Browse Articles

Immunomodulatory and neuroprotective effects of HEPPP in mice with status epilepticus 2259375

Abstract Introduction Epilepsy is a chronic neurological disorder marked by recurrent seizures caused by abnormal electrical discharges and neuronal hyperexcitability. Besides the neuroelectrical component, the active involvement of the immune system in the pathophysiology of this disease has been recognized. In this study, we evaluated whether DL-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP), an effective drug in refractory epilepsy, presents an immunomodulatory effect on microglia cells in a murine model of pentylenetetrazole (PTZ)-induced status epilepticus. Methods Three groups of five C57BL/6 mice were formed: control, epileptic untreated, and epileptic treated with HEPP. The behavioral assessment was conducted using the Racine scale. Flow cytometry was used to analyze microglial activation, cytokine production, and cell infiltration. Results We corroborated that animals with status epilepticus showed a sustained progression towards severe convulsive stages. In contrast, those treated with HEPP showed a significant decrease in the mean score, indicating a strong anticonvulsant effect of the compound. At the cellular level, we found a significant increase in the proportion of activated microglial cells in the brains of status epilepticus animals, as well as increased infiltration of peripheral cells; these findings were attenuated in the HEPP-treated group, suggesting a neuroprotective effect. Likewise, we identified an increase in the expression of TNF-α, IL-6, and IL-4 cytokines in activated microglia of the group of mice with status epilepticus, while treatment with HEPP decreased the expression of these cytokines, although it did not favor a transition towards an anti-inflammatory phenotype type M2, given the lack of statistical significance in CD206 cells. Conclusion Our findings suggest that HEPP not only modulates seizure activity but also provides immunomodulatory and neuroprotective effects, positioning itself as a promising therapeutic alternative for epilepsy associated with chronic inflammation. Funding Source The National Polytechnic Institute of Mexico provides the SIP20253908, SIP20254383, and SIP20253809 grants for this research. Topic Categories Neuroimmunology (NEUR)

First Oral Small-molecule Inhibitors Designed by Generative AI Achieve Biologics-Like Pan-Inhibition of IL-17AA, AF, and FF Dimers 2309250

Abstract Introduction The most effective therapies for immunological diseases are injectable biologics that many patients cannot access and often prefer to avoid. There remains a strong need for safe and effective oral treatment options. Targeting clinically validated cytokine pathways with small molecule modulators provides a viable route to first-in-class oral medicines. IL-17A and IL-17F are key drivers of multiple autoimmune diseases, yet small-molecule inhibitors developed to date have been restricted to IL-17A and lack activity on IL-17F. Building on AI-generated scaffolds, we developed orally bioavailable small-molecule IL-17 inhibitors that potently block the full spectrum of IL-17A- and F-containing dimers. Methods Candidate inhibitors were engineered via AI-enabled structure-based generative design and virtual screening. Binding was confirmed and assessed by SPR and NanoDSF. Functional antagonism was quantified in cellular assays, with Ki values derived via agonist shift assays. In vivo activity was evaluated in IL-17-driven pharmacodynamic models. Oral pharmacokinetics was profiled across multiple preclinical species. Results Our lead inhibitors demonstrate high-affinity binding to all relevant isoforms and disrupt receptor engagement. They achieve Ki < 0.1 nM for IL-17A and < 10 nM for IL-17F in cellular assays. The activity on IL-17A is over 10-fold more potent than leading IL-17A-specific small molecules. These inhibitors demonstrate favorable oral bioavailability and dose-dependently suppress IL-17F—driven cytokine production in vivo, achieving maximal inhibition levels comparable to the dual-specific antibody bimekizumab. Conclusion These data present the first orally bioavailable small molecules with strong IL-17F engagement, exceptional potency against all IL-17A and F dimers, and robust in vivo activity. By combining the efficacy of dual-cytokine blockade with the convenience of oral dosing, these inhibitors represent a potential best-in-class opportunity for next-generation autoimmune therapies. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Identification of Antigen-Specific T Cell Receptors with combinatorial peptide pooling 2259233

Abstract Introduction T cell receptor (TCR) repertoire diversity enables the orchestration of antigen-specific immune responses against the vast space of possible pathogenic peptides. Identifying TCR/antigen specificity from the large TCR repertoire and antigen space is crucial for biomedical research. Methods We introduce copepodTCR, an open-access tool for the design and interpretation of high-throughput experimental assays to determine TCR/antigen specificity. copepodTCR implements a combinatorial peptide pooling scheme for efficient experimental testing of T cell responses against large overlapping peptide libraries, useful for “deorphaning” TCRs of unknown specificity. The scheme detects experimental errors and, coupled with a hierarchical Bayesian model for unbiased results interpretation, identifies the response-eliciting peptide for a TCR of interest out of hundreds of peptides tested using a simple experimental set-up. Results Using in silico simulation, we demonstrated the applicability of our design scheme and the sensitivity of our results evaluation across varied experimental layouts and range of TCR-peptide activation signals. We experimentally validated our approach on a library of 253 overlapping peptides covering the SARS-CoV-2 spike protein, split across 12 pools. A single stimulation with combinatorial pools identified the correct epitope of two TCRs with known specificity and then deorphanized two SARS-CoV-2 associated TCRs shared among a large cohort of COVID-19 patients. Conclusion In conclusion, copepodTCR enables efficient and accurate mapping of TCR—peptide specificities through optimized combinatorial peptide pooling coupled with Bayesian inference. Beyond deorphanizing TCRs from established cell lines, we anticipate that copepodTCR can facilitate primary T cells deorphanization using single-sequencing as a read out, due to optimization of the pooling scheme, rational assignment of peptides and robust error-correction. Funding Source Simons Center for Quantitative Biology at Cold Spring Harbor Laboratory; Starr Centennial Scholarship; US National Institutes of Health Grants U01AI150747, R01AI136514, S10OD028632-01, 1R01AI167862; Simons Pivot Fellowship; National Natural Science Foundation of China Grant 62331002, National Science Foundation grant PHY-2210452. Topic Categories Computational and Systems Immunology (COMP)

Skin Immunization With ALFQ-Adjuvanted SARS-CoV-2-Spike Ferritin Nanoparticles Induces Broad and Durable Immunity in Young and Aged Mice 2259612

Abstract Introduction The development of next-generation SARS-CoV-2 vaccines with increased humoral and cellular immunogenicity and improved safety, durability, and thermostability is a high-priority goal for global public health. Methods Here, we introduce a next-generation SARS-CoV-2 vaccine candidate. We formulated SARS-CoV-2 spike protein ferritin nanoparticle adjuvanted with Army Liposome Formulation containing QS-21 into dissolvable microneedle patches. We (1) conducted the biophysical characterization of SpFN+ALFQ MNPs to probe their delivery performance and thermostability, (2) assessed the local and systemic innate responses, and (3) evaluated the humoral and cellular responses in systemic and mucosal compartments. Results SpFN+ALFQ MNP successfully delivered SpFN and ALFQ to the same antigen-presenting cell rich skin microenvironments and maintained its immunogenicity at room temperature for at least a year. SpFN+ALFQ MNP induced a proinflammatory local immune microenvironment (i.e., upregulation of Th1-predominant cytokines and chemokines) without local and systemic reactogenicity. Immunization with SpFN+ALFQ MNP evoked strong humoral and cellular responses in systemic and mucosal compartments, with Th1 bias. SpFN+ALFQ MNP-elicited antibodies were cross-reactive and long-lived (at least 76 weeks) and effectively neutralized many SARS-CoV-2 variants of concern. SpFN+ALFQ MNP-induced systemic and pulmonary antigen-specific polyfunctional CD4+ and CD8+ T-cell responses with robust lytic activity. Importantly, SpFN+ALFQ MNP induced comparable antibody responses in young and aged mice. Conclusion Together, these unique safety, thermostability, and innate and adaptive immunity characteristics of SpFN+ALFQ MNP provide a strong foundation for the development of rapidly translatable next-generation vaccines leveraging ferritin nanoparticle antigens, ALFQ, and MNPs against SARS-CoV-2 and other emerging pathogens. Funding Source Department of Defense, National Institutes of Health Topic Categories Vaccines and Immunotherapy (VAC)

Skin mites enhance virtual memory T cell responses against immune checkpoint inhibitor-resistant tumors 2304047

Abstract Introduction Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet some patients remain non-responsive. The current study aims to investigate the role of complex microbiota and commensals across body sites in this response. Methods Because traditional laboratory mouse models are limited by their lack of complex, natural microbiota, we explored ICI therapy in a colony of ‘wildling’ mice, the founders of which were generated by re-deriving C57BL/6 embryos in wild mice. Results Wildling mice significantly enhanced CD8 T cell—dependent antitumor responses upon ICI, in comparison to conventional laboratory mice on the same genetic background. This enhanced anti-tumor activity required IFN-γ and CXCR3—CXCL9/10—mediated recruitment of CXCR3+ CD49d⁻ virtual memory (TVM) CD8+ T cells. Wildling mice had markedly expanded, highly functional TVM cells across lymphoid and non-lymphoid tissues, with heightened effector signatures, increased cytokine responsiveness, and superior intratumoral accumulation upon ICI treatment. Screening of natural microbiota and commensals revealed that skin mites induced the wildling phenotype. Transfer of skin mites to conventional laboratory mice induced a substantial expansion of CD49d⁻ TVM cells and ICI responsiveness, whereas depletion of mites from wildling mice reduced both TVM abundance and ICI efficacy. Analysis of public databases demonstrated increased abundance of CD8 T cells with a TVM transcriptional signature correlated with melanoma of ICI responders, supporting the translational relevance of these findings. Conclusion This study identifies skin mite—driven expansion of CD49d⁻ TVM cells in anti-tumor immunity and ICI responsiveness. These findings offer new insights into targeting skin mites and Tvm as a strategy to overcome resistance to ICIs in cancer treatment. Funding Source Intramural research programs of NIDDK, NIH Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Persistent Microbial Peptidoglycan Drives Post-Infectious Autoimmunity in Lyme Disease 2265902

Abstract Introduction Persistent symptoms after infection remain a major clinical challenge, yet their immunopathogenesis is poorly understood. Post-Treatment Lyme Disease (PTLD) affects over one million individuals in the United States and is characterized by fatigue, pain, and cognitive dysfunction despite antibiotic clearance of Borrelia burgdorferi. We hypothesized that peptidoglycan–bacterial cell wall remnants that can persist in the host after antibiotic treatment–sustain inflammation and trigger autoimmune-like responses. Methods Peripheral immune cells from PTLD patients and healthy controls fro two clinical cohorts were profiled using single-cell RNA-sequencing analysis. To determine causality, monocytes and human spleen organoids from healthy donors were stimulated with peptidoglycan from Borrelia burgdorferi (PGBb) or from other autoimmune-associated bacterial species. Cellular activation, cytokine secretion, and autoreactive B-cell responses were assessed by flow cytometry, ELISA, and gene expression analysis. Results PTLD patients exhibited an expanded hyperinflammatory monocyte subset expressing autoimmune-associated transcriptional and metabolic programs, along with other immune features characteristic of classical autoimmune diseases. Stimulation of healthy monocytes with PGBb recapitulated these features and induced a distinct proinflammatory cytokine profile. In human spleen organoids, PGBb activated autoreactive B cells and triggered gene expression programs linked to autoimmunity across multiple immune subsets. Peptidoglycans from bacteria associated with rheumatoid arthritis also elicited proinflammatory responses, revealing a conserved yet context-specific mechanism of peptidoglycan-driven autoimmunity. Conclusion Persistent peptidoglycans drive chronic inflammation and may promote autoimmunity in PTLD and related diseases, shaped by species-specific microbial contexts. This work also establishes human spleen organoids as a robust platform for studying autoimmune mechanisms following infection. Funding Source NIH, HHMI, Bill and Melinda Gates Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)

The Water Behavior Chain: A Unified Framework for Solar Interfacial Evaporation

ABSTRACT Confronting the global freshwater crisis, solar interfacial evaporation (SIE) has emerged as a sustainable desalination technology. However, prevailing research remains anchored in a material‐centric or structural engineering innovation, treating water as a passive medium. This review proposes a unifying water‐centric framework by introducing the concept of a “water behavior chain” that maps the complete journey of water, from water transport and water state regulation to interfacial evaporation and product management. We systematically elucidate how hierarchical regulation of this chain enables breakthrough performance: engineering of water supply pathways for optimal thermal management, synergistic effects to reduce evaporation enthalpy and enhance evaporation rates, and design of smart interfaces for the synchronous reuse of both salt and vapor to ensure long‐term stability. Moving beyond freshwater production, we demonstrate how mastering the water behavior chain unlocks multifunctional SIE systems for synergistic water‐energy cogeneration, selective resource recovery and water pollutant purification. This review not only fills a critical gap by placing water at the heart of SIE analysis but also provides a unified roadmap to guide the development of next‐generation, high‐performance, and intelligent solar evaporation technologies.

A Chemically Programmable Retinomorphic GaN p–n Diode for Multimode Visual Sensing

ABSTRACT Real‐world visual scenes include wide illumination conditions with rapid fluctuations, demanding vision sensors that integrate multiple visual dynamics through diverse modulation strategies. However, most vision sensors suffer from limited tunability, mainly modulated via external physical stimuli (e.g., electric or light) while lacking chemical programmability critical for biorealistic vision. Here, we report a chemically programmable retinomorphic p–n diode that supports spiking response and light adaptation together with chemical tunability in an ultracompact device platform. Governed by the interplay between photoelectric carrier separation at the internal p–n junction and electrochemical carrier consumption at the semiconductor/electrolyte interface, the retinomorphic diode demonstrates switchable response modes with chemical programmability. Specifically, the device generates spikes upon illumination transitions under closed‐circuit operation, while varying ion/molecule species enables bidirectional tuning of steady‐state current, transforming dynamic‐only sensing into static–dynamic fused sensing. Moreover, it spontaneously shifts from scotopic to photopic adaptation with increasing illumination under open‐circuit operation, while both processes can be bidirectionally regulated through chemical programming. Leveraging this adaptive behavior, we further construct a proof‐of‐concept visual–motor pathway that exhibits chemically programmable, illumination‐dependent actuation. Together, this work demonstrates a chemically programmable retinomorphic platform combining physical and chemical modulation for bioinspired multimode visual sensing.

Modeling generative AI adoption among rural teachers: the moderating role of the digital divide in resource-constrained contexts

Assessing Medical Students’ Views on Using Music Parodies To Teach Immunology, As Well As The Impact of Music on Student Wellness 2257664

Abstract Introduction This study sought to determine the perspectives of medical students on the benefits of using music parodies to supplement immunology instruction, as well as to determine whether engaging in musical activities can help alleviate student stress. Methods Song parodies with lyrics related to the lecture’s topic were performed accompanied by slides that included the parody’s lyrics and relevant textbook images to visually explain concepts. YouTube videos were created for select parodies. Surveys were administered to assess student perspectives using questions on a 7-point Likert scale. To assess music’s role in student wellness, surveys with questions on a 7-point Likert scale were distributed to the members of Music Meets Medicine (MMM), a medical student-led organization that hosts events, such as music performances at senior centers, which allow students to connect with the community and each other through music. Results Most students believe song parodies can serve as useful mnemonic devices (average Likert score of 5.2, n = 33), found the song parodies to be entertaining (6.6, n = 33), and wished to see more song parodies (6.0, n = 33). Most MMM members felt participating in the group helped relieve their stress (5.8, n = 35), enjoyed participating in school karaoke and talent show events (5.7, n = 33) and found meaning and fulfillment while performing for senior citizens (6.2, n = 29). Conclusion Most students were enthusiastic about the use of song parodies and felt that they can be beneficial to learning. We previously reported that the creation and performance of immunology music parodies by students was also very well received by students. Most participating students believe that performing in a student-led music group is very rewarding and beneficial to their well-being. Music is a part of many students’ lives, and its ability to serve as a learning tool and stress reliever can be a valuable resource for students during their education. Funding Source Seed grant from California Northstate University, College of Medicine Topic Categories Immunology Education and Communication (EDU)

Mechanisms of mRNA lipid nanoparticle vaccines in enhancing the immunogenicity of conventional influenza and protein subunit vaccines 2253125

Abstract Introduction Lipid nanoparticles (LNP) used for mRNA vaccine delivery are known to be inflammatory at high doses. Here, we hypothesized that co-immunization with low-dose mRNA-LNP and conventional influenza or protein subunit vaccine would stimulate a unique set of innate responses, correlating with enhanced adaptive immunogenicity of co-vaccination, compared to either mRNA or protein vaccine alone. Methods We generated mRNA vaccines encoding influenza virus hemagglutinin (HA), neuraminidase (NA), and M2 ectodomain (M2e), as well as non-influenza glycoproteins, and then encapsulated them into LNP. Innate immune responses, adaptive immunogenicity, and efficacy were investigated in mice after immunization with mRNA-LNP, inactivated split or protein vaccines, and combinations of mRNA-LNP and split or protein vaccines. Results Co-immunization of mice with combined (mRNA-LNP + split or protein) low-dose vaccines induced synergistically enhanced levels of humoral, cellular immune responses, and protective efficacy, compared to mRNA-LNP or split (or protein) alone vaccination. Co-immunization modulated early cytokine and chemokine profiles in blood, and induced acute recruitment of activated monocytes, macrophages, dendritic cells, and natural killer (NK) cells in spleens, draining lymph nodes (dLNs), and lungs. Activated innate immune cells expressing an mRNA-encoded antigen were preferentially recruited to the lymphoid tissues and, to a lesser degree, the lungs. DBA/2J (NK defective) mice showed severely compromised innate immune responses, resulting in lower efficacy of protection. Conclusion This study provides an insight into a unique innate immune response pattern that correlates with enhanced adaptive immunity, supporting a new effective vaccination strategy. Funding Source NIH (1R01 AI154656-01A1) Topic Categories Vaccines and Immunotherapy (VAC)

Siglec-E functions as a brake for intestinal inflammation to protect from colitis-associated cancer 2260102

Abstract Introduction The lifetime risk for colorectal cancer (CRC) in the United States is approximately 4%. Individuals with Inflammatory Bowel Disease, including Ulcerative Colitis and Crohn’s Disease, have a substantially increased risk of developing colorectal cancer. Siglecs (sialic acid immunoglobulin lectin-like proteins) are a family of receptors that regulates the immune response. Siglec-E is a mouse inhibitory receptor that is primarily expressed by innate cells. While others have demonstrated that Siglec-E KO mice reject tumors faster in multiple tumor models, we have found that colorectal cancer is accelerated in Siglec-E KO mice. Here we aim to investigate the role of Siglec-E in immune homeostasis, inflammation and colorectal cancer development. Methods We used two models of colorectal cancer to assess the role of Siglec-E in tumorigenesis: TS4-cre LSL KRASG12D APClox468/wt (TAR mice) and the DSS/AOM model of colitis-associated cancer. Colons were prepared by separating lamina propria (LP) and epithelial (EP) fractions for flow cytometry. 2cm sections were taken from the middle of colons to generate lysates for ELISA. DSS was administered to WT and Siglec-E KO mice to assess the susceptibility to intestinal inflammation. H&E and IHC for PCNA were performed on colonic tissue from experiments. Results We have found that in both the spontaneous and DSS induced models of CRC, Siglec-E KO mice grow more tumors than WT mice. Siglec-E KO mice have an exquisite susceptibility to DSS induced inflammation and reduced number and proportion of neutrophils after treatment. Lastly, we have found that Siglec-E KO mice at baseline have increased VEGF-A in the colon. Conclusion Siglec-E has a critical role in regulating immune homeostasis in the colon. Siglec-E functions as a brake for intestinal inflammation which protects from the development of colorectal cancer. Funding Source This research was funded by NIH grant CA243545-01A1 (VSS), NIH T32 AI170478 (VSS/BM), and and grant R25 GM055252-26 Deans fellowship: Initiative for maximizing student development (IMSD). Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)

How do tissues sense proteolytic stress? 2309437

Abstract Introduction Excess proteolytic activity — from endogenous proteases, microbial toxins, venoms, and industrial enzymes — occurs during inflammation, infection, tissue injury, and genetic disorders (α1-antitrypsin deficiency). These activities contribute to major diseases including COPD, ARDS, rheumatoid arthritis, aneurysm, chronic wounds, and cancer, yet how tissues detect and resist proteolytic stress is poorly understood. Methods To address this, we developed an in vivo lung model using the bacterial protease LasB delivered either once (acute exposure) or three times at 24-hour intervals (repeated exposure). Acute exposure caused marked vascular injury, erythrocyte extravasation with heme release, neutrophil influx, and loss of lung function. Strikingly, repeated exposures produced a resilient phenotype: reduced protein leakage, fewer erythrocytes and neutrophils, and preserved lung function. Results Mechanistic studies using genetic mouse models, transcriptomics, and pharmacology showed this adaptation depended on sensing of oxidative molecules — erythrocytic heme — and activating tissue oxidative stress response. Alveolar macrophages emerged as the principal sensors activating NRF2 transcription factor which induces an antioxidant gene program including heme oxygenase 1 (Hmox1). Hmox1 catabolized heme to bilirubin, a metabolite that can relay stress information to neighboring fibroblasts. In response, fibroblasts produced several protease inhibitors in NRF2-dependent manner that directly bound and inhibited LasB activity, suggesting active resistance to proteolytic stress. Conclusion These results identify tissue-resident macrophages and an NRF2-dependent program as central mediators of lung adaptation to proteolytic stress, revealing a cellular circuit by which tissues detect protease-driven damage and actively restore homeostasis. Funding Source HHMI, FASI, NIH Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

High throughput CRISPR screens reveals novel roles for retroviral elements in proliferation and inflammation in murine macrophages 2259338

Abstract Introduction Ribosome Sequencing (RiboSeq) has identified translated open reading frames (ORFs) in “noncoding” elements of the transcriptome, including long noncoding RNAs (lncRNAs) and 5’ untranslated regions (5’UTRs). To date, targeted studies scratch the surface relative to the number of predicted ORFs, and the few high-throughput screens have focused on proliferation in cancer cell lines. To link novel translation events to immune cell function, we performed proliferation and NFkB reporter screens in murine macrophages, linking hundreds of novel ORFs to immune phenotype for the first time. Methods RiboSeq reads from 21 immune cell datasets were collected and processed. Input datasets included macrophages, dendritic cells, CD4/8 T cells, and B cells, with both resting and activated samples. Novel translation events were called against a custom transcriptome. RiboSeq predicted ORFs were validated using mass spectrometry data from immune cells and MHC I peptidomics. 3,000 high confidence novel ORFs on lncRNAs and in 5’UTRs were knocked out in a CRISPR dropout screen and a Tlr2-NFkB sorting screen. A top hit from each screen was characterized in follow-up studies. Results Over 20,000 novel translation events were predicted across all cell types (adj p < 0.01), and hundreds were found to have supporting proteomics data (adj p < 0.01). In follow-up CRISPR screens 200 novel ORFs impacted cell proliferation, notably ORFs in the 5’UTR of Tlr1, Tlr2, and Irf2. 15 novel ORFs were implicated in Tlr2-NFkB signaling. We followed up on two hits which were derived from retroviral envelope proteins, one acting as a secreted cytokine and one as a transmembrane protein. Conclusion We have generated a resource of novel translation events in immune cells and demonstrated that 100s of novel ORFs play a role in macrophage biology. Of the predicted ORFs, 8 were found to be derived from retroviral proteins, two of which were top hits in our proliferation and NFkB screens, indicating novel repurposing of retroviral elements. Funding Source NIH NIAID F31 Grant Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

Crosstalk Between Donor T Cells and Recipient IL-33+ Target Tissue Stroma Controls Alloimmune Responses Causing Graft-versus-Host Disease 2260079

Abstract Introduction Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation (AlloHCT). Conditioning with chemotherapy and radiation enables donor engraftment but causes tissue injury that upregulates the alarmin interleukin-33 (IL-33) in fibroblastic reticular cells (FRCs) in secondary lymphoid organs (SLO) and tissue stromal cells. While mechanisms releasing IL-33 from nuclear sequestration remain elusive, free IL-33 directly activates donor CD4+ T cells to promote Th1 differentiation and expansion. Early IL-33 blockade limits GVHD initiation, yet the role of local IL-33 in sustaining alloimmunity remains unclear. We used preclinical models to define how IL-33 signaling to donor T cells within SLO versus the gastrointestinal tract (GIT) stroma controls active GVHD and graft-versus-lymphoma (GVL) responses. Methods BALB/c recipients received B6 T cell—depleted bone marrow, A20 lymphomas, and T cells from donors with inducible ST2 (IL-33R) deletion to control IL-33 signaling during GVHD and GVL. To identify stromal functions, B6 recipients lacking IL-33 in FRCs (CCL19-Cre×Il33fl/fl) or gut epithelium (Vil-Cre×Il33fl/fl) were transplanted with BALB/c T cells and bone marrow. T cell—dependent IL-33 release was tested using GzmB⁻/⁻, St2+/+, and St2⁻/⁻ T cells. Results Late ST2 deletion resolved GVHD without compromising GVL. IL-33 signaling increased Foxp3 levels and reduced T-bet expression in donor CD4+ T cells, while sustaining TCF-1. Unexpectedly, loss of FRC-derived IL-33 exacerbated GVHD, whereas gut epithelial IL-33 deletion was protective. IL-33 induced GzmB, and GzmB⁻/⁻ T cells displayed impaired activation and expansion. Conclusion Early SLO-derived IL-33 establishes effector programming that influences later tissue responses. IL-33+ stroma—T-cell crosstalk programs donor CD4+ T-cell fate and shapes local alloimmunity during GVHD. IL-33—stroma feedback is a key signal to alloreactive T cells during GVHD. Funding Source NIH/NIAID F30AI147437, NIH T32 CA082084, NIH/NHLBI R01HL122489, NIH/NIAID R21AI121981, NIH/NIAID R56AI13927 Topic Categories Transplantation Immunology (TRAN)

Infection history and cellular origin shape long-term alveolar macrophage reprogramming 2301676

Abstract Introduction Alveolar macrophages (AMs) are essential sentinels of the lung, maintaining alveolar homeostasis through surfactant clearance, pathogen removal, and regulation of inflammation and tissue repair. During viral infection, circulating monocytes are recruited to the lung and may give rise to monocyte-derived AMs (Mo-AMs). Whether long-term differences between resident and Mo-AMs reflect intrinsic ontogeny or virus-specific imprinting remains unclear. Methods We integrated monocyte fate mapping with phenotypic, transcriptomic, and epigenetic profiling to delineate the relative contributions of cellular origin and virus-specific imprinting on AMs following infection with DNA (Murid herpesvirus 4, MuHV-4; Mouse adenovirus 1, MAV-1) and RNA (Influenza A virus PR8; Pneumonia virus of mice, PVM) viruses. Results Our results show that Mo-AMs emerge and persist long-term in a virus-specific proportion, with monocyte contribution to the AM compartment increasing over time. By 60 days post-infection, Mo-AMs acquire a transcriptomic profile broadly similar to resident AMs but retain enhanced expression of gene programs associated with fibrosis, activation, and metabolic reprogramming, while sustaining reduced expression of canonical resident AM markers. Transcriptomic profiling further revealed that infiltrating monocytes and repair-phase macrophages display virus-specific signatures, with subsets of these programs maintained long-term in AMs. MuHV-4 and MAV-1 infections elicited sustained interferon signaling, whereas PR8 preferentially maintained extracellular matrix—associated pathways accompanied by Stat3 and Srebf2 induction in AMs. PVM partially shared transcriptional features with MuHV-4 and MAV-1, yet exhibited distinct chromatin remodeling, highlighting virus-specific imprinting of the AM compartment. Conclusion Thus, infection history, more than ontogeny, imprints lasting transcriptional and epigenetic programs in Mo-AMs, potentially reshaping lung homeostasis and influencing disease susceptibility. Funding Source Fonds de la Recherche Scientifique (FNRS), European Research Council (ERC) Topic Categories Viral Immunology (VIR)

Reperfusion-Induced Low-Density Neutrophils Mediate Early Vascular Inflammation and Innate Reprogramming in Cardiac Grafts 2265648

Abstract Introduction The vascular endothelium acts as a mucosal-like barrier that regulates immune tolerance. During heart transplantation, ischemia—reperfusion injury (IRI) disrupts this barrier, exposing subendothelial antigens and activating innate responses. While neutrophils dominate early IRI, the significance of circulating low-density neutrophils (LDNs) remains unclear. We hypothesized that graft reperfusion induces a transient LDN surge that coordinates monocyte remodeling and defines a mucosal-vascular interface response similar to epithelial immune activation. Methods Eleven orthotopic heart-transplant recipients (mean 59.7 ± 6.3 y; BMI 27.0 ± 4.9; mixed gender; all DBD donors) were prospectively enrolled. Pulmonary-artery blood was collected pre-cross-clamp (Pre-Cx), post-reperfusion (Post-Cx), postoperative day 1, and 2 (POD-1 & 2), PBMC fractions were analyzed by flow cytometry to quantify LDNs (CD45+CD15+CD16+CD14⁻) and monocyte subsets–CM (CD14++CD16⁻), INT-M (CD14++CD16+), NCM (CD14+CD16++). Temporal shifts were assessed by repeated-measures ANOVA. Results LDNs were scarce Pre-Cx (5.4 ± 2.1%) but rose Post-Cx (25.3 ± 8.2%, p < 0.0001), peaked POD-1 (70.4 ± 9.8%, p < 0.0001), and declined POD-2 (34.9 ± 11.2%, p < 0.001). INT-M expanded (p < 0.001) while NCM fell >70% (p < 0.01). LDNs correlated with INT-M (r = 0.72, p = 0.004) and inversely with NCM (r = —0.65, p = 0.009). These kinetics parallel mucosal inflammation where activated neutrophils release IFN-β, CXCL9/10, and IL-10 to drive monocyte reprogramming and barrier repair Conclusion Reperfusion triggers a sterile mucosal-type cascade at the vascular interface, marked by an acute LDN surge and monocyte transition toward intermediate, reparative phenotypes. This neutrophil—monocyte axis links endothelial injury with early graft inflammation, defining an innate checkpoint that bridges vascular barrier immunity and transplant tolerance. LDNs represent a transient mucosal signature and potential biomarker of reperfusion-driven immune activation Funding Source n/a Topic Categories Mucosal and Regional Immunology (MUC)

Decoupling Photochemical and Photothermal Effects Using Molecular Motors Enables Fast, Intelligent, and Life‐Like Motions in Soft Materials

ABSTRACT The development of synthetic smart materials that perform on‐demand tasks in complex environments, while triggered noninvasively, is a major goal to develop the next generation of soft robotics. However, fast and complex locomotion with high spatial‐temporal precision using external stimuli controlling shape in such systems remains a major challenge. Here, we describe a light‐responsive soft material based on liquid crystal polymer networks (LCPNs) with variable stiffness comprising highly efficient light‐driven molecular rotary motors and dye molecules. This system selectively responds to light of specific wavelengths, enabling highly programmable and complex motions, such as jumping, rotating, and climbing. The rapid response of molecular motor triggered by UV‐light (photochemical effect) and the heat generated by dye upon red‐light irradiation (photothermal effect), can be decoupled and orthogonally controlled, due to unique features of the molecular motor. Our study shows how cooperativity and amplification of molecular motion can lead to the rapid actuation of synthetic materials, which offers novel molecular tools and materials engineering perspectives for the development of intelligent soft robotics.

Metabolic responses of diet–exercise combinations in women with obesity: a comparative lifestyle intervention study with different diet types

Targeting NOX1 to Reprogram T Cell Activation and Metabolism for Enhanced CAR T Efficacy 2251163

Abstract Introduction T-cell exhaustion is a critical roadblock to achieving durable remission with adoptive cell therapies. The immunosuppressive tumor microenvironment limits T-cell persistence and function, demanding new reprogramming techniques. Our genome-wide CRISPR screen in CD8+ T cells identified NOX1 as a novel, negative effector regulator. We hypothesize that NOX1 suppresses signaling downstream of the TCR, and its therapeutic inhibition will improve T-cell-based immunotherapies, particularly the next generation of CAR T therapies Methods We generated NOX1 knockout (KO) T cells from primary human T cells via CRISPR-Cas9, with KO efficiency validated by Western Blot. Mechanistic studies compared NOX1 KO to controls using TCR-induced calcium flux and ROS production for existing and induced ROS. Functional outcomes were assessed via cytotoxicity against melanoma lines and cytokine production. The enhanced anti-tumor efficacy was validated in a syngeneic in vivo mouse model Results Genetic knockout of NOX1 in T cells resulted in functional enhancement. NOX1 KO significantly reduced basal intracellular ROS levels and exhibited stronger, sustained TCR-induced calcium flux, confirming a key role in TCR signaling, relatively proximal to the TCR signaling event. NOX1 deficient T cells displayed increased cytotoxicity against B16 melanoma cells in vitro, with enhanced production of effector cytokines. This translated into improved anti-tumor efficacy and survival in a corresponding in vivo mouse model Conclusion NOX1 functions as a critical negative regulator that imposes a redox-dependent threshold, limiting TCR-initiated calcium flux and dampening T-cell activation. By demonstrating that NOX1 deletion enhances signaling, overcomes metabolic deficiencies, and achieves potent anti-tumor efficacy in vivo, we establish NOX1 as a novel therapeutic target. This work provides the strong rationale for genetically inhibiting NOX1 as a way to enhance durability and function of T-cell therapies to overcome T-cell exhaustion Funding Source N/A Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)