may be a mechanism behind this relationship. Funding Source Life Science Research Association Topic Categories Mucosal and Regional Immunology (MUC)

CCL20-CCR6 signaling modifies cellular metabolism in CD4 T cells and drives the differentiation of pathogenic Th17 cells 2258882

Abstract Introduction The chemokine receptor CCR6, a G-protein-coupled receptor, binds to its high-affinity ligand, CCL20. Within the CD4+ T cell population, both Th17 and regulatory T cells express CCR6, allowing them to migrate to regions rich in CCL20 and characterized by inflammation. As CCR6+ T cells move from secondary lymphoid organs into inflamed tissues, they encounter distinct metabolic conditions. The specific factors driving metabolic adaptation within these environments, as well as their influence on effector or regulatory T cell functions, remain incompletely understood. Methods Acute colitis was induced in C57BL/6 or CCR6-/- mice by giving dextran sodium sulphate (2% w/v) in the drinking water. Chronic colitis was induced by adoptive transfer of naïve CD4 T cells (CD4+CD25-CD44-CD62L+CD45RBhi cells) in RAG1-/- mice. Cells were analyzed using flow cytometry, immunohistochemical analysis, and RT-PCRs. Results During colitis, elevated CCL20 production in the gut facilitates the recruitment of specific immune cells. Our studies demonstrate that intrinsic CCL20-CCR6 signaling within CD4+ T cells enhances the differentiation of pathogenic Th1-like Th17 cells (T-bet+RORγt+, IFN-γ+IL-17A+) in both murine models and human patients. This pathway triggers rapamycin-sensitive phosphorylation events involving PI3K, Akt, mTORC1, and STAT3, contingent on CCR6 expression. Transcriptomic and proteomic analyses indicate that CCL20 modulates Th17 differentiation by affecting multiple metabolic pathways, particularly those associated with energy metabolism, which is further supported by changes in the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Notably, CCL20 markedly increases glycolytic activity while inhibiting oxidative phosphorylation, thereby promoting the generation of pathogenic Th17 cells. Conclusion Our results suggest that changes in Th17 metabolism triggered by CCR6 offer a promising avenue for developing a therapeutic strategy to control gut inflammation and autoimmunity. Funding Source GL received the Swarn Jayanti Fellowship (DST/LSA-01/2017-18) from the Department of Science and Technology (DST), TATA Innovation Fellowship (HRD-16012/5/2024) from the Department of Biotechnology, Ministry of Science and Technology, Government of India. Topic Categories Cytokines and Chemokines and their Receptors (CCR)

Development of Single-Administration Burkholderia pseudomallei Vaccines using Atomic Layering Thermostable Antigen and Adjuvant (ALTA®) Technology 2259779

Abstract Introduction Melioidosis, an infectious disease caused by Burkholderia pseudomallei (Bp), is difficult to treat due to intrinsic antibiotic resistance, latency with subsequent recrudescence and a diverse non-specific symptomatology. A vaccine is needed to effectively control this disease burden around the globe. Here we tested the efficacy of a novel Bp vaccine containing hemolysin-coregulated protein (Hcp1), capsular polysaccharide (CPS)-CRM197 conjugate, and CpG using the Atomic Layering Thermostable Antigen and Adjuvant (ALTA®) platform. Methods C57BL/6 mice were vaccinated and the protective efficacy as well as immunological profiles were evaluated pre- and post-aerosol challenge with B. pseudomallei K96243 strain. Results Each tested dose of Bp ALTA® formulation demonstrated protective efficacy (20-50%) over a non-vaccinated control. Mechanistically, the Bp ALTA® formulations increased Hcp1-directed IFN-gamma recall in splenocytes, and produced robust antibody response against the principal dominant antigen, CPS. High levels of anti-CPS antibodies were associated with significant decrease in bacterial burden in the lung. Conclusion The ALTA® platform, which has previously been shown to provide antigen thermostability, was utilized in this study for Bp vaccination achieving protective efficacy from a single-shot administration. Studies are ongoing to optimize the immunogenic potential and protective capacity of these novel formulations. Funding Source DTRA-JSTO Topic Categories Vaccines and Immunotherapy (VAC)

Spatial Electric Field Effect‐Driven Efficient Sulfur Reduction Reaction

ABSTRACT The uncontrolled diffusion of soluble polysulfides and their unregulated deposition of Li 2 S are key causes of capacity decay and reduced Coulombic efficiency in lithium–sulfur batteries (LSBs). Here, we construct a hollow urchin‐like NiCo 2 O 4‐x Se x framework featuring high‐curvature tips and a selenization‐derived gradient outer layer, and introduce a synergistic regulation mechanism that couples spatial electric‐field effects with electronic‐structure modulation. The localized electric field induced by high‐curvature tips drives polysulfides and Li + to preferentially accumulate toward the tip regions along a potential gradient and initiates rapid interfacial conversion. Meanwhile, Se regulation optimizes the electronic structure of Co sites, which strengthens Co─S interactions and renders the polarization and cleavage of S─S bonds. As a result, the polysulfide reaction pathway is transformed from disordered diffusion into a spatially vectorial process: conversion is initiated at the tips, propagated within the inner layer, and finalized by controlled deposition on the inner side, effectively suppressing the shuttle effect and preventing rapid surface accumulation of Li 2 S. Benefiting from this strategy, the cells deliver outstanding electrochemical performance under high‐rate operation, prolonged cycling, and high sulfur loading. This work demonstrates that synergistic spatial electric‐field engineering converts complex multistep interfacial reactions into a controllable spatial reaction process, offering a new avenue for LSBs.

Mitochondrial permeability transition in redox homeostasis and ferroptosis

FaceAge+: training-free synthetic augmentation for deep learning-based biological age estimation from facial images

Abstract Accurate biological age estimation from facial images has emerged as a promising non-invasive marker of human aging. It is potentially relevant to health assessment and geriatric research. However, progress in this field is constrained by a severe age imbalance in publicly available datasets, leading to poor representation of children and older adults. This limitation causes unreliable aging predictions in populations where accurate estimates are clinically relevant. In this work, we present FaceAge+, a data augmentation based method, that addresses age imbalance without requiring additional data collection or end-to-end model retraining. The proposed approach uses a novel training-free, age-conditioned face synthesis technique based on geometrically guided W-space traversal of StyleGAN2, enabling the disentangled generation of synthetic faces across target age groups. We incorporate a Vision Language Model-based perceptual face filter and self-supervised feature extraction using the state-of-the-art DINOv3 model. Extensive experiments on two datasets demonstrate that our method outperforms recent approaches, achieving mean absolute errors of 3.27 years on UTKFace and 2.20 years on IMDb-Wiki. This consistently improves predictions for underrepresented age groups, particularly individuals aged 60 and above. Age-stratified evaluation shows reductions of up to 25% in error for elderly cohorts compared to models trained on the original data. Our code is available at https://github.com/qaixerabbas/faceage-plus .

T cell adaption to bile acids is critical for their responses during liver tumors 2266175

Abstract Introduction CD8+ T cells have an incredible capacity to infiltrate almost every tissue in the body. Yet, it is not known how T cells adapt to different tissue microenvironments. This is particularly important during diseases such as cancer, as CD8+ T cells are often found to be in a state of dysfunction. Therefore, we presume that failure to adapt to the local microenvironment contributes to T cell dysfunction within tumors. Methods To determine how T cell adaptation influences their function, we used the liver and liver derived cancer as model system, as liver tumors showed elevated taurine-conjugated bile acids which are primarily synthesized by the liver. Using hepatocyte-targeting AAVs to knock out liver genes, we identified the role of bile acid synthesis enzymes in shaping T cell responses. Results We found that in liver tumors, tumor-reactive T cells took up elevated levels of conjugated bile acids than the non-tumor-reactive T cells. This uptake of bile acids was associated with lower expression of bile acid efflux transporters - Abcb1a/b and Slco3a1. Knockdown of either of these bile acid efflux transporters in T cells led to bile-acid-mediated mitochondrial toxicity and cell death. Whereas, overexpressing SLCO3A1 was sufficient to promote survival of T cells in bile-acid-rich liver tumors. More importantly, knocking down enzymes in the bile acid synthesis pathway led to the identification of the bile acid—conjugating enzyme BAAT as a negative regulator of T cell responses to the tumor. Thus, BAAT knockout liver tumors displayed lower conjugated bile acids associated with elevated tumor-reactive T cell responses, indicating its therapeutic potential. We are now determining the role of different bile acid receptors in T cell differentiation. Conclusion In conclusion, we found that bile acids in the liver act as tissue-specific regulators of T cell responses, and T cell adaptation to such bile acids is essential for survival and responsiveness, especially when the tumor arises in the liver. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)