Browse Articles

PD-L2 blockade alters myeloid cells and could promote innate behavior in T cells to treat melanoma in the aged host in mechanisms distinct from αPD1 2250522

Abstract Introduction Overall, immune checkpoint blockade (ICB) response remains low at ∼15%, indicating better treatment options are needed. ICB requires IFNγ for maximum efficacy but mechanisms for its elicitation are incompletely defined, and effects differ in young versus aged. Methods We published that aged mice but not young mice use IL17 to generate IFNγ with αPDL2 ICB. We hypothesized that IL17 induces innate-like IFNγ and that aged hosts were more susceptible to such behavior in adaptive cells. We used agonists for CD134 and CD137, αCTLA4, or cytokines (IL2+IL33) to elicit innate behavior in adaptive T cells in vitro and/or in vivo in young or aged immune cells. We generated scRNA-seq data from intra-tumoral immune cells in melanoma bearing aged-hosts and show αPDL2-driven alterations to melanoma infiltrating immune cells in the aged host, distinct from isotype or αPD1 treated hosts. Results In vitro, αCD134+αCD137 or IL2+IL33 elicited innate IFNγ and increased Eomes expression in CD4 and CD8 T cells as expected, and IL17 augmented the effect. Young mice with melanoma do not respond to αPDL2, but CD134 + CD137 agonists or αCTLA4 elicited αPD-L2 efficacy, with the former increasing CD8 T cell IFNγ and Eomes, consistent with augmented innate IFNγ from adaptive cells. In aged mice that respond to αPDL2 alone, scRNA-seq analysis showed αPD-L2 increases CD4 and γδ T cell abundance accompanied by a striking decrease in S100A9Hi cell abundance and other myeloid cell effects, distinct from αPD-1. Thus, myeloid cells could contribute to these effects. Conclusion PDL2 is a strong ICB target, distinct from PD-1 in important ways including myeloid cell effects and mechanisms of IFNγ induction unique from other ICB thus far, and αPDL2 could be used in rational combinations to overcome ICB resistance. Funding Source Gmelich chair and Guyre funds Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Characterization of endoglycosidase enzymes for treating autoimmune and inflammatory diseases 2257105

Abstract Introduction IgG-specific endoglycosidases offer a novel approach to modify IgGs and eliminate their effector function. These enzymes remove glycans from the Fc region of immunoglobulins, disrupting their binding to FcγRs and complement. This mechanism presents a promising treatment strategy for autoimmune and inflammatory diseases driven by autoantibody effector functions. Methods IgG binding to FcγRIIa and FcγRIIb-expressing cell lines, or primary monocytes, was measured following endoglycosidase treatment using flow cytometry. Immune complex-mediated cell activation was assessed in vitro using a reporter cell line incubated with aggregated IVIg following treatment. A mouse model of immune thrombocytopenia was used to examine the impact of endoglycosidase treatment on antibody effector functions. Results Our research demonstrates that an endoglycosidase effectively removes glycans from all human IgG subtypes. Glycan removal results in diminished binding to FcγRIIa and FcγRIIb-expressing cells, as well as reduced immunoglobulin binding to CD14+ monocytes in human whole blood. In vitro, endoglycosidase treatment of aggregated IVIg reduced SHIP-1 recruitment mediated by immune complex binding to FcγRIIb-expressing cells. Moreover, in a mouse model of immune thrombocytopenia, endoglycosidase treatment showed efficacy when administered both prophylactically and therapeutically. Conclusion To advance bacterial-derived endoglycosidases as therapeutics, T/B cell epitope removal is essential. At Seismic, we have developed an IMPACT platform that identifies and predicts immunogenic epitopes, supporting the development of bacterial-derived proteins. Funding Source N/A Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Innate Immune Sensing of HIV Defective Provirus Transcripts Contributes to Chronic Inflammation 2266501

Abstract Introduction The persistent HIV reservoir includes latently infected cells, which upon antiretroviral treatment (ART) interruption, reactivate HIV-1 expression and fuel rebound of disease progression. People living with HIV, even on ART, experience chronic inflammation associated with accelerated aging and comorbidities of the central nervous system, gut, and heart. The persistent reservoir is mostly composed of defective proviral genomes, unable to produce infectious virus due to deleterious mutations. However, the contribution of these defective viruses to chronic disease has not been well characterized. We have demonstrated that an intragenic element in the Env region of the HIV genome drives transcription of non-canonical RNA in defective proviruses. We hypothesize that these transcripts from defective proviruses contribute to chronic inflammation. Methods To model defective proviruses, we used CRISPR-Cas9 to engineer cells harboring HIV genomes with a nonfunctional 5’ LTR. Results We observed a correlation between levels of internally driven transcripts and in vitro pro-inflammatory cytokine production in Jurkats, macrophage-like ThP1 cells, and cells differentiated into macrophages. Additionally, we confirmed nuclear export of these transcripts and that shRNA-mediated MAVS knockdown in ThP1s decreases the inflammatory response. Conclusion We propose a model that innate immune sensing of these transcripts activates a MAVS-dependent pathway to contribute to chronic inflammation and HIV-associated comorbidities. Funding Source NIH RO1 AI187175, NIH RO1 AI138960, NIH RO1 DA055488, CFAR P30AI042853, Boston University Undergraduate Research Opportunities Program Faculty Matching Grant Topic Categories Viral Immunology (VIR)

MRGPRX2 Activation Triggers a Distinct Transcriptional Response That is Enriched in Chronic Spontaneous Urticaria and Atopic Dermatitis Lesions 2251623

Abstract Introduction MRGPRX2 is a mast-cell-specific G protein-coupled receptor that triggers rapid degranulation. Abnormal activation of MRGPRX2 has been implicated in chronic spontaneous urticaria (CSU) and atopic dermatitis (AD). Affected skin shows signs of mast cell degranulation, and endogenous MRGPRX2 agonist levels correlate with disease severity. Evidence for MRGPRX2-driven biology in disease, however, remains limited and motivated further study by transcriptomics. Methods We performed RNA sequencing of the LAD2 human mast cell line after stimulation with MRGPRX2-dependent and -independent agonists. Our analysis focused on identifying transcriptional changes specific to activation with MRGPRX2 agonists, and yielded an MRGPRX2 activation-specific signature. This signature was queried in public CSU and AD bulk and single-cell transcriptomic datasets. Results We identified an MRGPRX2 activation gene signature in LAD2 mast cells, distinct from complement C3a receptor or high-affinity IgE receptor (FcεR)- induced changes, which was validated using qPCR. MRGPRX2 activation signature was enriched specifically and consistently in CSU wheals and AD lesions, but not healthy adjacent skin, in multiple independent datasets. Furthermore, MRGPRX2 activation signature scores correlate with disease severity scores in AD. Conclusion MRGPRX2 activation is enriched in diseased skin from CSU and AD patients, and its inhibition has potential to address unmet clinical need. Funding Source n/a Topic Categories Computational and Systems Immunology (COMP)

Impact of a Modernized Immunology CURE on Undergraduate Student Learning and Scientific Literacy 2310320

Abstract Introduction Course-Based Undergraduate Research Experiences (CUREs) are effective tools that give students unique insights into the scientific process and opportunities to build creativity, analytical, and technical skills. CUREs also boost student retention in STEM fields and build stronger scientific literacy and communication skills. A successful CURE depends on many factors such as research topic, instructor, and even classroom dynamic, however access to modern equipment and facilities severely limits potential projects in the undergraduate setting. Designing an Immunology CURE is inherently difficult and complex due to reliance on sensitive equipment, expensive reagents, and limitations to facilities. This CURE was developed with those concerns in mind, all while giving students exposure to cell culture methods and assays utilizing the established THP-1 monocyte cell line. Additionally, the CURE was designed to encourage students to explore their own ideas and research questions with the hypothesis that doing so would significantly improve learning outcomes, science literacy and science communication. Methods On week 1, students toured our facilities and reviewed scientific literature through an assignment and guided discussion. Over the course of 13 weeks, students learned fundamental methods such as ELISA, immunofluorescence, apoptosis and phagocytosis assays via flow cytometry, and viability assays. Students presented their research findings at our annual research symposium. Results Feedback showed students responded well to the CURE, with most reporting stronger motivation and attachment to their project than in other science courses. Sentiment on belonging and confidence presenting a poster were also significantly higher. Conclusion This CURE was designed to give students a pertinent and modern Immunology research experience. Although many challenges still exist, the benefits were shown to be powerful and, in some cases, life-changing for the students. Funding Source n/a Topic Categories Immunology Education and Communication (EDU)

A Dipole‐Confined Charge Transport Paradigm for Ultrahigh‐Temperature Dielectric Polymers

ABSTRACT A pervasive challenge in materials science, the incompatible trade‐off among breakdown strength ( E b ), thermal stability ( T g ), and dielectric constant ( ε r ), has limited the development of polymer dielectrics for extreme‐environment film capacitors. Here, this trilemma is overcome via a dipole‐regulation strategy, confining polar methyl‐sulfonyl groups within a rigid semi‐aromatic polyimide framework using flexible methylene linkers. This dipole confinement domain structure of sulfonyl‐methylene‐benzene decouples dipolar response from charge transport: the flexible linkers enable polarization, while the rigid semi‐aromatic framework localizes charges and suppresses conduction. It results in a stable dipole network, yielding a material (STPCB‐PI) with a wide bandgap (4.38 eV) and a record T g (>400°C). It achieves a high ε r of 5.8, a modulus of 6.7 GPa, and exceptional energy storage, delivering 12.00 J cm −3 with 97% efficiency at 25°C, 9.98 J cm −3 with 94% efficiency at 150°C, and retaining 8.62 J cm −3 with 90% efficiency at 200°C, 293% improvement over the state‐of‐the‐art commercial polyetherimide. Even at 250°C, it maintains 4.24 J cm −3 with 93% efficiency. It also exhibits excellent self‐healing and cyclic endurance. This work sets a new performance benchmark and establishes a generalizable design paradigm that reconciles the intrinsic conflict between polarization and insulation in high‐temperature dielectric polymers.

Nitric Oxide Conjugation Transforms NIR‐II AIEgens Into Potent Hypoxia‐Tolerant Type I Photosensitizers

ABSTRACT Near‐infrared (NIR)‐activated type I photosensitizers (PSs) with aggregation‐induced emission (AIE) properties are highly attractive for photodynamic therapy (PDT) of deep‐seated and inoperable tumors. However, most NIR‐activated AIEgens, especially donor–acceptor–donor (D‐A‐D) benzobisthiadiazole derivatives, are mainly used for bioimaging and photothermal therapy due to their intrinsically small S 1 →S 0 energy gaps (Δ E S1‐S0 ) severely limiting reactive oxygen species (ROS) generation. Here, we present a strategy to convert widely adopted D‐A‐D NIR‐activated AIEgens into NIR‐activated type I PSs by conjugating nitric oxide (NO) to the electron‐donating units. Upon NO conjugation, the resulting compounds NO‐T‐TQT and NO‐2TT‐ o C6B become efficient generators of NIR‐activated hydroxyl radical (•OH), exhibiting a 13.2‐fold and 5.4‐fold increase in superoxide (O 2 •− ) production compared with their parent molecules, respectively. In contrast, T‐TQT, 2TT‐ o C6B, and related analogues produce negligible ROS and no detectable •OH. Mechanistic studies reveal that NO conjugation narrows the singlet‐triplet energy gap, strengthens spin‐orbit coupling to enhance intersystem crossing, optimizes redox potentials to favor electron transfer, and lowering hydrogen atom affinity. NO‐2TT‐ o C6B nanoparticles achieved potent in vitro cytotoxicity and effective in vivo tumor ablation under NIR irradiation. This work establishes a general approach to transform conventional NIR‐activated D‐A‐D AIEgens into high‐performance type I PSs, significantly advancing their clinical potential in PDT.

Thermally Modulated Metasurface Sensor for Dynamic and Time‐Resolved Isolation of Extracellular Vesicles

ABSTRACT Extracellular vesicles (EVs) are nanoscale lipid‐bilayered structures that mediate intercellular communications by transporting nucleic acids, proteins, and lipids across diverse biological fluids. Their diagnostic potential is immense, yet their heterogeneity poses persistent challenges for isolation and characterization, often leading to low yield, co‐isolation of contaminants, and vesicle damage. Here, we present a thermoresponsive polymer–integrated plasmonic metasurface sensor that enables spatiotemporally controlled, label‐free EV isolation. The metasurface, engineered by repurposing nanograted optical disks, was functionalized with poly( N ‐isopropylacrylamide) (PNIPAM) and anti‐CD63 antibodies to achieve selective EV capture at physiological temperature and gentle release upon a minute thermal change near the polymer's lower critical solution temperature (∼35°C). Using MCF‐7 and HEK‐293–derived EVs as a proof‐of‐concept, the platform exhibited a dynamic detection range spanning three orders of magnitude. Release efficiency reached 87.03 ± 23.5%, while both nanoparticle tracking analysis (NTA) and fluorescent NTA (fNTA) revealed up to ∼100‐fold increase in EV purity relative to the ultrafiltration process. Electron microscopy and Western blotting confirmed preserved vesicle morphology and marker expression. By integrating thermoresponsive chemistry with a cost‐effective metasurface platform, this system offers a non‐destructive, portable, and real‐time solution for precise EV manipulation, advancing EV‐focused biosensing and point‐of‐care strategies for liquid biopsy applications in the future.

Intermediate filament protein vimentin propels intrahepatic lipid accumulation in insulin-resistant mice

Prognostic impact of pathological complete response in hormone receptor–positive/HER2-negative breast cancer treated with neoadjuvant chemotherapy: a multicenter cohort study

Lactation-induced granulopoiesis and pulmonary epithelial remodeling enhance maternal antiviral defense 2259314

Abstract Introduction During pregnancy, the maternal systemic immune system shifts toward tolerance to safeguard the semi-allogenic fetus. However, how the maternal immune system adapts during lactation, a critical yet poorly understood stage across barrier tissues, where infections are most likely to occur, remains poorly understood. Methods We employed a murine timed-pregnancy model, combined with flow cytometry, imaging, and transcriptomic profiling to examine lung epithelium-immune crosstalk across reproduction. We further investigate maternal susceptibility to common respiratory viral and bacterial infections. Results We identified neutrophils as a unique expanded population in the lungs of lactating dams, increasing up to 3-fold in number compared to non-lactating and pregnant controls. Lung neutrophil induction was specific to lactation, increasing in the bone marrow, followed by recruitment into the pulmonary vasculature. Transcriptomic analysis revealed that the lung epithelium upregulated numerous innate defense pathways, including sulfactant, mucus, antimicrobial peptide, and complement production, and neutrophil recruitment. Strikingly, during lactation, lung neutrophils displayed heightened antiviral signatures. As a result of immune and epithelial remodeling, lactating dams exhibited reduced viral burden and improved survival following respiratory viral infection. Conclusion Our work reveals that lactation induces distinct and previously unrecognized remodeling of the pulmonary immune and epithelial landscapes. Such adaptations enhance maternal defense against respiratory pathogens and may represent a strategy to compensate systemic immunosuppression and survive in a pathogen rich environment at such a critical stage in life, protecting both the mother and offspring. Ongoing work focuses on dissecting the contributions of microbiota and hormones, and examining the conservation of these adaptations in marmoset and sugar glider models. Funding Source Princeton University Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

B cell intrinsic Ube2l3 is central to spontaneous germinal center formation and autoimmunity 2308393

Abstract Introduction UBE2L3, a ubiquitin-conjugating enzyme, is associated with increased susceptibility to systemic lupus erythematosus (SLE) and other autoimmune diseases. Spontaneously developed germinal centers (Spt-GCs) generate pathogenic autoantibodies (Auto-Abs) that promote SLE. Here, our goal is to elucidate the previously unknown B cell-intrinsic role of Ube2l3 in Spt-GC, auto-Ab responses, and systemic autoimmunity. Methods We generated B-cell-specific Ube2l3-deficient mice (FcR2bKO.Ube2l3BKO) on an SLE-prone FcR2bKO background. We determined spontaneous and imiquimod (a TLR7 ligand)- induced autoimmune and foreign antigen-driven B and T cell responses using flow cytometry. Auto-Ab forming cells (AFCs) and auto-Ab titers were measured by ELISpot, ELISA, and Hep-2 assays. C3 and IgG immune complex (IC) deposition in the kidneys was examined by immunofluorescence. Results B cell intrinsic Ube2l3 deletion resulted in significantly reduced splenomegaly, Spt-GC, Tfh cell, age-associated B cell, and auto-Ab responses, and kidney IC deposition and glomerulonephritis. While marginal zone B cells were increased, the pathogenic CD138+TACI+CD19-B220+ plasma cells were reduced in the spleen and bone marrow of Ube2l3BKO mice. These results were recapitulated in the TLR7-induced SLE model. In contrast, Ube2l3 deletion in B cells did not overtly affect foreign antigen-specific B cell and Ab responses. Conclusion We report for the first time that B-cell-intrinsic Ube2l3 is required for Spt-GC formation and SLE-autoimmunity development. Funding Source 080-03000-S52001 Topic Categories Basic Autoimmunity (BA)

Pathologic thymic atrophy caused by porcine reproductive and respiratory syndrome virus (PRRSV) infection is time- and pathogenicity-dependent 2242731

Abstract Introduction Pathologic thymic atrophy disrupts immune developmental processes in the thymus and can have short- and long-term negative impacts on immunity. Porcine reproductive and respiratory syndrome virus (PRRSV) causes thymic atrophy in pigs, yet progression of PRRSV-induced thymic atrophy and dependency on pathogenicity of infecting PRRSVs has not been well defined. Methods Time- and pathogenicity-dependent features of PRRSV-induced thymic atrophy were established by analyzing thymi collected from pigs infected with variable pathogenicity PRRSVs at 2, 6, and 10 days post-infection. Collected tissues were analyzed via whole genome sequencing and microscopic assessments. Results Microscopically, PRRSV detection, corticomedullary blurring, cell depletion, and apoptosis became more severe as post-infection time progressed and was exacerbated by more pathogenic PRRSVs. Gene expression changes detected via whole transcriptome sequencing increased with post-infection time and were exacerbated by more pathogenic PRRSVs. Gene set enrichment analysis for cell type-specific gene signatures suggested gene changes occurred due to thymocyte depletion, which was supported by microscopic assessment. Conclusion Results demonstrate synergistic dynamics of post-infection time and PRRSV pathogenicity in causing more severe thymic atrophy through microscopic and transcriptional alterations. Future work may address what the short- and long-term immune repercussions of PRRSV-induced thymic atrophy are and what specific viral attributes contribute to more severe thymic atrophy caused by highly pathogenic PRRSVs. Funding Source USDA ARS project #5030-32000-230-000-D Topic Categories Veterinary and Comparative Immunology (VET)

Waldenström macroglobulinemia cells as models for the regulation of human IgM 2252298

Abstract Introduction Waldenström macroglobulinemia (WM) is a B cell lymphoma distinguished by the overproduction of a monoclonal IgM antibody and the lack of class switch recombination (CSR). Despite the presence of apparently normal CSR machinery, it remains unknown why WM B cells fail to undergo CSR or what mechanisms regulate the overproduction of IgM. To date, three WM cell lines (BCWM.1, MWCL-1, and RPCI-WM1) have been generated from different patients. Each cell line secretes a monoclonal IgM, though at varying levels. The regulation of human IgM transcription relies on studies of polyclonal B cells from tonsils or peripheral blood, making it challenging to study regulation at the transcriptional level. Methods Through bulk RNA sequencing of B cell receptors (BCRs), we have identified V, (D), and J gene segment usage in the heavy (H) and light (L) chains of each cell line. We performed PacBio HiFi whole-genome sequencing on each WM cell line to verify the regions spanning the immunoglobulin loci and their associated regulatory regions. Results BCR sequencing identified a single dominant IGH and IGK/L rearrangement in each line, consistent with their clonal origin, along with only infrequent secondary rearrangements (< 30 reads). The ratio of light- to heavy-chain (L:H) transcripts ranged from 20—100 across the cell lines and correlated with the level of secreted IgM. Analysis of the PacBio data confirmed that the intronic regulatory sequence between the rearranged VDJ and constant regions is conserved in BCWM.1 and RPCI-WM1 but is disrupted by a gap in MWCL-1. Methylation profiles derived from the PacBio kinetic signals were broadly similar across the IGH region in all three cell lines, indicating that large-scale methylation differences are unlikely to account for variation in IgM expression. Conclusion The availability of monoclonal WM cell lines, coupled with BCR and PacBio sequencing, provides a platform to study the regulation of human IGH. Funding Source n/a Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Mechanisms Underlying Increased Susceptibility and Severity of Bacterial Keratitis in Diabetic Mice 2257255

Abstract Introduction Diabetic patients have a higher incidence of infections, with increased severity and a higher prevalence of multidrug resistance. This study was to investigate the role of programmed cell death (PCD) pathways as an underlying mechanism for increased susceptibility and severity of bacterial keratitis in diabetic C57BL/6 mice. Methods Streptozotocin-induced diabetic (DM) C57BL/6 mice were inoculated with Pseudomonas aeruginosa (Pa), and the PCD pathways in the control, normoglycemic mice and STZ-treated mice were determined by immunohistochemistry using antibodies that detect the active forms of Caspase-8 (intrinsic apoptosis) and RIPK3 (necroptosis). The role of PCD pathways was determined by Casp8 and RIPK3 inhibitors. The therapeutic effects of targeting necroptosis were assessed using RIPK3 and HMGB1 inhibitors as adjunctive treatments, concomitantly applied with antibiotics to eliminate the invading bacterial pathogen. Results At 1-day post-infection (dpi), hyperglycemia increased neutrophil but suppressed macrophage infiltration. While in the control corneas, cleaved casp8 was stained strongly in NL, phosphor-RIPK3 was mostly detected in DM epithelial layer and stromal infiltrates. Inhibition of caspase activity worsens the outcome of keratitis, whereas blocking RIOPK3 prevents Pa infection in NL and greatly reduces the severity of keratitis in DM corneas. At 16 h post-infection, concomitant application of RIPK3 inhibitor or cell impermeable inhibitor HMGB1, a prototype of alarmin released from lytic PCD pathways, reduced lingering inflammation in Pa-infected corneas at 3 dpi. Conclusion Hyperglycemia skews apoptosis towards necroptosis, leading to exacerbated bacterial keratitis in B6 mice. Preventing or reversing this PCD shift may serve as an adjunct therapy for treating microbial keratitis in diabetic patients. Funding Source NIH grants R01 EY035785, EY010869, and RPB Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

RNF144A enforces IL-2-STAT5 dominance over RAF-ERK-MAPK signaling in antiviral CD8 T cells 2309113

Abstract Introduction IL-2 is central to CD8 T cell responses and signals via JAK-STAT5, RAF-ERK-MAPK, and PI3K-AKT pathways, but how STAT5-dominant output is enforced from this shared receptor is unclear. We hypothesized that uncharacterized IL-2-induced, STAT5-regulated E3 ubiquitin ligases sculpt this signaling hierarchy to optimize antiviral CD8 T cell function. Methods RNA-seq of human CD8 T cells stimulated with IL-2 ± JAK inhibition plus STAT5 ChIP-seq identified IL-2/STAT5-regulated ubiquitin genes. Rnf144a-/- mice and mixed bone marrow chimeras were used to define CD8-intrinsic roles during influenza infection. RNF144A localization and substrates were mapped by biochemical and imaging assays, and whole-blood transcriptomes from patients with moderate or severe influenza were analyzed to relate RNF144A expression and gene signatures to clinical severity. Results IL-2 broadly remodeled the T cell ubiquitin program, with RNF144A emerging as the most strongly induced STAT5-bound E3 ligase. RNF144A localized to the plasma membrane, associated with IL-2Rβ and STAT5, and enhanced STAT5 recruitment and phosphorylation, sustaining STAT5-dependent transcription. In parallel, RNF144A acted as a bona fide E3 ligase that directly polyubiquitinated RAF1 for degradation, reducing ERK activation and thereby preserving JAK-STAT5 dominance over RAF-ERK-MAPK output. CD8 T cells from Rnf144a-/- mice showed impaired IL-2-induced effector gene expression, degranulation, and cytokine production, and CD8-intrinsic deficiency in mixed chimeras reduced antigen-specific responses and worsened weight loss and lung inflammation after influenza infection. In human influenza, RNF144A expression was reduced in severe disease, inversely correlated with an ERK-MAPK target gene signature, and discriminated severe from moderate cases with performance comparable to established severity markers. Conclusion RNF144A is an IL-2-STAT5-induced E3 ligase that enforces STAT5-dominant signaling and limits viral immunopathology. Funding Source N/A Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Loss of the microbiota unleashes harmful T cell responses against dietary antigen induced by enteric viruses 2221043

Abstract Introduction Celiac disease (CeD) is a complex disorder characterized by an inflammatory Th1-dominated CD4+ T cell response to gluten. CeD incidence has been rising in industrialized nations since the 1970s; it is not understood why, though studies have implicated viral infections and microbiome disruption in early life. In mice, specific enteric viruses have been shown to distort the response to dietary food antigen from a tolerizing pTreg-dominated to a Th1-dominated CD4+ response, perhaps the key priming event in CeD development. The microbiota can affect enteric viral replication and inflammatory potential, but how interplay between viruses and the microbiota shape dietary antigen responses is not understood. Given the frequency of broad-spectrum antibiotic administration to infants, there is strong potential for coincidence of enteric infections and microbiota disruptions during the critical period of gluten tolerization. Methods CD45.1+ OTII cells were transferred into mice either given antibiotics or maintained in GF conditions, then mice were gavaged with virus and exposed to new dietary antigen. OTII differentiation and cytokine production, as well as delayed-type hypersensitivity reactions, were examined in the treated mice. Results When the microbiota was removed, either in antibiotic-treated or germ-free mice, a normally innocuous reovirus became capable of driving strong Th1 polarization on dietary antigen reactive CD4+ T cells. Furthermore, the effects of enteric viruses harmful under normal conditions were also magnified by antibiotic treatment. This amplification was dependent on inflammatory cytokine production by a specific classical DC2 subset regulated by short-chain fatty acid GPCR signaling within the gut. Conclusion This suggests that the microbiota can protect against aberrant dietary antigen responses, and that early life antibiotic treatment may contribute to CeD initiation. Funding Source NIH T32 Training Grant Topic Categories Mucosal and Regional Immunology (MUC)

A Co-expression Network Identifies a Dominant Immune-Activation Module Predicting Severity in Nasal Polyps 2310328

Abstract Introduction Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease of the upper airway, yet the molecular pathways underpinning nasal polyps (NP) immunopathogenesis and endotypic diversity remain incompletely understood. Methods We profiled tissue bulk RNA-seq from 88 NP and 317 ethmoids from CRS. Weighted gene co‑expression network analysis (WGCNA) identified NP-associated modules, followed by differential expression and functional enrichment. Results WGCNA revealed six NP-associated modules compared to ethmoids, and the blue module was most NP-associated. Blue-module pathways were enriched for cytokine/chemokine receptor signaling, hematopoietic regulation, and immune differentiation, consistent with type 2 and mixed inflammatory programs. GSEA further highlighted cell adhesion/activation, leukocyte and mononuclear cell migration, actin filament organization, and GPCR signaling, supporting coordinated immune trafficking and epithelial—immune crosstalk in NP progression. Blue-module PPI mapping converged on SYK/BTK-centered B cell/Fc receptor signaling, integrin—ICAM1 adhesion/migration, and epithelial cytoskeletal remodeling. In addition, this module showed the strongest link to radiographic severity, correlating with Lund-Mackay (r = 0.60, p < 0.001), indicating that the coordinated immune gene expression best predicts disease burden. Conclusion Bulk transcriptomic network analysis identifies a dominant NP immune-activation program that reflects type 2 and mixed type 2/3 inflammation and shows the strongest association with radiographic disease severity. This module-level signal better captures disease burden than individual biomarkers and underscores coordinated epithelial—immune interactions–highlighting SYK/BTK signaling and integrin/ICAM1-mediated adhesion/migration alongside epithelial remodeling–as key drivers of polyp progression. Funding Source R01 AI134952, R01 DC016645, CRISP2 P01 AI145818. Topic Categories Immune Mechanisms of Human Disease (HUM)

Decoupling Activation and Preservation: Architectural Design Principles of Organic Frameworks for Selective Photocatalytic Methane Oxidation

ABSTRACT Photocatalytic methane (CH 4 ) conversion faces a dilemma, where C─H bond activation requires a substantial oxidative driving force, whereas partially oxidized C 1 products are intrinsically more susceptible to further oxidation. As a result, strengthening photocatalytic throughput while avoiding overoxidation remains challenging in the field of highly valuable CH 4 conversion. Organic semiconductor platforms, including polymeric carbon nitrides (PCN), metal–organic frameworks (MOFs), and covalent organic frameworks (COFs), exhibit structural features that fundamentally differ from those of conventional inorganic counterparts. Their electronic states originate from molecular building units, and their frameworks allow controlled positioning of redox centers, modulation of charge‐transfer pathways, and definition of pore environments, enabling systematic regulation of band energetics, carrier distribution, oxygen activation modes, and proton management of photocatalysts. This review examines how electronic structure engineering, interfacial charge routing, reactive species control, and microenvironment design influence pathway selection in CH 4 photooxidation. Particular attention is given to mechanisms that favor associative multi‐electron oxygen reduction or energy‐transfer processes while suppressing hydroxyl radical ( • OH)‐dominated chemistry. Although CH 4 ‐specific systems remain limited, mechanistic insights from related photocatalytic reactions provide transferable design principles. Establishing quantitative relationships between architectural parameters and reactive‐species identity is essential for advancing selective solar‐driven C 1 oxidation.

Splicing dependency between EIF4G2 introns is mediated by exon definition and relies on a downstream splicing event