Browse Articles

The Enteric Nervous System Primes Systemic Immunity in Response to Mucosal Infection 2258662

Abstract Introduction The enteric nervous system (ENS) is essential for gastrointestinal (GI) function and has recently been implicated in regulating immune activity at mucosal sites. However, its broader contributions to systemic immunity remain unclear. Because the ENS interfaces with extrinsic neural circuits, it is well-positioned to relay information between the gut and peripheral tissues. We hypothesized that enteric neurons detect disturbances in intestinal immune homeostasis and transmit signals that coordinate systemic defenses. Methods To test this, we combined an in vivo infection-challenge paradigm in mice with manipulations of ENS activity and measured downstream immune readouts. We also used ex vivo cultures to assess how enteric neurons respond to microbial cues. Results Our findings indicate that activating the ENS promotes rapid protective responses in distal organs. Upon stimulation, enteric neurons released inflammatory mediators, supporting the mobilization of innate immune cells to both intestinal and peripheral sites. Modulating ENS activity altered host susceptibility to a subsequent systemic challenge. Conclusion Together, these results suggest that the ENS functions as a sensor-effector hub, linking local GI infection to rapid, body-wide immune responses, and highlighting a previously understudied role for the ENS in systemic host defenses. Funding Source n/a Topic Categories Neuroimmunology (NEUR)

Loss of TET function in T regulatory cells yields Tfh-like ex-Treg cells with the features of heterochromatin dysfunction 2266533

Abstract Introduction FOXP3 is the lineage-defining factor of T regulatory (Treg) cells, which can lose FOXP3 and convert into pathogenic ex-Tregs under strong inflammation. Ten-eleven translocation (TET) proteins maintain FOXP3 and CD4 expression by demethylating Foxp3 enhancers and the Cd4 locus. Methods CD4+ FOXP3+ Tregs from WT or CD4-Cre Tet2/3fl/fl mice were co-transferred with naïve CD4+ T cells into Rag1⁻/⁻ mice. This method allows us to isolate “pure” Tet2/3 double-knockout ex-Treg cells. Results WT Tregs maintained FOXP3 and CD4 expression, whereas Tet2/3 double-knockout (DKO) Tregs lost both, generating FOXP3⁻ CD4⁻ ex-Treg cells. Bulk and single-cell RNA-seq revealed that Tet2/3 DKO ex-Tregs expressed T follicular helper (Tfh)-related genes, exhibiting a Tfh-like phenotype. When transferred into immunocompetent WT mice, Tet2/3 DKO ex-Tregs expanded and induced severe inflammation, and there was also a striking expansion of plasma cells and CD8+ T cells. Base-resolution “6-base” sequencing revealed hypermethylation at Prdm1 and Bcl6 loci in Tet2/3 DKO ex-Tregs. Prdm1 mRNA was decreased as expected from the correlation of increased methylation with decreased gene expression; whereas Bcl6 expression increased, associated with decreased CTCF binding to the first intron of the Bcl6 gene. The Cd4 locus exhibited hypermethylation extending over several Kb. Although TET deficiency is expected to promote DNA methylation, heterochromatic regions in Tet2/3 DKO ex-Tregs underwent hypomethylation, accompanied by de-repression of transposable elements (TEs). Furthermore, ChIP-seq showed FOXP3 binding near TEs, suggesting that FOXP3 may regulate TEs expression. Conclusion Tet2/3 loss converts Tregs into Tfh-like ex-Tregs that trigger inflammation. Heterochromatic demethylation and TEs activation may underlie the strong pro-inflammatory phenotype of Tet2/3 DKO ex-Tregs, which FOXP3 may suppress. Funding Source the Tullie and Rickey Families SPARK Awards for Innovations in Immunology at La Jolla Institute Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

TRIM21 Orchestrates Inflammasome Assembly and Drives Autoinflammatory Pathology 2300561

Abstract Introduction Inflammasomes are pivotal cytoplasmic scaffolds that drive the maturation of interleukin (IL)-1β and IL-18 and initiate pyroptotic cell death. Tight regulation of inflammasome activity is critical, as uncontrolled IL-1β release underlies chronic inflammation and autoinflammatory disease. The adaptor protein ASC is essential for inflammasome assembly, and its polymerization and extracellular release amplify inflammatory responses. TRIM21, an E3 ubiquitin ligase and common autoantigen in autoimmune diseases, has been implicated in pyroptosis regulation; however, its role in inflammasome assembly and autoinflammatory disease remains unclear. Mechanistic insights into ASC polymerization and particle release are also incomplete. Methods We investigated TRIM21’s role in inflammasome activation using TRIM21-deficient human monocytes and bone marrow—derived macrophages from conditional Trim21 knockout mice. Systemic autoinflammation was assessed in murine models of cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF), and findings were validated in plasma from CAPS patients. Results TRIM21 is a conserved and essential mediator of inflammasome assembly. It interacts with, ubiquitinates, and promotes polymerization of ASC, facilitating inflammasome assembly and the release of ASC/TRIM21 particles during pyroptosis in human and mouse macrophages. Notably, systemic ASC/TRIM21 particles and corresponding autoantibodies were detected in both murine and human autoinflammatory disease. Conclusion Our findings establish TRIM21 as a critical regulator of inflammasome assembly and particle release, linking it to the pathogenesis of autoinflammatory disease. These results extend TRIM21’s known role in autoimmunity to a previously unrecognized function in driving inflammasome-mediated inflammation, highlighting it as a potential therapeutic target in autoinflammatory disorders. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)

Exploring Female Obesity and Type 1 Interferon Signaling in the Context of Multiple Sclerosis 2310319

Abstract Introduction Multiple sclerosis (MS) is a demyelinating autoimmune disease that is heterogeneous in prognosis. This variability is evident with interferon-β (IFN-β) therapy, where certain patients are non-responders. Elevated type I IFN signatures have been associated with IFN-β non-response. Obesity, an increasingly prevalent environmental factor, can elevate innate immune responses. We hypothesized there is an amplification of type I IFN signaling in obese females that impairs IFN-β efficacy. Here, we examine the relationship between obesity, interferon signaling, and IFN-β treatment response in female patients and in the EAE models. Methods Chart reviews were performed for 86 patients treated with IFN-β and 113 treated with glatiramer acetate (GA) to determine relapse status on therapy. Multivariable logistic regression assessed demographic factors associated with relapses during treatment. Serum proteins were quantified using Olink Explore 1536 and stratified by sex and obesity status. Complementary studies were conducted in high-fat diet fed mice with EAE treated with IFN-β or vehicle. Results In IFN-β treated patients, obesity was associated with increased relapse risk, whereas this was not observed in GA treated patients. This reduction in IFN-β efficacy was observed in women but not men. Proteomic profiling of serum from untreated obese women revealed increased type I IFN pathways, along with increased Th1 and Th17 signatures. In obese female mice, high-fat diet was associated with elevated IFN-α in gonadal adipose tissue, increased interferon-stimulated gene expression in the spleen, and more severe EAE that was not ameliorated by IFN-β treatment. Conclusion Elevated type I interferon signaling was associated with reduced IFN-β treatment efficacy in obese females across human and mouse studies, suggesting obesity-associated dysregulation of innate immune signaling as a contributor to reduced therapeutic responsiveness in MS. Funding Source OCASCR, NIH NIDA, NIH NIGMS Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Type 1 interferons (T1 IFNs) regulate cellular redox balance by suppressing the host antioxidant response during influenza A virus infection in vivo 2267523

Abstract Introduction Influenza A virus (IAV) infection leads to a wide spectrum of outcomes, from asymptomatic cases to severe disease, emphasizing the pivotal role of the host immune response in determining disease severity. NRF2, a key transcription factor that governs the cellular antioxidant (AOX) response, is critical in maintaining redox balance during viral infections. Disruption of NRF2 activity can lead to accumulation of reactive oxygen species (ROS) and insufficient AOX defenses, a characteristic of influenza pathogenesis. Type I interferons (T1 IFNs) are well-established host factors implicated in antiviral immunity as well as influenza severity. We hypothesize that elevated T1 IFNs may exacerbate disease severity in response to influenza infection by altering cellular redox balance through suppression of the NRF2-driven AOX responses. Methods To test this hypothesis, we infected WT and Ifnar1-/- mice with influenza A virus and sorted alveolar macrophages (AMs), inflammatory monocytes (IM), and neutrophils (PMNs) at D3 post infection for assessment of the NRF2-regulated AOX response. Results Influenza-infected mice showed increased transcription of NRF2-regulated AOX genes in AMs and PMNs from Ifnar-/- mice compared to WT mice, with the most dramatic effects observed within neutrophils. However, acute stimulation of purified neutrophils directly with T1 IFNs or T3 IFNs (IFN-lambda) increased rather than decreased the expression of NRF2-dependent AOXs. Conclusion These observations suggest that autocrine T1 IFNs produced in response to influenza infection profoundly alter neutrophil redox balance in vivo but this effect may be indirect or subject to differential kinetic regulation. Furthermore, manipulating the T1 IFN-NRF2-AOX axis could represent an approach for intervening in influenza-induced acute lung injury, such as acute respiratory disease syndrome. Funding Source NIH R21 HD112848-01 Topic Categories Viral Immunology (VIR)

Targeting MDSC activation via the RAGE/TLR4 pathway during early TB modestly reduces lung inflammation but not granuloma bacteria loads 2310052

Abstract Introduction Tuberculosis (TB) causes more than a million deaths annually. Drug-sensitive TB is treated with an arduous antibiotic regimen taken for an extended duration but drug resistant TB is increasingly prevalent. Alternative treatments including host-directed therapies (HDTs) are being considered to shorten or improve conventional antibiotic therapy. Myeloid-derived suppressor cells (MDSCs) may inhibit immunity against the bacterium that causes TB, Mycobacterium tuberculosis (Mtb), and have been viewed as a HDT target for TB. Tasquinimod (TSQ) is a small molecule inhibitor of the RAGE/TLR4 pathway that has been tested in mice where it modestly reduced bacteria loads and inflammation, suggesting it may have value for TB treatment. More information on the role MDSCs play in TB and if they can be safely targeted to improve outcomes will help identify the value of this approach for treating TB. Methods Mtb-infected cynomolgus macaques were followed during early stages of TB, with TSQ treatment beginning at three weeks post infection for half of the animals and continuing for three weeks. During the study, blood was sampled for complete blood counts, chemistry panels, and plasma cytokine quantification, PET-CT scans were acquired at three weeks post-infection and prior to necropsy at six weeks, and bacteria loads were quantified from tissues post-necropsy. TSQ-treated and untreated control groups were compared to evaluate the effects of treatment. Results We found that TSQ treatment modestly, but not statistically significantly, reduced PET-measured lung inflammation, CT-measured granuloma size, and the rate of new granuloma formation. Plasma cytokine and bacterial LAM concentrations were equivalent between groups, but reduced concentrations of the neutrophil and MDSC-associated protein S100A9 were seen in the TSQ-treated group. Conclusion These data suggest that TSQ treatment may reduce inflammation without directly augmenting anti-Mtb immunity, shedding light on how MDSC function affects early TB. Funding Source NIH R01 AI164970 and AI184666 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

Development & clinical validation of microneutralization assays for the robust quantification of neutralizing antibodies to human cytomegalovirus 2305514

Abstract Introduction mRNA-1647 is an investigational vaccine composed of six mRNAs encoding human cytomegalovirus (hCMV) gB and pentamer antigens. To evaluate vaccine immunogenicity, we developed two hCMV microneutralization (MN) assays to measure neutralizing antibodies that can block viral entry and serve as potential correlates of protection. Methods Cell-based MN assays were validated for fibroblast-tropic AD169 and epithelial-tropic VR1814 strains. Infection was measured as foci-forming units via immunofluorescent detection of immediate early-1 protein. Neutralization titers were expressed as ID50, the serum dilution yielding 50% inhibition relative to virus-only controls. Validation followed a prespecified plan assessing limits of quantitation (LOQs), relative accuracy, dilution linearity, precision, specificity, and stability. Results Dynamic LOQs were 22—7,842 (fibroblast) and 13—206,687 (epithelial), with broader linearity for the epithelial assay. Relative accuracy met the ±2-fold criterion for both assays; the overall geometric mean fold bias (GMFB) was 1.00, and all dynamic-LOQ samples fell within ±2-fold criterion, confirming accuracy. Intra-assay precision CVs were 23.7% and 20.4%, and intermediate precision CVs were 53.7% and 28.7% for fibroblast and epithelial assays, respectively demonstrating acceptable precision. Specificity was confirmed in both assays by observing a ≥ 4-fold titer reduction when competed with homologous antigens, while heterologous antigen competition produced ≤2-fold reductions in ≥ 80% and ≥60% samples in fibroblast and epithelial assay respectively. Serum samples were demonstrated to be stable through 15 freeze—thaw cycles and up to 72 hours at ambient temperature. Conclusion These validated hCMV MN assays demonstrated acceptable accuracy, precision, linearity, stability, and specificity across the dynamic range, enabling reliable, strain- and cell type—specific quantification of nAb responses for clinical evaluation of mRNA-1647. Funding Source Moderna, Inc funded this project. Topic Categories Vaccines and Immunotherapy (VAC)

Dorsiventrally Bicolored Leaf‐Inspired Metamaterial Absorbers for Tailorable Electromagnetic Absorption

ABSTRACT Realizing tailorable broadband electromagnetic absorption within structurally concise architectures remains a key challenge for advanced absorber design. Inspired by dorsiventrally bicolored leaves that integrate broad‐spectrum light management with directional regulation, we propose a bioinspired hybrid metastructure in which an impedance‐graded hexagonal‐frustum absorber serves as the broadband absorption backbone, and an underlying resonant feedback layer selectively reinforces weak‐absorption frequencies in the baseline absorption spectrum. Mechanistically, the broadband absorption arises from continuous impedance transition, enhanced wave coupling, and multistage attenuation, while the reinforcement of selected frequencies is governed by the interplay of resonant feedback, material loss, and phase‐assisted reflection suppression. Experimentally, the metastructure exhibits an intrinsic X‐band absorption peak and a broadband high‐absorption platform with absorptance exceeding 80% from 18 to 40 GHz. In addition, feedback‐layer engineering enables targeted reinforcement at prescribed weak‐absorption frequencies, forming tailorable absorption windows in selected X─K‐band regions. In parallel, a genetic‐algorithm‐optimized ExtraTrees surrogate model enables rapid inverse identification of feedback‐layer geometries, and the selected candidates show good agreement with full‐wave simulations and experiments. This work establishes a bioinspired framework that integrates broadband response, targeted reinforcement, and inverse design, offering a promising route toward high‐performance, tailorable electromagnetic absorbers.

HO-1 and NLRP3-associated lung dysfunction and systemic inflammation in a noninfectious COVID-19 spike protein murine model

Collaboration among the common gamma chain cytokine family supports circulating and tissue-resident CD8+ T cell memory 2259059

Abstract Introduction We recently demonstrated resilience of circulating and tissue-resident memory (TRM) CD8+ T cells to loss of interleukin-7 (IL-7) signaling, revealing a compensatory relationship with its fellow common gamma chain (γC) cytokine IL-15. We found that across subsets and tissues, IL-7 and IL-15 act in concert to support memory CD8+ T cells. This confers resilience to altered availability of either cytokine, in contrast to the widely accepted model of exclusive roles for each in CD8+ T cell memory. How the broader γC cytokine family supports memory CD8+ T cells (especially TRM) in homeostasis and particularly inflammation is unclear. We hypothesize that conserved γC cytokine sensitivity confers adaptability extending beyond IL-7/15 when cytokine availability is altered. Methods We have now used cytokine therapies and infection to interrogate the broader capacity of pathogen-specific memory CD8+ T cells to adapt to cytokine availability, irrespective of homeostatic requirements. Results All γC cytokines assessed were capable of eliciting proliferation and expansion of circulating and tissue-resident memory CD8+ T cells, albeit with cytokine-, tissue-, and subset-specific nuance. This was a conserved feature of memory CD8+ T cells of different specificities and elicited by different pathogens, occurring in response to cytokines alone without cognate antigen. We observed similar behavior of bystander virus-specific memory CD8+ T cells during helminth infection. Conclusion Thus, irrespective of dependence, circulating and tissue-resident memory CD8+ T cells share cell-intrinsic sensitivity to multiple γC cytokines within tissue- and subset-specific constraints, providing additional adaptability. We propose that adaptability is a fundamental feature of CD8+ T cell memory, conferring resilience to changing tissue environments and inflammation to preserve immune memory. γC cytokine therapies are also an antigen-agnostic means to expand TRM in the laboratory and potentially the clinic. Funding Source NIAID: K22 AI177360 (NNJ), F31 AI176750 (SDO), F31 AI188630 (TAD), T32 AI007313 (KMA), K99/R00 AI139381 (HBdS), R01 AI038903 (SCJ). Damon Runyon Cancer Research Foundation DRG-2427-21 (NNJ). NCI: F30 CA250321 (KMW), K00 CA245735 (NJM), K99 CA296729 (NJM), F30 CA253992 (NVG). Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

B cell-intrinsic CCR6 expression is required for IgE production in a murine model of galactose-alpha-1,3-galactose syndrome 2267251

Abstract Introduction Alpha-gal syndrome (AGS) is acquired through bites from the lone star tick (LST), leading to IgE-mediated reactions to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) present in non-primate mammalian meat and derived products. The mechanisms driving IgE production to alpha-gal are unknown. We previously identified a significant association of CCR6+ memory B cells in the peripheral blood of AGS patients vs healthy controls. Thus, we hypothesized that CCR6 is required for IgE production after tick exposure. Methods Wild-type (WT) and CCR6-/- mice were sensitized with LST extract. After 35 days, serum tick-specific IgE and IgG1 levels were measured by ELISA. To assess the B cell-intrinsic requirement for CCR6, muMT mice were reconstituted with purified B cells from WT or CCR6-/- donors prior to sensitization. Splenocytes were stimulated in vitro with anti-CD40 and IL-4 for 5 days, and expression of eGLT, Bcl6, and Blimp1 were quantified by qPCR. Results CCR6-/- mice showed a significant reduction in tick-specific IgE without affecting IgG1 responses. Reconstitution of muMT mice with WT but not CCR6-/- B cells restored IgE production after tick sensitization, indicating a B cell-intrinsic role for CCR6. In vitro, CCR6-/- splenocytes showed reduced expression of genes associated with IgE class switching and plasma cell differentiation. Conclusion CCR6 expression on B cells is required for IgE production following tick sensitization. Our findings suggest that CCR6 signaling promotes IgE class switching and plasma cell differentiation, providing new mechanistic insight into AGS. Funding Source NIH R01 AI172112 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

Elucidating the Function of Redox-Signaling Mechanisms Underlying Trained Immunity in Alveolar Macrophages 2303944

Abstract Introduction Trained immunity represents a functional state of the innate immune system characterized by long-term epigenetic and metabolic reprogramming, enabling enhanced and rapid responses to future pathogenic challenges. While nitric oxide (NO) and reactive oxygen species (ROS) production are recognized as part of the innate immune response to pathogens, their role in establishing innate immune memory remains poorly understood. This study examines the role of redox signaling in establishing trained immunity in alveolar macrophages (AMs). Methods To investigate the function of redox signaling, AMs were treated with flagellin as the first stimulus, and redox inhibitors were used to block ROS/NO production during flagellin treatment. After 5 days of resting, cells were rechallenged with LPS. To analyze redox-dependent training, we used a combination of techniques, such as qPCR, ELISA, NO quantification, flow cytometry, mass spectrometry, and bulk RNA sequencing. Further histone modifications and metabolic changes were confirmed by Western blot and Seahorse analysis. Results Flagellin-induced trained immunity resulted in enhanced pro-inflammatory gene expression and cytokine production upon LPS restimulation. Additionally, flagellin increased the production of ROS/NO, and blocking the accumulation of these redox molecules significantly reduced the training effect. Interestingly, the treatment with inhibitors also induced training. Bulk RNA-Seq analysis revealed the upregulation of oxidative phosphorylation genes in trained cells. Mechanistically, flagellin-induced trained cells rewired AMs metabolism, increased glycolytic capacity, and histone acetylation and methylation levels. Furthermore, identification of redox-modified proteins revealed novel regulatory mechanisms in trained immunity. Conclusion Redox signaling is essential for establishing training in AMs, providing new insights for developing target-based immunotherapies in trained immunity. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

Prolonged IL-10 Exposure Modulates Adaptive and Innate Immune Responses in Secondary Lymphoid Organs during Experimental Autoimmune Encephalomyelitis 2332777

Abstract Introduction Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that suppresses pro-inflammatory cytokine production, reduces antigen presentation by myeloid cells, promotes M2 macrophage polarization, and inhibits T cell activation. However, the clinical application of recombinant IL-10 is limited by its short plasma half-life and insufficient exposure in the secondary lymphoid organs (SLOs), key sites of autoreactive T cell priming in autoimmunity. Methods To address these limitations, we previously engineered a serum albumin-IL-10 fusion protein (SA-IL-10) with extended half-life and enhanced exposure in the SLOs. Here, using experimental autoimmune encephalomyelitis (EAE), a murine model of neuroinflammation, we subcutaneously administered SA-IL-10 and performed immunophenotyping in the SLOs and spinal cord to examine how sustained IL-10 exposure modulates immune responses under neuroinflammatory conditions. Results Immunophenotyping of the SLOs revealed that SA-IL-10 treatment reduced pathogenic, antigen-specific RORγt+ TH17 T cells, CD86+ M1-like macrophages, CD86+ dendritic cells and pro-inflammatory cytokine production, while expanding immunoregulatory CD206+ M2-like macrophages. Sustained IL-10 exposure expanded a novel checkpoint-high immunoregulatory TH2 phenotype, with GATA3+ TH2 cells expressing multiple immune checkpoint receptors, including CTLA-4, PD-1, TIGIT, and ICOS. Despite the absence of direct central nervous system targeting, SA-IL-10 treatment also reduced the infiltration of macrophages, dendritic cells, and CD4+ T cells in the spinal cord. Conclusion Together, these findings demonstrate that increasing IL-10 exposure in the SLOs alters peripheral immune priming and is associated with reduced pro-inflammatory immune cell infiltration in the spinal cord during EAE. Funding Source Alper Family Fund Grant (Awarded to Prof. Jeffrey A. Hubbell) Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Targeting genome organizer Satb1 in regulatory T cells safely and potently enhances cancer immunity 2309560

Abstract Introduction Rigorous research over the years has revealed that the cellular composition of the tumor microenvironment (TME) matters, and a major constituent that facilitates tumor progression is the regulatory T cell (Treg). Tregs are essential for maintaining immune homeostasis and preventing autoimmune conditions but can also be a detriment via their suppression of immune responses against cancer. The significance of Treg research is far-reaching as supported by the 2025 Nobel Prize in Physiology or Medicine awarded to Drs. Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi, “for their discoveries concerning peripheral immune tolerance”. However, identifying differences in Treg subtypes to specifically disrupt the activities of tumor-promoting Tregs, without affecting Tregs that maintain immune homeostasis remain elusive. Here, we sought to discover how to blunt pro-tumorigenic Tregs without compromising the abilities of Tregs in mediating self-tolerance. Methods To this end, we used state-of-the-art methods in immunology, including high dimensional flow cytometry, lineage-specific loss-of-function studies and single-cell RNA sequencing, as well as multiple tumor models in animals to investigate these fundamental gaps in the field. Results In doing so, we discovered that expression of the genome organizer special AT-rich sequence binding protein 1 (Satb1) could readily separate two Treg subtypes: pro-tumorigenic Tregs (termed Satb1+) and immune-regulatory Tregs (termed Satb1-). Deletion of Satb1 specifically in Tregs impaired the function of Satb1+ pro-tumorigenic Tregs, leading to enhanced CD8+ T cell antitumor immune responses, and complete tumor eradication without any systemic autoimmune conditions. Notably, Satb1- Tregs remained intact in knockout mice and were necessary for maintaining immune homeostasis and preventing autoimmunity. Conclusion Our results reveal a key mechanism to safely and potently enhance cancer immunity without causing systemic autoimmune diseases. Funding Source Pelotonia Institute for Immuno-Oncology Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Tissue-Resident Memory B cells Mediate Local and Metastatic anti-Cancer Immunity 2310347

Abstract Introduction Tissue-resident memory B cells (BRM) have been identified in barrier tissues such as the lung, where they provide durable protection against microbial infection. Whether analogous tissue-resident B-cell populations can be established in peripheral tissues and actively contribute to anti-cancer immunity has remained unknown. Methods Here, we define the dynamics and functional role of BRM in cancer using a localized extracellular vesicle (EV)—based vaccination strategy to deliver DEL or HEL together with OVA antigens directly to the skin. This approach selectively seeded antigen-specific BRM within defined cutaneous niches, arising either endogenously from HEL- or OVA-specific B cells or following adoptive transfer of Hy10 (DEL-specific) B cells with cognate OTII (OVA-specific) T-cell help. Results Phenotypic profiling revealed sustained expression of CD69, CXCR3, and CCR6, consistent with a long-lived tissue-resident memory program. Functionally, the presence of BRM conferred robust, localized protection against antigen-matched MOC2 squamous cell carcinoma expressing DEL/OVA or HEL alone, establishing a direct causal role for skin BRM in suppressing local tumor growth. Extending beyond primary tumors, we further demonstrate that lung BRM contribute to protection in metastatic settings, revealing a role for lung-resident BRM in limiting tumor spread. Ongoing single-cell transcriptomic and mechanistic studies in murine and human tumors are defining the molecular programs and effector pathways that underpin BRM-mediated tumor control. Conclusion Collectively, this work establishes tissue-resident memory B cells as an active and previously unrecognized component of anti-cancer immune surveillance for the first time, demonstrates that BRM can be intentionally programmed by local vaccination, and identifies BRM as a promising target for tissue-directed B cell—based cancer immunotherapies. Funding Source Melanoma Research Alliance, 1253470; Elsa U. Pardee Foundation; Knight Cancer Institute, OHSU Topic Categories Vaccines and Immunotherapy (VAC)

Early-life mucosal T cells direct intestinal stem cell fate via a coordinated developmental program 2305986

Abstract Introduction Although early-life immunity was once considered immature, the human fetal immune system is dynamic and compartmentalized by the 2nd trimester. By the 21st gestational week, T lymphocytes dominate the fetal small intestine (SI), yet their mucosal functions prenatally are unclear. Because fetal T cell infiltration is concomitant with rapid intestinal epithelial growth and differentiation in utero, we hypothesized that early-life intestinal T cells support normal mucosal development and function. Methods We generated an ex vivo co-culture model where SI T cells from fetal or adult donors are integrated with SI organoids, assessing organoid generation and differentiation by microscopy, single-cell RNA sequencing, and multiplexed cytokine assays. To complement our ex vivo approach, we also performed spatial transcriptomics on healthy and diseased SI tissue to investigate T cell-epithelial interactions throughout the human lifespan. Results Fetal SI T cells significantly promoted organoid generation and cell cycling gene programs, even in organoids derived from adults or diseased neonates, suggesting they can reprogram the epithelium towards a regenerative state. Uniquely, fetal SI T cells also directed intestinal stem cell (ISC) differentiation towards the secretory lineage. Yet, adult SI T cells did not support organoid growth or differentiation, highlighting specialized roles of fetal T cells. To test whether secreted factors direct ISC fate, we cultured organoids with T cell-derived conditioned media, which was insufficient to stimulate organoid generation. Additionally, fetal SI T cells were significantly more likely to localize near ISCs, supporting the need for physical interactions. Conclusion Overall, we report a unique and coordinated developmental program where fetal SI T cells shape ISC programming by balancing growth and differentiation, offering a new therapeutic angle for intestinal diseases where these processes are disrupted. Funding Source NIH AI171980, AI179570; NIH P30DK034854-36; YSM Science Fellows 2024 Program and Grant; Yale Department of Pediatrics Trainee Pilot Grant Topic Categories Mucosal and Regional Immunology (MUC)

Solvent Engineering Enabled Fast Long‐Range Ion Transport in Mn/Fe‐Based Prussian Blue Analogues for High‐Loading‐Mass Zn‐Ion Batteries

ABSTRACT Prussian blue analogues (PBAs) are promising cathode materials for Zn‐ion batteries (ZIBs) due to their open framework and high operating voltage. However, the blocked long‐range ion transport caused by structural collapse during the repeated ion intercalation/deintercalation at high loading mass remains a critical issue to address in practical applications. Here, we propose the promotion of long‐range ion transport in model cathode of Mn/Fe‐based PBAs by solvent intercalation, which expands the ion channel and regulates the coordination number of Fe active center. This suppresses the lattice oscillation related to the evolution between Fe 2+ ‐C≡N‐M 2+ and Fe 3+ ‐C≡N‐M 3+ and decreases the ion long‐range transport barrier under high loading mass. Consequently, it achieves a capacity enhancement of 185% at 9 mg cm −2 and good cycling stability at 18 mg cm −2 , surpassing other reported PBAs cathodes in ZIBs. This study provides a new direction for addressing the high‐loading‐mass challenge of PBAs cathode for ZIBs.

Ethane dry reforming for CO2 utilization and H2 generation

Abstract The dry reforming of ethane offers a promising pathway for the co-utilization of CO 2 , which are two abundant industrial byproducts to produce blue H 2 and CO, enabling sustainable routes toward carbon circularity. This study investigates the performance of CeO 2 supported metal catalysts and the effect of catalyst loading in the dry reforming process across a range of temperatures. Catalyst characterization included H 2 -TPR, NH 3 -TPD, CO 2 -TPD, H 2 -TPD, XRD and SEM/EDS mapping to correlate surface acidity, basicity, reducibility, and metal dispersion with catalytic performance. Among all formulations, 2% Rh/CeO 2 showed the highest ethane conversion of ~ 98.5%-91.2% with early reduction behavior, but suffered from minor byproduct of ~ 15 − 12% methane generated from ethane dissociation. Ni/CeO 2 catalysts, especially at 15% loading, demonstrated excellent balance between performance up to 80 − 52% conversion, CO 2 utilization ~ 70 − 48%, with ~ 99% selectivity toward H 2 and CO, and less than 1% formation of methane and ethylene byproducts. Increased Ni loading improved performance due to better reducibility and moderate surface acidity. These findings highlight CeO 2 role in enhancing metal dispersion, particularly Ni/CeO 2 catalyst offers a cost-effective alternative to noble metal of Rh/CeO 2 for dry reforming of ethane, enabling efficient CO 2 valorization for decarbonized energy systems.

Endogenous Retrovirus Neoantigen Enables Personalized Cancer Vaccine in glioblastoma, IDH-wildtype 2259068

Abstract Introduction Glioblastoma (GBM) remains refractory to immunotherapy due to low mutational burden and limited neoantigens. Aberrant expression of endogenous retroviral elements (ERVs), reactivated insertions of ancient viruses within the genome, may provide a source of tumor-specific antigens for personalized vaccines targeting traditional and ERV-derived neoantigens. Methods Tumor and matched normal tissues from 25 GBM patients, including 18 long-term survivors (LTS; >5 years) and 7 short-term survivors (STS; 12—18 months), underwent whole-genome and RNA sequencing. Candidate antigens were predicted using two AI-based pipelines: one for mutation-derived neoantigens and one for ERV-derived antigens. Predicted epitopes were ranked by expression, MHC class I and II binding affinity, clonality, and immunogenicity. Top candidates informed the design of a personalized DNA vaccine encoding 10 patient-specific neoantigen sequences with a CCL19 adjuvant to enhance dendritic cell recruitment. Results High-quality canonical neoantigens were rare (median 3/ patient), consistent with prior reports. Yet, all tumors expressed abundant, patient-specific ERV transcripts independent of mutation load. ERV-derived epitopes exhibited strong predicted MHC class I and II binding, comparable to viral antigens, with 22 of 25 tumors containing ERV peptides suitable for vaccine inclusion. These mapped primarily to HERV-K and HERV-W families and frequently overlapped interferon-stimulated loci. Comparison of LTS and STS cohorts is ongoing to define ERV expression patterns associated with durable immune control. Conclusion ERVs are consistently expressed and immunogenic in GBM, representing a scalable, tumor-specific antigen source that may overcome limitations of low mutational burden. These data provide a proof-of-concept for personalized vaccines targeting ERV-derived neoantigens. Funding Source Duke Brain Tumor Omics Program Fellow Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Diet-Specific Microbial Rewiring Governs Immune Activation Across the Gut—Liver—Kidney Axis in Experimental MASLD 2303975

Abstract Introduction Metabolic dysfunction—associated steatotic liver disease (MASLD) often advances beyond hepatosteatosis to systemic immune dysregulation and kidney injury, yet the ways in which different dietary models reprogram immunometabolic circuits remain poorly defined. To test this, we directly compared two widely used MASLD models, prolonged high-fat diet (HFD) and the rapidly injurious choline-deficient, L-amino-acid—defined high-fat diet (CDAHFD), to delineate diet-specific immunopathogenic signatures. Methods C57BL/6 mice were fed either a 16-week high-fat diet (HFD) or an 8-week choline-deficient, L-amino-acid—defined high-fat diet (CDAHFD). We assessed systemic metabolic markers (ALT, AST, BUN, creatinine), histopathologic injury (H&E, Picrosirius Red, PAS), renal immune composition (Ly6C+ monocytes, dendritic cells, and T-cell subsets), and gut microbiota structure (16S rRNA sequencing analyzed with STAMP using Welch’s test). Results The CDAHFD regimen induced a hyperacute immunometabolic profile manifesting as profound hepatocellular damage and marked renal tubular degeneration. This pathological state was associated with a robust infiltration of CD11b+Ly6C+ inflammatory monocytes and cytotoxic CD8+ T cells–an immunophenotype distinct from that observed in the HFD cohort. Microbiome profiling identified a CDAHFD-specific dysbiosis defined by the expansion of Kineothrix alysoides, a taxon linked to gut barrier disruption and endotoxemia, suggesting a mechanism driving enhanced renal immune activation. In distinct contrast, HFD favored the retention of gut taxa implicated in the preservation of epithelial integrity, the attenuation of hepatic inflammation, and the modulation of renal immune responses. Conclusion Despite its shorter duration, CDAHFD provoked a markedly more aggressive and microbiota-amplified immunopathology across the gut—liver—kidney axis than HFD. These findings reveal diet-specific immune—microbial signatures that shape the MASLD—CKD trajectory. Funding Source 111-2314-B-A49-072, NSTC 112-2314-B-A49 -028 -MY3 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)