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UVB Phototherapy Induces a Stress-Driven Anergy Pathway as a Novel Axis of T Cell Regulation 2257995
Abstract Introduction Phototherapy is widely used to treat autoimmune diseases, yet the mechanisms underlying UVB’s immune modulation remain unclear and disease specific. UVB suppresses Th1/th17 activity in vitiligo and psoriasis, but can activate immunity in lupus. We hypothesized that these diverse effects arise from a shared stress-related mechanism rather than cytokine-specific modulation. Specifically, we proposed that chronic UVB exposure induces atypical T cell activation leading to a novel form of anergy. Methods We combined single-cell RNA sequencing of skin-draining lymph nodes and spleen with peripheral blood analysis of vitiligo patients before and after phototherapy. Computational analyses of gene expression, transcription factor activity, and pathway enrichment were integrated with flow cytometry and RT-PCR to validate the cellular and molecular features of UVB-induced immune modulation. Results Chronic UVB exposure activated T cells independently of canonical TCR signaling, producing a distinct anergic state characterized by AP-1 activation in the absence of NFAT activity. We term this mechanism stress-driven anergy -a condition is the inverse of classical anergy, which arises from NFAT activation without AP-1 . It promotes expansion of ICOS+Ly6a+ activated Tregs while suppressing naïve CD4+, CD8+, and IL-17-producing γδ T cells through induction of AP-1 inhibitory genes. Type I interferon signaling emerged as a critical upstream component, sustaining AP-1—dependent activation. In human, this process cuntribute to inhibition of vitiligo-specific memory T cells following phototherapy. Conclusion Our findings identify stress driven anergy as a previously unrecognized regulatory axis explaining the diverse outcomes of UVB phototherapy. This mechanism reframes UVB not merely as an immunosuppressive agent but as a physiological stressor that reprograms T cell activation, offering new conceptual and therapeutic opportunities for targeted immune modulation in autoimmunity. Funding Source Pfizer Global Medical Grants Topic Categories Therapeutic Approaches to Autoimmunity (THER)
Unlocking Wafer‐Scale 3D Photonic Systems With Ion‐Beam‐Induced Origami
ABSTRACT Scalable manufacturing of three‐dimensional (3D) micro‐/nano‐architectures with nanometric precision remains a pivotal challenge in photonics. Here, we introduce a parallel broad‐beam ion beam etching (IBE) technique that decouples this fundamental trade‐off, enabling the simultaneous and uniform transformation of two‐dimensional (2D) patterns into well‐defined 3D geometries across entire 4‐inch wafers. The IBE platform achieves angular uniformity exceeding 97% and reduces fabrication time by over two orders of magnitude compared to serial focused‐ion‐beam (FIB) methods. Leveraging this approach, we fabricate two distinct functional devices: a chiral 3D bending metasurface with a giant experimental circular dichroism of 0.8 in the mid‐infrared, and a collectively buckled plasmonic grating whose resonance is dynamically tunable over 150 nm in the visible spectrum via curvature control. This technology uniquely combines nanoscale precision with wafer‐scale throughput, enabling the construction of 3D metasurfaces via meta‐atom assembly and the global modulation of optical responses. Our work establishes a versatile platform that bridges the gap between design complexity and scalable manufacturing for next‐generation 3D integrated photonics.
V-domain Ig suppressor of T-cell Activation (VISTA): Bone Marrow Derived Macrophage Reprogramming as Treatment for Immune Dysfunction 2335044
Abstract Introduction Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation leading to increased microvascular permeability, pulmonary edema, and organ failure. ARDS commonly complicates septic patients, and accounts for 10% of intensive care unit admissions with a 35-45% mortality and no effective pathological-pharmacological treatment available. Bone marrow-derived macrophages (BMDMs) contribute to pulmonary damage in ARDS by adopting a pro-inflammatory phenotype and producing inflammatory mediators in the lung tissue. V-domain Ig Suppressor of T-cell Activation (VISTA), a negative checkpoint regulator expressed across the hematopoietic compartment, has been shown to promote an anti-inflammatory phenotype in macrophages and maintain a protective effect on survival in response to both septic and ARDS challenge. Methods Using an indirect ‘double hit’ ARDS mouse model of fixed pressure hemorrhagic shock (Hem) followed by a polymicrobial sepsis insult through the cecal ligation and puncture (CLP) procedure, we examined VISTA function in BMDMs from wild-type (WT) and VISTA deficient (VISTAKO) mice. Bone marrow samples were harvested from Hem/CLP challenged mice and BMDMs were cultured and polarized in-vitro for characterization through flow cytometry analysis and functional assays. Results Early data shows that VISTA KO BMDMs exhibit higher pro-inflammatory markers and MHCII expression in both Hem/CLP and sham control mice compared to WT macrophages. Lastly, VISTA KO Hem/CLP BMDMs exhibit higher production of inflammatory cytokines such as IL-6 and TNF-α even when polarized with IL-4 compared to Hem/CLP WT macrophages. Conclusion Our results highlight the role of VISTA function in BMDMs in the development of pulmonary damage seen during ARDS. Future studies will analyze how anti-inflammatory cytokine production is affected by VISTA and if VISTA agonistic treatment can alleviate increased proinflammatory function exhibited by BMDMs during ARDS. Funding Source R35 GM118097 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
Building Immunity: From LEGO to α-Cells 2321870
Abstract Introduction Legos and immunology are great Methods Lego bricks, lego brick, lego bricks! Results Glorious lego creations Conclusion Immunology and legos are the best Funding Source NIH Topic Categories Immunology Education and Communication (EDU)
De novo pyrimidine synthesis controls lupus-prone germinal center B cell and plasma cell fates 2304696
Abstract Introduction The role of pyrimidine metabolites in SLE-prone germinal center (GC) and plasma cell (PC) responses is unknown. Methods A combination of steady-state metabolomics analysis and isotopic 15N-glutamine tracing were used to examine metabolic flux through de novo pyrimidine synthesis pathway in SLE-prone B cells. To examine role of the de novo pyrimidine synthesis pathway in the SLE autoimmune phenotype, global inhibition in SLE-prone mice was tested first, then UMPS conditional knockout SLE-prone mice were generated and phenotyped. Steady-state metabolomics, mitochondrial stress test, and metabolic flow cytometry were employed to elucidate a role for de novo pyrimidine synthesis in regulating metabolic pathways. Results Metabolomics and 15N-amide glutamine tracing reveal enhanced flux through pyrimidine synthesis in SLE-prone B cells. Global inhibition of de novo pyrimidine synthesis in SLE-prone mice dampened GC, PC and autoantibody responses, and kidney immune complex (IC) deposition. This inhibition did not overtly affect foreign antigen-driven GC, PC, and antibody responses. Newly generated UMPS conditional knockout SLE-prone mice revealed a B cell-intrinsic requirement of de novo pyrimidine synthesis in spontaneous GC, PC and autoantibody responses, and kidney IC deposition. Metabolomics, mitochondrial stress-test and metabolic flow cytometry helped delineate a crucial role for pyrimidine synthesis in B cell metabolic reprogramming that promotes autoimmunity. Mechanistically, mTORC1 and S6K1 downstream of TLR7 and CD40 signaling in B cells activate CAD, which catalyzes the first three steps of pyrimidine synthesis and upregulates de novo pyrimidine synthesis. Conclusion We identify a previously unknown B cell-intrinsic requirement of the pyrimidine pathway in autoimmune GC and PC responses, development of autoreactive B cells, and autoantibodies in SLE. Funding Source RO1 AI162971 RO1 AI194568 Finkelstein Memorial Student Research Award Topic Categories Basic Autoimmunity (BA)
Senolytic Activities of TLR Agonist Stimulated Mesenchymal Stem Cell Secretome Based Cosmetic GlowSelle™ 2265705
Abstract Introduction Conditioned media of TLR stimulated mesenchymal stem cells (MSC) have been shown to induce various regenerative activities including stimulation of endogenous progenitor cells and anti-apoptotic effects in dermal progenitor cells. Numerous studies have shown senolytics possess anti-aging properties. The current study assessed effects of GlowSelle on senescent cells. Methods GlowSelle was administered dermally in a mouse model of stress induced senescence. Assessment of senescence associated cellular markers (p16, p21, SA beta-gal) was performed in GlowSelle-treated and vehicle-treated animals. Quantification of senescence associated secretory phenotype (SASP) proteins was assessed locally and systemically. Antibody blocking studies were performed to assess mechanism of senolytic activity. Results Using the photoaging model, a stress-dependent increase in expression of senescence markers was observed. GlowSelle treatment reduced senescent cells through apoptotic mechanisms. Dose dependent SASP reduction was observed locally and systemically. Blockade of HGF activity indicated a partial involvement of this cytokine in GlowSelle-mediated senolysis. Conclusion In addition to stimulation of regenerative activity, GlowSelle appears to mediate rejuvenating activity through an HGF-dependent senolytic activity. Funding Source Robles BioCeutics Topic Categories Translational and Interventional Immunology (TI)
Evaluating the Hia adhesin as a potential vaccine antigen against Nontypable Haemophilus influenzae 2309156
Abstract Introduction Nontypable Haemophilus influenzae (NTHi) is a major cause of respiratory tract disease, prompting ongoing vaccine development efforts. Nasopharyngeal colonization is the initial step in NTHi pathogenesis, making bacterial adhesins attractive vaccine targets. Hia (Haemophilus influenzae adhesin) is a conserved, surface-exposed protein present in a substantial percentage of NTHi clinical isolates and promotes adherence to respiratory epithelial cells. While the Hia passenger domain (HiaPD) exhibits sequence variability, the Hia binding domain (HiaBD1) is highly conserved across diverse strains. The capacity of HiaPD and HiaBD1 to elicit protective immune responses has not been determined. Methods BALB/c mice were immunized intranasally with purified recombinant HiaPD or HiaBD1 formulated with the adjuvant dmLT and challenged with homologous or heterologous NTHi strains. Bacterial burdens were quantified in nasal tissue. Antigen-specific antibody responses were measured in serum and mucosal samples. Cellular immune responses were evaluated in nasal and lung tissues using flow cytometry to characterize CD4+ T cells activation and cytokine production. Results Intranasal immunization with HiaPD or HiaBD1 significantly reduced nasal bacterial burdens compared to adjuvant controls. Immunized mice developed robust Hia-specific systemic and mucosal antibody responses. Agglutination assays and whole-bacteria ELISA revealed largely strain-specific antibody responses. Passive antibody transfer using sera from HiaPD-immunize mice showed a significant but partial reduction in bacterial burden following homologous challenge. Conclusion These findings demonstrate that the Hia adhesin elicits protective immune responses against NTHi following mucosal immunization. Hia-specific antibodies contribute to protection against homologous challenge , while CD4+ T cell responses likely support protection across diverse strains. Funding Source n/a Topic Categories Vaccines and Immunotherapy (VAC)
CYP1B1 Inhibitor Chlorprothixene Increased Survival Rate of Cigarette Smoke-exposed Mice in Lethal IAV Infection 2253710
Abstract Introduction Cigarette smoke (CS) exposure increases the incidence and severity of influenza A virus (IAV) infections in humans, and increases mortality in mice. Cytochrome P450 family 1 subfamily B member 1 (CYP1B1) is highly induced in CS-exposed humans, and genetic deletion in mice protects against CS-enhanced susceptibility to IAV infection. Several approved drugs inhibit CYP1B1. Repurposing them to target CYP1B1 is a translational strategy to improve influenza outcomes in smokers. Methods To test CYP1B1’s effects on survival during IAV infection, we used an in vivo mouse model. Therapeutic doses of CYP1B1 inhibitors–ticagrelor (5 mg/kg), chlorprothixene (1.3 mg/kg), and TMS (1.5 mg/kg)–were administered daily for 9 days post-infection (p.i.) in CS-exposed, IAV-infected mice. We compared survival, lung-to-body weight ratios, and immune responses between treated and untreated groups following IAV, with or without prior CS exposure. Results IAV infection survival was 36% in CS and 80% in nonsmoking (NS) mice. The CYP1B1 inhibitors ticagrelor and TMS did not improve survival in CS-exposed, IAV-infected mice (43 and 36% survival, respectively). Chlorprothixene treatment at 1.3 mg/kg increased survival to 64% in CS-exposed IAV-infected mice but not in NS IAV-infected mice (67% survival), and TMS treatment at the same dose worsened outcomes in NS IAV-infected mice (40% survival), suggesting that chlorprothixene benefits CS-exposed, IAV-infected mice. We tested 5.2 mg/kg and 0.26 mg/kg concentrations of chlorprothixene in CS-exposed, IAV infected mice. Both doses yielded lower survival rates (50% and 40%) than the 1.3 mg/kg dose. CS exposure suppressed total immune cell counts in bronchoalveolar lavage fluid (BALF). Chlorprothixene treatment restored immune cell recruitment in BALF and attenuated lung injury. Conclusion Conclusions: Our findings show treatment with chlorprothixene improved survival outcomes and decreased lung injury during IAV infection in CS-exposed mice. Funding Source Merit Review Program of the Department of Veterans Affairs, grant number I01 BX005023 to JPM, and the National Institute of General Medical Sciences, grant number P30GM149368 to JPM. Topic Categories Vaccines and Immunotherapy (VAC)
A Novel Nanoparticle Strategy to Stimulate Regulatory CD8 T Cells Directly In Vivo for the Treatment of Multiple Sclerosis 2258793
Abstract Introduction We and others have described a regulatory CD8 T cell subset (CD8 Treg) restricted by nonclassical major histocompatibility complex Ib molecules, Qa-1 in mice and HLA-E in humans (collectively called Q/E). Previous studies from our laboratory and others have also shown that Q/E-restricted CD8 Treg can directly eliminate activated autoreactive, pathogenic CD4 T cells. However, the unknown identities of pathogenic T cells in human patients pose a significant barrier to the clinical translation of Q/E-restricted CD8 Treg. Methods To remove this barrier, we previously developed a novel technology to map Q/E epitopes in proteins. Using this new technology, we identified a peptide in myelin oligodendrocyte glycoprotein (MOG), MOG_OLP105, that stimulated both Qa-1- and HLA-E-restricted CD8 Treg. Additionally, immunization with activated dendritic cells (DCs) pulsed with MOG196, the optimal Qa-1 epitope in MOG_OLP105, significantly suppressed ongoing experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis. However, DC-based therapy entails technological challenges and high costs. Here, we present a novel nanoparticle strategy that specifically targets DCs and delivers signals necessary to stimulate and expand myelin-specific, Q/E-restricted CD8 Treg directly in vivo. Results Our data showed that the DC-targeting nanoparticle specifically targeted and activated mouse and human DCs, accompanied by enhanced presentation of MOG196 and MOG_OLP105 by Qa-1 and HLA-E, respectively. DCs loaded with the nanoparticle stimulated autologous mouse and human CD8 T cells that suppressed the proliferation of autologous CD4 T cells in response to myelin antigens. Additionally, injection of the nanoparticle at disease onset led to a full recovery and induced resistance to disease reinduction. Furthermore, administering the nanoparticle at the peak of the disease also eliminates the disease. Conclusion Our data support the nanoparticle as a potential cure for multiple sclerosis. Funding Source Tang Gene Inc. Topic Categories Therapeutic Approaches to Autoimmunity (THER)
A Current‐Adaptive Polyoxovanadates Protected Anode for Efficient and Stable Ampere‐Level Seawater Electrolysis
ABSTRACT Seawater electrolysis is promising for green hydrogen production, while intensified chloride corrosion at high‐current density (HCD) poses significant challenges to the activity and stability of the anodes. Conventional anode catalysts leverage anion electrostatic repulsion to repel chloride but often fail under industrially relevant ampere‐level HCD conditions, restricting their applications. Here we report a corrosion‐resistant cobalt‐vanadium‐oxide catalyst featuring in situ formed, current‐adaptive polyoxovanadates (POVs) for efficient and stable seawater electrolysis at HCD. As the current densities increase, the vanadate monomers dynamically self‐assemble into POVs with significantly increased steric hindrance to Cl − , thereby enhancing chloride repulsion. The catalyst works stably for over 5000 h at 1000 mA cm −2 with a low decay rate of 0.83 µV h − 1 in seawater electrolyte. Furthermore, the anion exchange membrane seawater electrolyzer only needs 1.64 V at 1000 mA cm −2 and maintains stable operation for over 1500 h. Technoeconomic analysis results show that H 2 production cost is $1.17/GGE H 2 , which surpasses the U.S. Department of Energy's $2.0/GGE H 2 target. This work reports a novel dynamic chloride repulsion behavior at HCD conditions and paves the way for robust corrosion‐resistant anode catalysts for seawater electrolysis.
Autonomously Motile Nano‐PROTACs Act as Protein‐Sweeping Robots to Enhance Targeted Protein Degradation
ABSTRACT Although nanoparticle‐based PROTACs (nPROs) provide a modular strategy to improve the biological fate of PROTACs, their degradation performance was fundamentally limited by restricted intracellular diffusivity. Here, we introduced an unconventional solution: Imparting autonomous motility to nPROs to transform them from passive carriers into active protein‐seeking degraders. We engineered nano‐motoring PROTACs (nMPROs) through asymmetric modification of gold nanoparticles, displaying POI ligands and E3 recruiters on one hemisphere while anchoring catalase on the opposite hemisphere. Within the H 2 O 2 ‐rich tumor cell microenvironment, catalase‐generated oxygen fueled directional propulsion, enabling nMPROs to actively navigate the intracellular space rather than relying on random diffusion. This propulsion fundamentally enhanced intracellular target‐search efficiency: nMPROs function as “nanoscopic protein‐sweeping robots,” autonomously interrogating a larger intracellular landscape and capturing more sparsely distributed target proteins. As a result, nMPROs achieved a threefold increase in ERα degradation potency relative to static nPROs and enabled modular, ligand exchange–based degradation of PD‐L1, demonstrating platform generality. Overall, this work establishes a new mechanistic paradigm for enhancing targeted protein degradation of nPROs and lays the foundation for generalizable next‐generation PROTAC nanoplatforms.
Cancer Immunotherapy with IL-15Rα-armed Oncolytic Myxoma Virus Enhances Antitumor Immunity Against Solid Tumors 2260773
Abstract Introduction Immunologically cold tumors and metastatic lesions are a major therapeutic challenge due in part to tumor heterogeneity, a lack of immune infiltration, and defects in tumor-associated antigen presentation. Oncolytic virotherapy is a promising strategy that can overcome immunosuppression and enhance antitumor responses. Myxoma virus (MYXV), a rabbit-specific poxvirus, can infect and kill cancer cells while leaving healthy cells unharmed. MYXV can be genetically modified to delete non-essential host-regulatory genes to enhance oncolytic activity; or to insert cytokines that improve immune cell recruitment and activation. The present study evaluated and compared the local and distant anti-tumor efficacy of a MYXV engineered to express the IL15-IL15Rα cytokine complex and lacks the viral anti-apoptotic Bcl2 homolog M11L gene. Methods Immunocompetent mice bearing contralateral tumors of colon carcinoma or lung metastatic melanoma were treated intratumorally on one side with vMyx-M11KO-IL15Rα alone or in combination with Selinexor, an oral chemotherapeutic that inhibits the nuclear exporter XPO-1 and enhances MYXV replication in cancer cells. Results We observed a significant reduction in tumor burden of both treated and untreated sides (abscopal effect) with virus alone or in combination with Selinexor when compared to the untreated group. Combination therapy prolonged survival and ∼12% of mice had total tumor regression 60 days post-treatment. Mice treated with virus or combination therapy had significantly higher infiltration of CD45+ leukocytes, specifically CD8+- and CD4+-effector memory T cells, activated natural killer and dendritic cells. Conclusion This therapeutic combination enhanced viral replication and cancer cell death mediated by improved immune cell activation and infiltration into the tumor bed. Our results indicate that engineered oncolytic MYXV is synergistic to chemotherapy and produces an abscopal effect that targets untreated distal tumors and prolongs survival. Funding Source NIH Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Targeting Novel DNase Therapeutic to Intracellular cGAS—STING Pathway for DNA Clearance in TREX1-Deficient Aicardi-Goutières Syndrome 2329186
Abstract Introduction Aicardi—Goutières syndrome (AGS) is an early onset progressive encephalopathy induced by biallelic pathogenic variants in genes responsible for degrading or sensing cytoplasmic nucleic acids. AGS exhibits phenotypic overlap with Systemic lupus erythematosus (SLE) in that both are type 1 interferonopathies, but AGS may additionally induce microcephaly, seizures, developmental delays, and significant mortality in infants. Approximately 30% of AGS cases are due to TREX1 deficiency. To investigate the role of extracellular nucleic acid signaling in the pathogenesis of AGS we examined the effects of a long acting DNase biologic with dual DNAse1/DNAse1L3 activity (called 1687) on the survival and cytokine profiles of Trex1-/- mice. Methods We treated Trex1-/- mice weekly with vehicle or subcutaneous injections of 1687 at 1 mg/Kg, and monitored survival for 250 days. A smaller cohort underwent mechanistic analysis of immune biomarkers (cytokines, autoantibodies) and molecular pathways. Results Vehicle treated Trex1-/- mice succumbed to disease as early as five weeks of age with a median survival of 98.5 days, while mortality in the Trex1-/- treated mice began around 10 weeks of age and did not reach a median survival within the 250-day window. At 250 days approximately 80% of the vehicle treated Trex1-/- mice had expired, compared with approximately 45% of the 1687 treated Trex1-/- mice. Treated mice displayed reductions in extracellular inflammatory cytokines along with reduced anti-dsDNA and MYH6 auto-antibodies. However, no differences in cytokines induced by the intracellular cGAS—STING pathway were observed in treated and untreated animals. Conclusion Our findings document a pathogenic role for extracellular DNA signaling in AGS, a disease whose accepted pathogenic mechanism is defective intracellular nucleic acid signaling. Our results further suggest that extracellular DNA clearance may offer a therapeutic benefit to AGS patients. Funding Source Colton Center for Autoimmunity Topic Categories Therapeutic Approaches to Autoimmunity (THER)
Investigating Th1 Cell Positioning and Cross-Regulation with IL-4 in Immune Defense 2257324
Abstract Introduction Leishmania major (L.major) is an intracellular parasite that causes cutaneous leishmaniasis, a disease in which the balance between the response of Th1(protective) and Th2 (suppressive) determines the outcome of infection. While Th1-derived interferon-γ (IFN-γ) activates infected phagocytes, Th2-derived interleukin-4 (IL-4) suppresses Th1 activity and aggravates parasite persistence. The way in which IL-4 shapes the spatial organization and dynamics of effector T cells within inflamed tissue, however, remains enigmatic. Methods In this study we employed the OVA/CFA model, where CXCL10-rich immune-niches that optimize Th1 activation have been well described, as a mechanistic proxy for L. major infection to examine how IL-4 shapes Th1 motility and niche organization. Results Neutralizing IL-4 prior to immune-cluster formation markedly increased T-cell motility, did not alter CXCL10 expression, and was associated with more dispersed and less confined immune aggregates. In contrast, blocking IL-4 after niches had formed reduced T-cell motility and converted the clusters into large chemokine-dense hubs. Conclusion These findings reveal that IL-4 may exert distinct, phase-specific control over tissue immunity. Early IL-4 confines emerging immune niches and limits Th1 movement, while late IL-4 disperses established niches and contributes to immune resolution. Together, these findings identify IL-4 as a dynamic regulator of spatial immune architecture and provide a framework for understanding how IL-4 shapes Th1 positioning and cross-regulation during L. major infection. This offers insights that may guide new strategies to enhance protective immunity against parasitic infections. Funding Source n/a Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)
XTEP: A Structure-Informed Algorithm to Predict T Cell Cross-Reactivity 2267697
Abstract Introduction Each T cell is able to recognize multiple unique peptides presented on MHC molecules in a phenomenon referred to as Cross-Reactivity. Cross-reactivity is important in heterologous immunity and autoimmunity and can be both beneficial and deleterious in both contexts. For example, infection can prime T cells to recognize different pathogens that have similar proteins, which can provide protection against disease, or to recognize similar self-proteins, which can induce autoimmune disease. To elicit cross-reactivity from the same T cell, two peptides need to be chemically similar enough to both bind the same MHC and be recognized by the same T cell receptor; however, in certain instances peptides that appear chemically different can elicit a cross-reactive response. Methods We sought out to develop an approach that can predict cross-reactivity using only sequence information about the peptides involved. To develop this approach, we leverage structural information to create an algorithm that emphasizes key epitope residues for homology comparison. Results We show that combining TCR-pMHC structural information with machine learning MHC binding predictions provides a reliable method of predicting cross-reactivity. We tested our algorithm using datasets measuring T cell cross-reactivity between viral peptides in cases both where the presenting MHC is known and in cases where it is not known. Our prediction approach, Cross-reactive T cell Epitope Predictor (XTEP), is TCR-sequence independent and MHC agnostic. Conclusion Our approach can be used to predict if a T cell epitope will be cross-reactive, which can be important in contexts such as vaccine design. Additionally, XTEP can predict epitopes that can be used to show cross-reactivity is occurring —for example when evaluating similarity between self-epitopes and viral peptides in autoimmunity. Our findings imply this approach is more predictive of cross-reactivity than predicting MHC binding alone or comparing full peptide similarity. Funding Source NIH T32 AI132152 Topic Categories Computational and Systems Immunology (COMP)
Single-cell blood immune cell atlas of immune diseases 2309369
Abstract Introduction Immune cells play multifaceted roles in the body, ranging from systemic and local pathogen surveillance to pathogenic auto-reactivity in conditions such as autoimmune diseases. While we can detect these immune abnormalities using transcriptomic methods, the complete cellular landscape of these diseases has not yet been comprehensively explored. Methods We profiled blood immune cells with single-cell RNA sequencing method. Results We generated single-cell profiles for 2,098,547 circulating immune cells from 231 individuals spanning 22 distinct immune-related conditions. We delineated five major immune lineages and characterized their transcriptomic alterations. We examined cross-lineage correlations in cellular responses and their associations with disease contexts. Conclusion This study present overall cellular architecture of blood immune cells, and provide broad landscape of systemic multicellular responses in immune-related diseases. Funding Source The Single Cell Atlas of Immune Diseases (SCAID) project Topic Categories Immune Mechanisms of Human Disease (HUM)
AXL tyrosine kinase inhibition restores anti-PD-1 efficacy in melanoma through tumor-associated macrophage—dependent mechanisms 2255689
Abstract Introduction Immune checkpoint blockade (ICB) has transformed melanoma care, yet resistance is common and often driven by tumor-associated macrophages (TAMs). AXL, a Gas6-activated tyrosine kinase, is classically a tumor-intrinsic driver of invasion but is predominantly expressed by TAMs in melanoma, suggesting a role in regulating the tumor-immune microenvironment. We tested if AXL inhibition could reprogram macrophage function, disrupt PD-1:PD-L1 interactions, and restore responsiveness to PD-1 blockade. Methods AXL expression was analyzed using TCGA, serum ELISA, and single-cell RNA-seq datasets. ICB-resistant melanoma models (Yumm1.7, B16F10) were treated with warfarin or bemcentinib (AXL inhibitors) alone or with anti-PD-1, with or without macrophage depletion. PD-1:PD-L1 interactions were quantified by immune Förster resonance energy transfer (iFRET). In vitro, polarized macrophages were analyzed for AXL-dependent efferocytosis, T cell crosstalk, and cytokine secretion. Results AXL was enriched in TAMs across cohorts, with soluble AXL highest in stage IV disease. AXL inhibition reduced tumor burden and synergized with anti-PD-1, efficacy was lost after CSF1R depletion and enhanced by F4/80 depletion. iFRET showed restoration of PD-1:PD-L1 blockade despite unchanged PD-L1 expression. In vitro, AXL function was context-dependent: M1-like macrophages upregulated AXL with immunostimulatory outputs, while M2-like macrophages became more AXL-driven under anti-PD-1. Combination therapy reprogrammed the secretome toward a Th1/Th17, chemokine-rich milieu ↑CXCL9/10, IL-12, IL-23; ↓IL-10, MCP-1). Conclusion AXL is a dominant TAM-driven regulator of ICB resistance in melanoma. AXL inhibition restores functional PD-1:PD-L1 blockade and rebalances macrophage signaling toward immunostimulation in a microenvironment-specific manner. These findings support AXL as both a biomarker and therapeutic target to overcome ICB resistance, with implications for tailoring macrophage-targeted strategies in refractory melanoma. Funding Source N/A Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Inhaled Particulate Matter Exposure Worsens the Outcome of Influenza Infection Through Direct Effects on Macrophages 2259112
Abstract Introduction Air pollution is a global health problem associated with increased morbidity and mortality from respiratory diseases, particularly in the elderly, due to the inhalation of particulate matter. However, the mechanisms of how particulate exposure affects lung immunity is not well understood. Methods We developed a mouse model of particulate matter (PM) exposure to evaluate its impact on respiratory immunity. Young (8-12 weeks) and aged (70-80 weeks) mice were divided into four groups: naïve, PM only, PR8 only, and PM+PR8. PM groups received intranasal PM for two weeks (5 days of treatment and 2 days of rest), followed by intranasal PR8 influenza infection delivered in PBS (PR8 only) or in PM solution (PM+PR8). PM exposure continued post-infection. Lungs were isolated 4 days post infection (dpi) and analyzed by confocal microscopy, flow cytometry and multiplex cytokine profiling. Results Both young and aged mice exposed to PM exhibited increased morbidity following influenza infection compared to infection alone, indicating that particulate exposure exacerbates viral responses. Histological and multiplex analyses of lungs at 4 days post infection revealed reduced alveolar space with interstitial and intra-alveolar inflammation in both age groups, with notably increased mucus production in young mice. PM exposure with PR8 infection also induced age-specific cytokine and chemokine upregulation, fostering a pro-inflammatory environment. PM was predominantly contained within alveolar macrophages, which exhibited an increased pro-inflammatory phenotype and reduced expression of regulatory markers following PM challenge with PR8 infection. Conclusion These findings demonstrate that PM exposure primes the lung for heightened inflammation and worsened outcomes following respiratory viral infection. Funding Source NIH Grant: 5K01AG078439-03 (Ural, BB) Topic Categories Mucosal and Regional Immunology (MUC)
Phase Transformation Accompanied by Evolution of Internal Stress and the Coupling Mechanism of Chemical‐Mechanical Degradation in Single‐Crystal NiRich Cathodes
ABSTRACT Operating LiNi x Co y Mn 1‐x‐y O 2 (NCM, x ≥ 0.92) cathodes at high temperature/voltages (≥4.3 V or 45°C) to achieve high capacity inevitably leads to accelerated capacity fade. Despite extensive research into cycling behaviour under various cut‐off voltage and phase degradations, the fundamental mechanisms governing internal phase transformations, lattice deformations, and internal stress generation remain poorly understood. By using HAADF–STEM characterization with DFT and MD simulations, we disclose a new chemo‐mechanical degradation rule: lattice bending leads to the formation of O1/LiNi 2 O 4 (Fd‐3m) and unstable intermediate transition phase Ni 3 O 4 (Cmmm), the bending and distortion of the lattice are the direct causes of internal stress. Unlike previous findings, both RS, Ni 3 O 4 /LiNi 2 O 4 and O1 phases were detected in various crack regions. Stress concentration from bending‐induced O1–LiNi 2 O 4 and LiNi 2 O 4 –Ni 3 O 4 –RS (Fm‐3m) phase transformations leads to intracrystalline cracking, impairing capacity retention. Lattice deformation can lead to the emergence of stress and the formation of micro‐cracks, even during the O3‐O1 phase transition. This work confirmed the relationship between phase transformation and stress in the in cracked areas and stress. Meanwhile, this research provides new insights into the degradation mechanism for lithium‐ion batteries, specifically paving the way for the design and optimization of high‐energy‐density.
Derivation of Mesenchymal Stem Cells from Induced Pluripotent Stem Cells and Their Application in Genetic Disease Modeling 2307485
Abstract Introduction Thymic stromal cells are essential for T-cell progenitor proliferation and differentiation. While thymic epithelial cells are well studied, non-epithelial stromal populations–particularly neural crest—derived mesenchymal cells–are increasingly recognized for their roles in thymus formation and function. Mesenchymal defects contribute to thymic abnormalities in congenital syndromes such as DiGeorge syndrome (DGS), CHARGE syndrome, and Trisomy 21 (T21), yet human studies are limited by the rarity of these conditions and restricted access to thymic tissue. Methods We generated iPSCs from individuals with TBX1, CHD7, HOXA3, and PAX1 mutations, as well as DGS and T21 patients. Control and patient iPSCs, derived from PBMCs or skin biopsies, were differentiated into mesenchymal stem cells (MSCs). Primary thymic mesenchymal cells (ThyMCs) were also isolated from human thymi. All cell populations were analyzed by flow cytometry and bulk RNA-seq. Tri-lineage differentiation assays (adipogenic, chondrogenic, osteogenic) were performed to assess functional pathway defects. Results Flow cytometry confirmed robust expression of MSC markers (CD73, CD146, CD105) in all MSC and ThyMC samples, absent in undifferentiated iPSCs. Principal component analysis revealed clear segregation of iPSCs, MSCs, and ThyMCs. Transcriptomic profiling showed that all patient-derived MSCs acquired mesenchymal identity, but each disease group displayed distinct transcriptional changes. MSCs with TBX1, HOXA3, or PAX1 mutations had the highest number of differentially expressed genes, affecting pathways such as extracellular matrix and cartilage development.DGS-derived MSCs and ThyMCs showed marked upregulation of ECM and collagen genes (FBLN5, PCOLCE, EMILIN1, COL3A1, COL1A2). Conclusion Our findings reveal disease-specific mesenchymal defects underlying thymic abnormalities in congenital syndromes.This platform enables mechanistic studies of thymic stromal dysfunction and advances understanding of immune deficits in these disorders. Funding Source This work was supported by the Division of Intramural Research, NIAID, NIH. Topic Categories Hematopoiesis and Immune System Development (HEM)