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Organ-scale control of persistent, host-destructive T cell responses following infection 2256259
Abstract Introduction The mammalian immune system deploys potent inflammatory responses to defend host tissues from invading pathogens, but these responses also damage the very tissues they evolved to protect. This challenge is exemplified by the influenza-infected lung, where organ-scale tissue damage threatens lung physiology. T cells play a dual role in this process: they are critical for clearing infected cells, yet they also release diffusible inflammatory mediators that drive off-target tissue damage. We investigated how these T cell responses are regulated at the organ scale to balance pathogen clearance against protecting tissue integrity. Methods We combined high-resolution multiplexed and optically cleared 3D volumetric imaging with antibody-mediated perturbations to dissect the spatiotemporal control of T cell responses, tissue damage, and repair during sublethal influenza infection. Results We found that damaged lung regions exhibited intense T cell accumulation that persisted even as the epithelium repaired post-viral clearance. Strikingly, despite their potential to exacerbate injury, these T cells were surrounded by widespread up-regulation of PD-L1 spanning millimeters of damaged and regenerating tissue. Temporally controlled blockade of PD-1—PD-L1 interactions locally reactivated effector T cell functions within these regions and markedly disrupted epithelial repair. Together, these results reveal that PD-L1 induction protects the lung from T cell—mediated damage post-infection, and they reveal a spatially coordinated, organ-scale mechanism that restrains inflammation to enable tissue recovery. Conclusion Our results demonstrate that even after viral clearance, residual effector T cells threaten tissue integrity, necessitating organ-scale, PD-L1—mediated inhibition to preserve lung structure and function. These findings highlight a fundamental principle of immune regulation: tissue recovery depends not only on resolving inflammation over time, but also on spatially containing it across the organ. Funding Source This material is based upon work supported by a National Science Foundation Graduate Research Fellowship under award number 2141064; by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM087237; Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)
Repeated brain resident memory T cell reactivation induces microglial and T cell remodeling and sustained microglia activation in Alzheimer’s disease 2259954
Abstract Introduction Resident memory T cells (TRM) are a subset of memory T cells that persist in lymphoid and non-lymphoid tissues. Brain TRM (bTRM) can protect against reinfections, and their reactivation induces transient activation and recruitment of local immune cells, including microglia. In Alzheimer’s disease (AD), immune involvement has been shown to influence pathology, but the role of bTRM in AD progression is largely unknown. Activated microglia, key mediators of AD pathology, can phagocytose amyloid-beta (Aβ) plaques, protein aggregates that are a hallmark of AD pathology. Due to reported increased numbers of CD8+ TRM in AD brains and the increased risk of AD development through latent viral infections, we sought to test the impact of bTRM recall functions on AD pathology. Methods We took a reductionist approach to model TRM reactivation due to recurrent infection by introducing cognate viral peptide intracranially three times one month apart. Results Consistent with successive expansion, we saw a dramatic increase in bTRM numbers in both 5xFAD AD-model mice and wildtype mice. Intriguingly, we observed sustained microglial activation as indicated by elevated MHCII expression over one month after the last reactivation in 5xFAD mice. These microglia were part of a cytokine-response microglia subset that were specific to recurrent reactivation in both WT and 5xFAD mice. Additionally, bTRM exhibit increased upregulation of a granzyme-expressing population in response to multiple bTRM recall events. Females had stronger phenotypes, and strikingly, we observed increased soluble Aβ in female brains but not in males. Conclusion This data reveals unique microglial and bTRM remodeling driven by repeated bTRM reactivation, suggesting an inflammatory role of bTRM in AD and providing insight into neuroimmune crosstalk that can guide AD immunotherapies. Funding Source NIA R01 AG078761 NIAID T32 AI007363-31A1 Topic Categories Neuroimmunology (NEUR)
Combination XPO1/PD1 inhibition for canine cutaneous T cell lymphoma: a comparative oncology approach 2258208
Abstract Introduction Cutaneous T cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma marked by malignant T cell infiltration of the skin, which is often accompanied by chronic inflammation and progressive immunosuppression. While most human CTCL cases express CD4, a subset present with aggressive CD8+ lymphoma. Recent studies suggest that epitheliotropic lymphoma (EL) that develops spontaneously in pet dogs closely resembles CD8+ CTCL subtypes, indicating its potential value as a translational model for studying novel therapies related to CTCL. The objective of this study was to evaluate the efficacy and safety of combined PD1 and XPO1 inhibition in pet dog CTCL, and to identify differentially expressed immune genes linked to treatment response and prognosis. Methods Six client-owned pet dogs with biopsy confirmed CTCL were enrolled in a non-randomized clinical trial of gilvetmab (canine anti-PD1) and verdinexor (XPO1 inhibitor). Over sixteen weeks, skin biopsies and tape strips were collected from each canine at weeks 0, 8 and 16 to assess longitudinal gene changes. Clinical evaluations tracked progression-free survival (PFS) and overall survival time (OST). Differential gene expression was compared between healthy controls and short vs long term PFS using microarray technology. Results Combination therapy achieved a 50% overall response rate, with a median OST of 480 days and n = 4 pets alive at study end. Pet dogs with a longer PFS demonstrated distinct immune gene signatures compared to shorter PFS: SAA1 and CXCL13 were upregulated in short-term PFS, while C1R and CCL21 were elevated in longer PFS. Conclusion PD1 and XPO1 inhibition is a feasible and potentially immunoprotective strategy in CD8+ CTCL. Transcriptomic findings reveal immune genes linked to poor prognosis, as well as candidate biomarkers associated with improved outcomes. Given the parallels between pet dog and human CD8+ CTCL, this model offers promising insights for advancing comparative oncology and developing more effective immunotherapies. Funding Source Merck Animal Health Gilvetmab Grant Topic Categories Veterinary and Comparative Immunology (VET)
An integrated cell atlas of the innate lymphoid cells in health and disease 2255047
Abstract Introduction Innate lymphoid cells (ILCs) represent a highly diverse family of lymphocytes that play pivotal roles in tissue homeostasis, inflammation, and cancer immunity. Despite growing evidence of their plasticity and functional heterogeneity, a comprehensive understanding of human ILC diversity across pathological contexts remains limited. Methods We performed large-scale single-cell RNA sequencing (scRNA-seq) analysis of 3,322 human samples spanning 60 physiological and pathological conditions. Results By integrating and harmonizing ILC transcriptomes across tissues and diseases, we systematically characterized the cellular states, transcriptional regulators, and disease-specific adaptations of ILC subsets. Our atlas reveals both conserved and disease-specific transcriptional programs of ILCs. Pathological conditions induce profound compositional and phenotypic shifts in ILC subsets. Comparative analyses between TCF7+ ILC1 and ZNF683+ NK-derived IFNG+ ILC1 populations highlight distinct transcription factor dependencies and microenvironmental stimuli shaping their effector programs. Notably, GZMB+ ILC2 cells, enriched in multiple cancer types, were associated with improved patient prognosis, suggesting a potential cytotoxic role. In contrast, NR4A1+ ILC3 cells within NCR⁻ ILC3 clusters were preferentially enriched in tumors and inflammatory diseases, correlating with poor prognosis and resistance to immunotherapy. Conclusion This comprehensive single-cell atlas delineates the dynamic landscape of human ILCs across diseases. Funding Source n/a Topic Categories Computational and Systems Immunology (COMP)
T-bet—dependent CD4+ T cell effector programming is essential for chronic resistance to Toxoplasma gondii 2308788
Abstract Introduction Protective immunity to the intracellular parasite Toxoplasma gondii relies on a rapid and robust CD4+ Th1 effector response. The transcription factor T-bet is classically regarded as the master-regulator of IFN-γ in CD4+ Th1s; however, while T-bet—deficient CD4+ T cells can still produce IFN-γ, global T-bet-deficient (Tbx21⁻/⁻) mice rapidly succumb to infection. Therefore, we investigated if T-bet-dependent programming is required for long-term immunity against T. gondii. Methods Using a cyst-forming strain, ME49, we compared wild-type (WT), Tbx21⁻/⁻, and CD4-restricted T-bet-deficient mice (CD4-Cre × Tbx21flox/flox; CD4-Tbx21⁻/⁻). Results As expected, Tbx21⁻/⁻ mice succumbed to infection by day 10 post-infection (p.i.), coinciding with high parasite burden. In contrast, CD4-Tbx21⁻/⁻ mice survived acute infection, but eventually succumbed by 25 days p.i., revealing a selective requirement for CD4-intrinsic T-bet during chronic disease. Across all infected groups, IFN-γ production was confined to early apoptotic CD4+ T cells. However, in CD4-Tbx21⁻/⁻ mice, this apoptotic subset lacked Ly6C but retained CD44, supporting a requirement for T-bet in the generation of IFN-γ+Ly6C+ CD4+ effector cells. Although CD4-Tbx21⁻/⁻ mice showed WT-like parasite burden at day 8 p.i., they developed markedly increased peripheral burden by day 14. Furthermore, we observed that CD4-Tbx21⁻/⁻ mice had reduced CD4+ T cells in the spleen and the brain at day 14 p.i., suggesting that T-bet expressing CD4+ T cells in the CNS are essential for long-term host resistance. Simultaneously, parasites failed to convert into cysts, and IFN-γ-inducible GTPases essential for parasite clearance were significantly reduced in CD4-Tbx21⁻/⁻ brains, likely due to diminished CNS T-bet-dependent CD4+ T cell-derived IFN-γ. Conclusion Mechanistically, we demonstrate T-bet-expressing CD4+ T cells in the CNS are critical for efficient conversion of T. gondii from the fast-growing tachyzoite stage to life-long cysts, ensuring host survival. Funding Source NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)
Spider Silk‐Inspired High‐Damping Liquid Crystal Elastomer Fibers Enabled by Semi‐Interpenetrating Networks
ABSTRACT Inspired by the β‐sheet nanocrystals in natural spider silk, we develop a high‐damping polycrystalline‐phase liquid crystal elastomer (LCE) fiber enabled by a semi‐interpenetrating network. Continuous large‐scale fabrication of this crosslinked system is realized using a unique channel‐confinement strategy. By innovatively designing the end‐group molecular structures of linear polymers, we precisely regulate the liquid‐crystal phases within the semi‐interpenetrating network fibers. Four distinct liquid‐crystal phases are constructed, mimicking the β‐sheet nanocrystals of spider silk to enable efficient energy dissipation. The resulting fibers exhibit a high elastic modulus of 47.6 MPa, outstanding toughness of 60.4 MJ m −3 , a high dissipation coefficient of 88.6%, an ultra‐broad damping temperature window, a wide damping frequency range, and a strong actuation stress. When woven into damping nets for impact buffering, the nets exhibit a tunable memory recovery time and an exceptionally low dynamic rebound ratio of 5.9%, enabling efficient impact‐energy adsorption and secure capture. Overall, this work overcomes the long‐standing trade‐off among mechanical, actuation performance, and damping capacity of LCEs, and provides a universal strategy for elastomer‐based damper design and precise liquid crystal phase control, opening new opportunities for applications in elastomer dampers, artificial muscles, and soft robotic systems.
Development and Validation of High Sensitivity SimpleStep Ignite® ELISAs for Quantitative Measurement of Human Immune Checkpoint Proteins 2333298
Abstract Introduction Immune checkpoint pathways play critical roles in regulating T cell activation, tumor immune evasion, and responses to immunotherapy. Quantitative assessment of checkpoint related proteins–such as Fibrinogen Like Protein 1 (FGL1), Programmed Death Ligand 1 (PD L1), Programmed Death 1 Ligand 2 (PD L2), Programmed Death 1 (PD 1), and Lymphocyte Activation Gene 3 (LAG 3)–is essential for mechanistic studies, biomarker discovery, and preclinical immuno-oncology research. To address the need for rapid, highly sensitive, and user-friendly immunoassays, we developed a suite of ELISA kits optimized for detection of these key checkpoint molecules in biological matrices. Methods Antibody pairs were screened to identify optimal sensitivity and dynamic range. Biological validation included precision, spike and recovery performance, and dilutional linearity to ensure minimal matrix effect across serum, plasma, cell culture supernatant, and relevant immune cell lysate matrices. Cross reactivity and interference testing ensured assay specificity. Results The resulting ELISAs demonstrated low pg/mL range LOD, with broad dynamic ranges supporting quantification in diverse sample types. Spike and recovery values ranged from 80—120%, and parallelism studies confirmed reliable quantification across diluted matrices. Each assay exhibited high specificity, with no detectable cross reactivity to related family members. The streamlined single wash protocol enabled completion in under 55 minutes while extending sensitivity compared to traditional sandwich ELISAs. Conclusion These newly developed SimpleStep Ignite® ELISA kits for human FGL1, PD L1, PD-L2, PD 1, and LAG 3 provide rapid, sensitive, and reproducible tools for quantifying key immune checkpoint proteins. Their strong analytical performance and simplified workflow support high throughput immuno-oncology research, enabling deeper characterization of checkpoint pathways and accelerating biomarker driven discovery. Funding Source Abcam Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Butyrate and Secondary Bile Acids-Producing Gut Microbes Suppress Insulitis in NOD Mice 2258407
Abstract Introduction Gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs) such as butyrate and secondary bile acids (SBAs), are key regulators of immune homeostasis. In a pilot study of individuals with type 1 diabetes (T1D), higher circulating SCFA levels were associated with improved glycemic control. Moreover, longitudinal studies have shown that children who later developed multiple islet autoantibodies displayed early alterations in SBA profiles, implicating bile acid dysregulation in T1D pathogenesis. We therefore hypothesize that a defined probiotic consortium capable of producing both butyrate and SBAs will suppress islet autoimmunity and prevent T1D onset. Methods To develop a safe and effective strategy for T1D prevention, we assembled four probiotic consortia comprising six butyrate-producing and eleven SBA-producing bacterial species from the Symbiotic Bacterial Strain Bank. Female NOD mice were orally gavaged with the consortia (∼5 × 108 CFU per species) or saline for four weeks post-weaning. Bacterial colonization was quantified by qPCR two weeks after the final administration, and insulitis severity and immune cell profiles were analyzed at 12 weeks of age. Results Of the species tested, Bacteroides ovatus, Phocaeicola vulgatus, and Anaerostipes caccae successfully colonized the NOD mice. Consortia-treated mice exhibited slightly increased intestinal length at 12 weeks, consistent with reduced gut inflammation. Importantly, insulitis severity was significantly suppressed in treated mice compared with controls. Conclusion Developing probiotic consortia enriched in SCFA- and SBA-producing gut microbes may offer a promising and safe strategy to prevent T1D. Funding Source 2024 Study Abroad Grant, Manpei Suzuki Diabetes Foundation Topic Categories Mucosal and Regional Immunology (MUC)
Engagement of the T cell receptor against an oncolytic virus generates a population of hypereffector CAR T cells with potent antitumor activity 2256915
Abstract Introduction We have shown that combining CAR T cells with oncolytic viruses (OVs) generates a subpopulation of highly cytotoxic CAR T cells that can mediate long-term solid tumor therapy. Methods To profile these CAR T cells, we used C57BL/6 mice bearing B16F10 tumors expressing EGFRviii, treated with anti-EGFRviii CAR T cells and the OV vesicular stomatitis virus (VSV). TCR signaling in CAR T cells was investigated using the novel Tocky transgenic mouse model, which reports T cell activation over time using an unstable fluorescent protein reporter of Nr4a3. We further investigated CAR T phenotypes using CyTOF and scRNA-Seq. Results Using an MHC I tetramer for the dominant VSV epitope VSV N52-59, we found that 20-50% of transfused CAR T adopted TCR specificity against VSV N (referred to as TCR-primed), indicating significant in vivo expansion. Ex vivo, these TCR-primed CAR T produced increased levels of granzyme B and IFNγ over tetramer-negative CAR T against either TCR or CAR targets. However, TCR-primed CAR T cells were notably less activated via Nr4a3 as compared to non-TCR-primed CAR T. CyTOF and scRNA-Seq analyses demonstrated a hypereffector phenotype among TCR-primed CAR, with increased expression of T-bet, CD44, granzyme B, IFNγ, and perforin. TCR sequencing revealed hyperexpansion of VSV N-specific CAR T cells and little overlap in clonotypes between CAR T co-treated with PBS versus VSV. These TCR-primed CAR T cells exhibited a CD4-helped phenotype with increased expression of chemotactic and migratory transcripts. When CAR T and OV were administered with antibody-mediated CD4 depletion, the TCR-primed CAR population was significantly diminished, emphasizing the importance of the immune triad for CAR T expansion. Conclusion Overall, CAR T cells that undergo endogenous anti-viral TCR priming and signaling adopt a unique phenotype that promotes their expansion and cytotoxic function. Interactions with CD4 T cells appear to be integral for the generation of this subpopulation of CD8 CAR T cells. Funding Source NIH Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Epigenetic reprogramming of terminal T cell differentiation via DNMT1 inhibition reverses terminal DNA methylation and enhances multipotency 2259880
Abstract Introduction The effectiveness of T cell-based immunotherapy is limited due to T cell exhaustion, a state of impaired cytotoxicity, diminished cytokine production, and restricted proliferative capacity during chronic antigen exposure. Epigenetic modifications, such as the acquisition of repressive DNA methylation, sustain T cell exhaustion. Here, we investigate the role of hypomethylating agents in reversing T cell dysfunction via DNA demethylation. We hypothesize that using a selective inhibitor of DNA methyltransferase 1 (DNMT1i), GSK-3685032, can overcome the fate restrictions unique to terminally differentiated T-cells. Our preliminary data show that the fate and subset specificity of human and mouse T-cells can be epigenetically altered to mediate the reversal of repressive epigenetic programs. Methods Methylation profiling revealed that DNMT1i treatment results in robust loss of DNA methylation, notably at critical memory and stem-associated gene loci including TCF7 and LEF1. Results Notably, DNMT1i-treated T cells that underwent division had decreased methylation coupled to heightened multipotency and plasticity. Single-cell transcriptomics post DNMT1i treatment reinforced our findings by revealing a unique subset of memory T cells that have homing potential and a long-lived memory gene signature. Conclusion Collectively, we describe an epigenetic approach that facilitates the reversal of repressive DNA methylation and are now using this approach to alter the fate of T cell subsets for immunotherapy. Funding Source R01CA237311 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)
Cisplatin presentation to CD4 T cells involves robust activation and immunotoxicity 2258176
Abstract Introduction Cisplatin, a platinum-based chemotherapeutic agent, remains one of the most efficacious drugs in the clinical management of a broad spectrum of malignancies. Despite its therapy, Cisplatin causes off-target toxicity like hepatotoxicity, neurotoxicity, and especially nephrotoxicity leading to chronic renal impairment. The role of Cisplatin in immunotoxicity is largely unknown, except for its formation of DNA adducts, leading to replication stress and trigger apoptosis in neoplastic cells. The objective of this study is to test whether CD4+ T cells react to platinum (Pt)-containing compounds, and to characterize their role in T cell activation and potential contribution to Pt-induced kidney tissue pathology. To this end, we evaluated the immunogenicity of several Pt-based agents, including Carboplatin (CarbPt), Oxaliplatin (OxaliPt), a Pt-Standard compound, and a Multi-Element Platinum (ME-Pt) formulation. Methods We performed the IL2 assay to evaluate CZD9.2 T cell activation. Morphological changes and cell death were observed through microscopy imaging. Immune cell infiltration was assessed using IHC staining. Results Compared to Nickel, CisPt, CarbPt, OxaliPt, and Pt-standard, Pt ion can be presented by DR1-expressing APCs, and induces strong CZD9.2 TCR activation. CisPt showed low T cell cytotoxicity and can stimulate T cells at high concentrations. The ME-Pt is highly toxic and does not activate CZD9.2 TCR. Antibody blockade assays revealed that the unbound forms of Cisplatin and related Pt compounds can activate CD4+ T cells by modifying the HLA/peptide complex, independent of classical antigen processing pathways. Conclusion For the first time, we identified a Pt-responsive CD4 T cell clone. Cisplatin can robustly stimulate human CD4+ T cell responses through the release of Pt ions. These findings suggested that the Pt ion could potently modify the surface of MHCII/peptide and directly bind the CZD9.2 TCR, potentially contributing to localized inflammation and organ-specific toxicity. Funding Source NIDDK Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)
New insights into the regulation of γδ T cells in diabetic wounds 2254952
Abstract Introduction Diabetes is a widespread metabolic disorder. One of its most severe complications is diabetic foot ulcers (DFUs)-open wounds characterized by chronic inflammation and delayed healing. DFUs are the leading cause of non-traumatic lower limb amputations globally due to poor repair capacity and increased infection risk. Gamma delta (γδ) T cells are key immune cells involved in the skin’s defense and repair processes, making them an important population to study in the context of DFUs. The activity of γδ T cells is shaped by butyrophilin-like (BTNL) proteins. One member of this family, BTNL2, regulates T cell activation and may be altered by chronic conditions such as diabetes. Methods Here, we utilize an STZ-induced diabetic mouse model to investigate the role of multiple γδ T cell subsets (Vγ1—4) in both diabetic and non-diabetic skin, at steady state and during wound healing. Using GFP γδ T cell reporter mouse, flow cytometry and immunofluorescence, we assess γδ T cell activation and localization. Additionally, we examine BTNL2’s role in modulating γδ T cell activity through in vitro coculture assay. Results Under hyperglycemic conditions, γδ T cell subsets are dysregulated, with an increase in pro-inflammatory Vγ1 cells and a decrease in pro-repair Vγ3 dendritic epidermal T cells (DETCs). Diabetic mice display delayed wound closure six days post-injury, confirmed by H&E and Keratin 6 staining. Using the GFP γδ T cell reporter mice, we observe γδ T cell localization at the wound edge, predominantly Vγ1 cells, alongside with increased BTNL2 expression. Coculture assays reveal that BTNL2 immunomodulates human Vδ1 but not Vïδ2 γδ T cells. Conclusion Overall, our findings highlight the distinct roles of skin γδ T cell subsets and BTNL2 expression during wound healing and provide important clues to design BTNL2-based therapeutics that can modulate the skin T cell immune responses in chronic inflammatory conditions. Funding Source NIH T32 University of Miami “Predoctoral Training in Translational Immunology,” NIH/NINR, R01NR015649-01 NIH/NIDDK, R01DK136241 Topic Categories Mucosal and Regional Immunology (MUC)
Highly dynamic dural sinuses support meningeal immunity 2308983
Abstract Introduction The central nervous system is surrounded by three interconnected meningeal membranes, including the dura mater, which contains venous sinuses traditionally viewed as passive drains for blood and cerebral spinal fluid. Because the sinuses collect fluid and cellular traffic from the brain and skull, they are also major sites of innate and adaptive immune surveillance. However, it is unclear how the endothelial cells comprising these sinuses sense and respond to changing fluid forces and immune cues to support steady-state immune surveillance and effective protection against infection. Methods We used intravital, light-sheet, and confocal microscopy, complemented by genomic analyses and pharmacological perturbations, to examine sinus structure, sinus endothelial cell (SEC) behavior, fluid transport, and immune activity. Results We found that the dural sinuses and SECs are highly dynamic surfaces that continually restructure to modulate fluid movement and immune surveillance. The murine sagittal sinus is a bifurcated structure that regulates fluid movement through smooth muscle-dependent vasomotion. SECs further support fluid movement by forming transient micron-sized openings within and between cells. Sinus porosity increased with VEGFA treatment and in the absence of meningeal lymphatics. These openings enabled macromolecules and microbes to move between the sinus lumen and leukocyte-rich perisinus space. Genomic and pharmacologic studies revealed that SEC boundary dynamics depend on RAMP2 signaling. Transcranial RAMP2 antagonism impeded SEC junctional activity, reduced immune cell movement along the sinus wall, and impaired local antiviral immunity after systemic infection. Conclusion These findings demonstrate that dural sinuses are highly dynamic neuroimmune interfaces. Specialized SECs regulate fluid transport and barrier permeability while coordinating steady-state immune surveillance and mounting effective antiviral immunity through continuous structural remodeling. Funding Source This work was supported by the intramural program at the National Institute of Neurological Disorders & Stroke (NINDS) within the National Institutes of Health (NIH). Topic Categories Neuroimmunology (NEUR)
Dual‐Site‐Binding Ligand‐Driven (100) Orientation for Efficient and Stable Perovskite Solar Cells
ABSTRACT Regulating crystal orientation is a powerful strategy for enhancing the optoelectronic performance of perovskite solar cells (PSCs). However, most existing approaches rely on single‐site ligand binding, which not only forms insulating layers that hinder charge transport but also involves weak coordination that limits orientation control. Here, we report a holistic strategy based on a dual‐site‐binding ligand, dithiopyr, that simultaneously modulates nucleation kinetics, crystal orientation, defect passivation, and charge transport in perovskite films. By coordinating its dual thioester functionalities with adjacent Pb 2+ defect sites, dithiopyr effectively relieves lattice strain and promotes a preferential (100) orientation, thereby facilitating efficient charge transport. As a result, the inverted PSCs achieve power conversion efficiencies of 26.90% (certified 26.14%) (1.55 eV), 22.02% (1.25 eV), and 23.11% (1.68 eV), respectively. Notably, large‐area modules (30 × 30 cm 2 ) deliver an efficiency of 21.28%, which is among the highest values reported for inverted perovskite solar cells. Unencapsulated devices retain 93.1% of their initial efficiency after 3600 h under ambient conditions and maintain over 95% of their initial performance after 1100 h of maximum power point tracking. This work establishes dithiopyr as a versatile and robust platform for precise crystal orientation control toward high‐performance perovskite photovoltaics.
IL-33 Expands M2 Macrophages population and Restrains Inflammatory Monocyte Recruitment During Clostridioides difficile Infection 2332432
Abstract Introduction Antibiotic exposure predisposes to Clostridioides difficile infection (CDI) by disrupting intestinal immune homeostasis. In the colon, TRMs are defined as CD11b+ Ly6C⁻ MHCII+ CD4+ TIM4+ macrophages and represent a long-lived population adapted to the intestinal microenvironment. We previously showed that IL-33 promotes a protective type-2 immune program during CDI by activating colonic ILC2s that limit epithelial damage and mortality. However, how antibiotics and IL-33 signaling influence TRMs and related macrophage programs during CDI remains incompletely understood. Methods Using spectral flow cytometry, we analyzed colonic immune populations at day 2 post-CDI. Uninfected mice with or without antibiotic treatment served as controls. Results CDI significantly reduced TRMs and was associated with decreased CX3CR1 expression across the CD11b+ CD64+ Ly6C⁻ MHCII+ macrophage compartment, indicating disruption of resident macrophage identity. Within this macrophage pool, IL-33 selectively expanded CD4+ TIM4⁻ macrophages, an intermediate population with both tissue-resident and monocyte-derived features. IL-33 also enhanced CD206 expression, consistent with a reparative and regulatory macrophage program, and significantly increased F4/80+ macrophages compared to PBS-treated infected controls, suggesting preservation of mature, tissue-adapted macrophages. In contrast, CDI induced a marked accumulation of Ly6Chi inflammatory monocytes in PBS-treated mice, which was significantly reduced following IL-33 administration. Conclusion Collectively, these findings demonstrate that antibiotics and CDI disrupt defined TRM populations, while IL-33 reshapes macrophage composition toward immune-regulatory and tissue-repair phenotypes, promoting restoration of intestinal immune balance during CDI. Funding Source R01 AI152477 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
Ozureprubart, a next-gen anti-IgE antibody, inhibits IgE binding to FcαRI, dissociates FcαRI-bound IgE, and reduces FcαRI expression on basophils 2258455
Abstract Introduction Immunoglobulin E (IgE) plays a central role in the pathogenesis of allergic inflammatory diseases. Omalizumab, the only FDA-approved anti-IgE therapy currently available to patients, has been shown to be effective in treating moderate-to-severe persistent asthma, chronic spontaneous urticaria (CSU), chronic rhinosinusitis with nasal polyps (CRSwNP), and in reducing allergic reactions to accidental exposure to IgE allergens in food-allergic individuals, including anaphylaxis. Methods Ozureprubart (also known as JYB1904 and RPT904) is a next-generation, half-life extended, anti-IgE monoclonal antibody designed to target the same epitope as omalizumab that uses the YTE mutation (M252Y/S254T/T256E) to significantly increase half-life. Additional modifications resulted in increased binding avidity to IgE, improvement of antibody stability, and reduction of the potential for immunogenicity. Results We report here that ozureprubart shows a 2-to-3-fold increase in ability to block IgE binding to FcαRI compared with omalizumab. Additionally, ozureprubart, like omalizumab, dissociates IgE bound to FcαRI and reduces levels of receptor-bound IgE and FcαRI on basophils. Conclusion These data show that ozureprubart shares many of the mechanisms of action of omalizumab. In combination with its extended half-life, these properties give ozureprubart the potential to be an improved anti-IgE therapy. Ozureprubart is currently in Phase 2 clinical development for the treatment of food allergy*, asthma**, and CSU**. *Study sponsored by RAPT Therapeutics, Inc. **Studies sponsored by Shanghai Jeyou Pharmaceutical Co., Ltd. in China Funding Source n/a Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)
From Marrow to Model: a human bone marrow-derived neutrophil assay to study neutrophil development and function 2257049
Abstract Introduction Neutrophils play critical roles in innate immunity, autoimmune disease and cancer, however drug development to target these cells have been impeded by poor in vitro systems. There is a need to develop reliable long-term culture methodology to generate abundant neutrophils at various developmental stages, not possible with peripheral blood-derived neutrophils, the current neutrophil biology gold standard. Methods Human bone marrow isolated from healthy volunteers was enriched for CD34+ hematopoietic stem cells, then differentiated in vitro to neutrophils for up to 23 days. Cells from various developmental stages were assessed for morphologic changes, cell surface maturation markers and functional responses. Results Bone marrow differentiated neutrophils (BMN) exhibited nuclear lobulation by day 8 and maturation markers by day 13. Cell surface marker expression patterns on BMN and morphology matched those of peripheral blood neutrophils (PBN). Additionally, BMN exhibited full functional capabilities like PBN including elevated ROS and NET production. Moreover, BMN is also capable of phagocytosis. Conclusion In vitro culture of CD34+ cells from human bone marrow can give rise to large numbers of mature neutrophils that are morphologically and functionally like PBN, but unlike PBNs, can survive for 3 weeks in culture. This method can provide better understanding of neutrophil development and function and support drug development in neutrophil mediated diseases. Funding Source n/a Topic Categories Hematopoiesis and Immune System Development (HEM)
CD3-epsilon/delta heterodimer recombinant protein induced diverse antibodies binding to Jurkat cells and primary T cells in mice 2260655
Abstract Introduction The T cell receptor (TCR)/CD3 complex is assembled by pairwise interactions involving the formation of dimers of CD3 epsilon with either CD3 delta or CD3 gamma. CD3-epsilon/delta (CD3ε/γ) and CD3-epsilon/gamma (CD3ε/γ) complexes are essential for T-cell activation and signaling. These molecules are key targets for biotherapeutic drugs such as T-cell engagers and bispecific antibodies, to treat cancers by linking T cells to tumor cells for targeted killing. To mimic the dimeric conformation of CD3ε/γ, we engineered a novel human CD3ε/γ cis-heterodimer recombinant protein. Methods To engineer the CD3ε/γ heterodimer, the ECDs of CD3 epsilon and delta subunits were fused with a heterodimer motif at the C-terminus of each chain. The recombinant CD3ε/γ heterodimer protein was expressed/purified from HEK293 cells. The CD3ε/γ protein were characterized by binding of CD3 specific antibodies. To evaluate the immunogenicity, mice were immunized with CD3ε/γ protein. The CD3ε/γ specific antibody titers in mice were measured by ELISA and antibody binding to Jurkat cells and primary T cells were measured by flow cytometry. Results The recombinant CD3ε/γ heterodimer protein could potently bind to the CD3-specific antibodies including OKT3 and UCHT1. The immunogenicity study in mice demonstrated that the CD3ε/γ heterodimer protein induced high titers of CD3-specific antibody responses. More importantly, the antibodies elicited by CD3ε/γ heterodimer protein demonstrated very good binding abilities to the T cell line Jurkat cells and primary human T cells as evaluated by flow cytometry. Conclusion The engineered CD3ε/γ cis-heterodimer protein could mimic the native conformation for in vitro antibody assessment. It can generate high levels of CD3-specific antibodies binding to T cell lines and primary T cells by immunization. This novel CD3ε/γ cis-heterodimer recombinant protein can be a very useful tool for basic immunology research and drug discovery. Funding Source n/a Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Reduced BCMA Signaling Disrupts the BAFF/APRIL Axis and Promotes Inflammatory Cytokine Production by B Cells in Multiple Sclerosis 2258573
Abstract Introduction Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. While anti-CD20 therapies reduce disease activity, atacicept, a BAFF/APRIL inhibitor, unexpectedly worsened MS. BAFF and APRIL signal through BAFF-R, TACI, and BCMA to regulate B cell survival and function. In EAE, BCMA deficiency disrupted regulatory balance and exacerbated disease, suggesting that BAFF/APRIL signaling supports both protective and inflammatory B cell functions. We therefore investigated how BAFF/APRIL signaling through BCMA modulates disease activity in MS. Methods Peripheral blood mononuclear cells from treatment-naïve relapsing-remitting MS patients and healthy controls were analyzed by flow cytometry to quantify B cell subsets and expression of BAFF and APRIL receptors. Serum BAFF, APRIL, and neurofilament light chain levels were measured using OLINK-PEA assays. In vitro cultures assessed cytokine production in transitional and memory B cells after BAFF/APRIL stimulation with or without BCMA blockade. Results During relapse, transitional B cells, an IL-10, producing regulatory subset, were markedly reduced compared to remission, accompanied by expansion of class-switched memory B cells. These alterations correlated with low serum BAFF and elevated NfL, indicating disrupted B cell regulation during active disease. Transitional B cells from MS patients showed reduced BCMA expression. Functionally, BAFF and APRIL enhanced IL-10 production via BCMA signaling and limited IL-6 secretion by memory B cells, whereas BCMA blockade disrupted this regulatory balance and increased inflammatory cytokine production. Conclusion Together, these findings identify BCMA as a key mediator of BAFF/APRIL-driven regulatory B cell function in MS. Impaired BCMA signaling may disrupt the balance between inflammatory and regulatory B cells, linking altered B cell homeostasis to disease activity. These results highlight BCMA as a potential therapeutic target to restore immune balance without global B cell depletion. Funding Source NIH R56AI118787 Topic Categories Therapeutic Approaches to Autoimmunity (THER)
Characterization of the circulating T-cell landscape in cutaneous lichen planus patients 2266750
Abstract Introduction Cutaneous lichen planus (cLP) is a T cell—mediated skin disease in which cytotoxic CD8+ T cells attack basal keratinocytes at the dermo-epidermal junction. While studies have characterized T cell subsets in lesional tissue, circulating immune signatures in cLP are incompletely defined. We performed deep immunophenotyping of circulating T-cell subsets to map systemic alterations in cLP patients vs healthy controls. Methods We included 12 treatment-refractory cLP patients (mean age 63.6 ± 13.6 years) and 2 healthy controls (37.5 ± 10.6 years). Whole blood was profiled for 27 markers by flow cytometry. Sequential gating: singlets → live → CD3+ T cells → CD4+/CD8+/γδ; FOXP3+ Tregs were defined within CD4+. Frequencies were expressed as % of the immediate parent population. Group comparisons used two-tailed exact Mann—Whitney tests with Hodges—Lehmann median differences. Results Across frozen specimens, cLP patients exhibited broad T-cell activation. Proliferation increased in CD4 (Ki67+, p < 0.05), CD8 (6.785% vs 0.885%; Δ=5.90; p < 0.05), and Tregs (83.0% vs 46.8%; Δ=34.1; p < 0.05). Intracellular CTLA-4 was higher on CD4 (11.07% vs 2.615%; Δ=8.45; p < 0.05), CD8 (21.05% vs 9.30%; Δ=11.6; p < 0.05), and γδ T cells (47.20% vs 24.45%; Δ=22.75; p < 0.05). CXCL13+ cells expanded in CD4 (28.20% vs 12.45%; Δ=15.5; p < 0.05), CD8 (18.05% vs 3.595%; Δ=14.46; p < 0.05), γδ (2.805% vs 0.465%; Δ=2.285; p < 0.05), and Tregs (7.56% vs 1.17%; Δ=6.39; p < 0.05). Tregs were TBET-high (78.75% vs 61.55%; Δ=17.3; p < 0.05); GITR+ Tregs trended up (p = 0.1978). Conclusion cLP blood displays a CXCL13+, proliferative T-cell signature with increased intracellular CTLA-4 across CD4, CD8, γδ, and Treg compartments. CXCL13 elevation aligns with lesion-level literature implicating CXCL13+ CD8+ T cells that are suppressed in JAK-STAT therapy responders. Tregs exhibit a GITR upregulated, Th1-like phenotype that suggests loss of suppressive capacity, warranting further investigation on whether Treg dysfunction plays a causative role in cLP. Funding Source N/A Topic Categories Immune Mechanisms of Human Disease (HUM)