Browse Articles

Evaluating Bruton Tyrosine Kinase Inhibition in T-Cell Leukemia and Lymphoma Models 2258370

Abstract Introduction Bruton’s Tyrosine Kinase (BTK) is a cytoplasmic kinase best known for its role in B-cell receptor signaling, but aberrant activation of related kinase pathways has also been observed in T-cell malignancies. Targeting BTK and associated signaling nodes represents a potential therapeutic approach for T-cell cancers. This study investigates the effects of BTK inhibition on two T-cell models, Jurkat (human T-cell leukemia) and EL4 (mouse T-cell lymphoma), to assess cross-species responses and therapeutic relevance. Methods Jurkat and EL4 cells were cultured under standard conditions and treated with a selective BTK inhibitor. Cell proliferation was measured using colorimetric viability assays, and ELISA was used to evaluate phosphorylation of downstream signaling proteins. SDS-PAGE was performed to assess changes in protein expression patterns following inhibitor treatment. Results BTK inhibition decreased proliferation in both Jurkat and EL4 cells compared with controls. ELISA data indicated reduced phosphorylation of signaling intermediates associated with cell survival, and SDS-PAGE analysis revealed distinct shifts in protein banding consistent with suppression of kinase-dependent pathways. Conclusion These results suggest that BTK-related signaling contributes to proliferation in T-cell leukemia and lymphoma models. Continued experiments will further define the pathways affected by BTK inhibition and evaluate its potential as a therapeutic target in T-cell malignancies. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)

Multimodal Interrogation of Autoimmune Disease Patients Reveals Highly Diverse Biomarker Signatures 2259778

Abstract Introduction Autoimmune diseases (AIDs) like multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD) share common etiologies and are characterized by dysregulation of the immune system. Nonetheless, they are highly heterogenous disorders that are caused by distinct underlying mechanisms—termed endotypes. AID endotypes—each associated with genetic predisposition, treatment response, and altered molecular pathways—are emerging as clinical phenotypes. Endotype-driven diagnosis, prognosis and treatment rely on biomarkers to select the optimal therapeutic intervention. Methods In this study, we interrogated human plasma samples from AID patients (i.e., MS, SLE, and IBD) and age- and sex-matched healthy controls for biomarker signatures using multiple platforms. We assessed multiple serum protein using a Meso Scale Discovery (MSD)® platform, a high-sensitivity Quanterix® platform as well as O-Link® technology based on proximity extension. In addition, we employed unbiased mass spectrometry to evaluate the lipidome and the metabolome of the samples. Eventually, we integrated the obtained experimental data with available clinical metadata using DIABLO and analyzed the dataset to extract key predictive features with multiple regularization approaches such as elastic net. Results We demonstrated the establishment of a workflow for end-to-end data generation, from human sample acquisition to biomarker discovery and potential patient stratification, including an in-silico framework for data integration and analysis. In addition, we identified three inflammatory clusters among the analyzed patient samples indicating the underlying AID endotypes. Moreover, we found analytes that have significant discrimination power for biomarker discovery. Conclusion Multimodal characterization and analysis enable identification of relevant disease endotypes and clinically relevant biomarkers to support patient stratification for clinical studies. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)

Modulatory Effects of Mdivi-1 on OxLDL-Induced Metabolic Alterations, Inflammatory Responses, and Foam Cell Formation in Human Monocytes 2253928

Abstract Introduction Atherosclerosis, a leading cause of cardiovascular disease, is characterized by lipid accumulation and chronic inflammation within arterial walls, where oxidized low-density lipoprotein (OxLDL) plays a pivotal role. OxLDL promotes monocyte differentiation into foam cells and triggers metabolic reprogramming alongside pro-inflammatory signaling, thereby accelerating disease progression. Methods This study examined the effects of Mdivi-1, a mitochondrial fission inhibitor, and S1QEL, a selective inhibitor of complex I—associated reactive oxygen species (ROS), on OxLDL-induced responses in monocytes. Primary human monocytes isolated from healthy donors were treated with OxLDL in the presence or absence of Mdivi-1 or S1QEL and analyzed for metabolic alterations, cytokine expression, foam cell formation, and ROS generation. Results OxLDL treatment enhanced glycolytic activity (ECAR), increased expression of pro-inflammatory cytokines IL1B and CXCL8, and promoted foam cell formation accompanied by elevated mitochondrial ROS (mtROS). Both Mdivi-1 and S1QEL significantly attenuated OxLDL-induced glycolytic reprogramming, cytokine expression, foam cell formation, and mtROS production. Conclusion These findings indicate that Mdivi-1 and S1QEL effectively modulate key metabolic and inflammatory responses in OxLDL-treated monocytes, highlighting their therapeutic potential in atherosclerosis. Funding Source AHA, NIA Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)

TREM-1-mediated modulation of innate immune response in acute and chronic inflammation: Effect of treatment timing and cell specificity on outcome 2223031

Abstract Introduction Triggering receptor expressed on myeloid cells 1 (TREM-1) is a promising target in inflammation-related diseases such as cancer, sepsis, acute lung injury (ALI) and pulmonary fibrosis (PF). Myeloid cells, including neutrophils, monocytes and macrophages, may play dual roles in inflammation and diseases depending on the stage and context of the disease process. The aim of this study was to test my hypothesis that the outcome of TREM-1 blockade can be different depending on whether TREM-1 signaling is suppressed in all cells that express TREM-1 (pan-TREM-1 blockade) or only in specific cells (e.g., macrophage-restricted TREM-1 blockade). Methods Animal models of cancer, sepsis, ALI and PF were used to test ligand-independent TREM-1 inhibitory peptides GF9 and GA31 (the latter in a form of macrophage-targeted lipopeptide complexes, GA31-LPC) as pan-TREM-1 and macrophage-restricted TREM-1 inhibitors, respectively. Results In fully immunocompetent mice, macrophage-restricted but not pan-TREM-1 blockade overcomes pancreatic cancer (PC) resistance to PD-L1 blockade and synergizes with immunotherapy. In PC xenograft-bearing athymic nude mice, macrophage-restricted and pan-TREM-1 inhibitors both increase complete response rate and survival when combined with chemotherapy but exhibit opposing dependence on timing of treatment initiation. Pan-TREM-1 treatment is effective only when given with but not after chemotherapy. In contrast, macrophage-restricted TREM-1 treatment is effective only when given after but not together with chemotherapy. Critical dependence of the outcome on the type of TREM-1 inhibitor and treatment timing was also observed in animal models of sepsis and ALI but not PF. Conclusion In summary, this is the first direct evidence that pan-TREM-1 and macrophage-restricted TREM-1 blockades may differ in their therapeutic efficacy depending on the disease, timing of treatment initiation and the type and stage of inflammatory response. Funding Source This work was supported in part by grants R44CA217400 from the National Cancer Institute of (NCI), R43AR078110 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), R43GM128369 from the National Institute of General Medic Topic Categories Translational and Interventional Immunology (TI)

Reconstructing Immune Time from a Single Snapshot: The Single-Cell Brownian Bridge Framework for Reverse-Time Evolutionary Inference 2248645

Abstract Introduction Modeling the temporal evolution of the immune system remains a central yet unsolved challenge in computational immunology. While single-cell transcriptomics provides unprecedented cellular resolution, most analyses are confined to static distributions that lack true temporal context. We introduce Single-Cell Brownian Bridge (SCBB), a novel stochastic—deep learning framework that infers the hidden temporal dynamics of immune cell evolution from a single timepoint. Methods SCBB establishes a mathematical bridge between static molecular snapshots and continuous biological time. By representing immune state transitions as Brownian bridge diffusions constrained by biologically meaningful endpoints, and embedding these within a forward Markov process, SCBB enables reverse-time learning–the ability to reconstruct developmental or pathological immune trajectories backward from their mature states. This fusion of stochastic process theory and generative modeling transforms static scRNA-seq data into dynamic maps of immune evolution. Results Applied to human and murine immune datasets, SCBB reveals latent differentiation hierarchies, transition probabilities, and emergent attractor states underlying tolerance, aging, and autoimmunity. Conclusion By mathematically grounding biological time within probabilistic manifolds, SCBB represents a conceptual shift from snapshot-based inference to stochastic temporal reconstruction, opening a new avenue for decoding immune system evolution across lifespan and disease. Funding Source n/a Topic Categories Computational and Systems Immunology (COMP)

Electrostatic Potential Tuning by Low‐Volatility Halogenated Additive: Boosting PTQ10‐Based Binary OPV to Near 20% Efficiency with High Scalability

ABSTRACT The commercialization of organic photovoltaics (OPVs) is hampered by the trade‐off between high power conversion efficiency (PCE) and processability, particularly in thick‐film and large‐area fabrication. Herein, three halogenated diphenyl ether additives with similar structures but distinct physical properties, 1‐bromo‐2‐phenoxybenzene ( o ‐BPB), 1‐bromo‐4‐phenoxybenzene ( p ‐BPB), and 4,4′‐oxybis (bromobenzene) (BDPE), are selected to regulate the film‐forming process of the PTQ10: m‐ TEH system. Studies reveal that BDPE exhibits the lowest electrostatic potential (ESP), maximum electron delocalization, and highest decomposition temperature, enabling its retention in the drying film. Through dibromo‐induced negative ESP and π–π complementarity with m ‐TEH, BDPE forms directional noncovalent interactions that delay acceptor nucleation, suppress oversize phase separation, and promote ordered molecular stacking. This ESP‐driven interaction simultaneously optimizes the vertical phase distribution, enhances crystallinity, reduces energy loss, extends exciton diffusion lifetime, and accelerates charge transport while suppressing recombination. Benefiting from these synergistic effects, the BDPE‐based PTQ10: m ‐TEH device achieves a PCE of 19.80%, delivers a short‐circuit current density of 30.49 mA cm −2 at 500 nm thickness. BDPE also shows universality in various binary systems (20.11% PCE for D18:L8‐BO) and good processability in large‐area modules. This work provides an efficient strategy for low‐cost thick‐film OPVs, offering new theoretical and engineering pathways for their up‐scale production.

The transcription factor C/EBPβ promotes hyperglycemia-elicited glycolysis and liver cancer progression

Abstract Hyperglycemia and its related diseases, such as diabetes, dramatically accelerate cancer progression. However, the underlying mechanisms remain poorly understood, and the development of anticancer therapies based on them has largely stalled. Transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) is strongly associated with glucose metabolic disorders and cancer progression. Here we show that C/EBPβ is significantly upregulated in hepatocellular carcinoma patients previously diagnosed with diabetes. Notably, high glucose activates C/EBPβ transcription via ROS-dependent PERK-eIF2α-ATF4 signaling. Intriguingly, the LAP isoforms of C/EBPβ, but not the LIP isoform, upregulate key glycolytic effectors (GLUT1 and LDHA) and the oncoprotein HRAS, thereby promoting glycolysis and proliferation in liver cancer cells. Remarkably, hyperglycemia-accelerated hepatocellular glycometabolism and hepatocellular carcinoma progression in male mice are greatly prevented by hepatocyte-specific C/EBPβ deletion or Lucicebtide (ST101) treatment, a clinical phase-II C/EBPβ inhibitory peptide. Moreover, human C/EBPβ isoform LAP1 mimics the effect of hyperglycemia to boost hepatocellular glycometabolism and accelerate hepatocellular carcinoma progression. Thus, C/EBPβ is a critical regulator and potential therapeutic target for glucose-fueled cancer progression.

Serum factor regulation of mast cell desensitization following combined immunotherapy 2308953

Abstract Introduction Our laboratory recently developed cell culture systems allowing selective differentiation of MCs co-expressing tryptase and chymase (MCTC), similar to those residing in peripheral connective tissues, and expressing tryptase alone (MCT), the principal phenotype found in mucosal epithelium. Due to their in vivo location, MCT are likely central drivers of allergic responses in the airways and digestive tissues, but little is known about the differential sensitivity of each subset to both activation and desensitization. Methods To test this, we selectively differentiated MCT and MCTC from peripheral blood-derived CD34+ cells and sensitized them using patient serum samples from a recent study of cat allergic individuals evaluating effects of subcutaneous immunotherapy (SCIT), Tezepelumab (TEZE) treatment, or combined TEZE/SCIT. We then evaluated and compared MCT and MCTC activation via flow cytometry. Results Our findings indicated that MCT exhibit a striking increase in sensitivity to cat dander compared with MCTC. Both treatments in isolation lead to decreased MC activation, with TEZE limiting MC priming and SCIT limiting MC activation through blocking allergen recognition in an IgG-independent manner. Evaluation of the TEZE/SCIT group indicated that combined therapy leads to robust desensitization of both subsets to a greater degree than either therapy in isolation. Conclusion Use of combined therapies like TEZE/SCIT may provide necessary alternatives to more effectively target both MCT and MCTC. Funding Source NIH grant AI007306, Immune Tolerance Network, FASI Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

Modeling immune responses to autologous and allogeneic human stem cell-derived islet grafts in vivo 2332710

Abstract Introduction Stem cell-derived β cells offer a promising strategy for Type 1 diabetes (T1D) treatment, yet the mechanisms driving immune infiltration and graft rejection remain unclear. Using human immune system (HIS) mice, we sought to compare immune responses to autologous versus allogeneic iPSC-derived islet grafts and to test whether increasing the frequency of autoreactive T cells is sufficient to trigger insulitis in autologous grafts. Methods HIS mice were generated by engrafting human fetal liver CD34+ cells and thymic tissue with HLA-A2, -DR4 and -DQ8 alleles. Autologous or fully mismatched allogeneic iPSC-derived islets were transplanted under the kidney capsule. In subsets of mice, human T cells transduced with multiple islet antigen-reactive (IAR) TCRs were adoptively transferred. Fourteen-eighteen weeks after grafting, iPSC-derived islets were analyzed by imaging mass cytometry (IMC) and flow cytometry. Results Allogeneic grafts exhibited dense CD45+ immune infiltration, CD8+ T-cell enrichment, macrophage accumulation, and marked fibrosis and cellular proliferation. In contrast, autologous grafts showed minimal infiltration, limited fibrosis, and restricted proliferation. Despite robust engraftment and splenic persistence of IAR-TCR+ T cells, no detectable infiltration of these cells into autologous grafts was observed. Circulating human C-peptide remained stable in both settings, correlating with β-cell differentiation efficiency. Conclusion While allogeneic grafts undergo strong immune infiltration and tissue remodeling, autologous stem cell-derived islet grafts remain largely protected, even in the presence of autoreactive T cells, indicating that additional stimuli may be required to trigger autoimmune β-cell targeting in vivo. Funding Source ADA Postdoctoral Fellowship #1-25-PDF-01, JDRF 2-SRA-2022-1220-S-B Topic Categories Immune Mechanisms of Human Disease (HUM)

Interferon Regulatory Factor 5 modulates CD11b+ cell composition and NLRP3-related factors in emphysema pathogenesis 2258665

Abstract Introduction Although interferon regulatory factor 5 (IRF5) is known to play a central role in inflammation, its function in chronic obstructive pulmonary disease (COPD) remains unclear. Previous evidence revealed that IRF5 expression is elevated in the lungs of cigarette smoke (CS)—induced emphysema models. Methods We investigated the function of IRF5 in emphysema using Irf5-knockout (KO) mice. Alveolar destruction, inflammatory cell infiltration, cytokine levels, and pyroptosis-related gene expression were assessed in CS-induced emphysema. To further define immune cell contributions, Ly6C ++ (Ly6Chigh) monocytes and Ly6Chigh T cells from Irf5-KO mice were introduced into emphysema mice. Results Irf5-KO mice showed decreased alveolar destruction after CS exposure. NLRP3 expression was suppressed, and gasdermin D cleavage was altered in Irf5-KO mice, indicating a protective effect against pyroptotic cell death. Among CD11b+Ly6G+ population, CD244.2, a PMN-MDSC-associated marker, was significantly elevated in Irf5-KO mice following CS exposure although Siglec-E, a neutrophil-associated marker, was most highly expressed in CS-exposed WT mice compared to all other groups. Moreover, Ly6Chigh monocytes and Ly6Chigh T cells were more abundant in the lungs of Irf5-KO mice after CS exposure, and their transfer attenuated NLRP3 expression and alveolar damage. Conclusion Our findings highlight IRF5 as a critical regulator of emphysema pathogenesis through NLRP3-mediated pyroptosis, altered composition in CD11b+Ly6G+ populations, and modulation of Ly6Chigh-expressing immune cells. Targeting IRF5 may be a potential therapeutic strategy for COPD. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)

Ebola virus exploits host lncRNA LINC01740 to enhance ATF3 and suppress antiviral immune responses 2259953

Abstract Introduction Ebola virus (EBOV) causes a highly lethal hemorrhagic fever marked by uncontrolled cytokine release and impaired antiviral defense. EBOV primarily infects human macrophages, where uncontrolled replication reprograms host transcription and fuels hyperinflammation. Long non-coding RNAs (lncRNAs), potent regulators of transcription and immunity, remain largely unexplored in EBOV pathogenesis. We identified EBOV-induced lncRNAs co-regulated with transcription factors (TFs) in primary human macrophages, revealing a novel mechanism by which EBOV rewires host gene expression to promote immune suppression and persistence Methods Using the highly virulent EBOV (Mayinga variant), we infected primary human macrophages from nine donors. We compared protein-coding and lncRNA transcriptomes of EBOV-infected vs. MOCK-infected macrophages at 24- and 48-hours post-infection. Differentially expressed lncRNAs were correlated with adjacent protein-coding genes to infer cis-regulatory relationships. Functional validation used antisense oligonucleotides, CRISPR interference (CRISPRi), and inducible CRISPR—Cas13d knockdown, followed by qPCR, RNA-seq, and Western blotting Results EBOV infection triggered extensive remodeling of macrophage transcriptome. LINC01740 was strongly induced and tightly co-expressed with its neighboring gene, ATF3, a stress-responsive transcription factor known to repress antiviral signaling. LINC01740 knockdown reduced ATF3 expression in macrophages. ATF3 inhibition restored interferon-beta production, enhanced innate immune activation, and induced strong antiviral responses in EBOV-infected macrophages. Our data show that ATF3 impairs IFN-I responses in macrophages, contributing to immune paralysis Conclusion Our data revealed LINC01740 as a novel host lncRNA co-opted by EBOV to enhance ATF3 and suppress antiviral responses. Here we show a novel LINC01740—ATF3—IFN-I regulatory axis driving immune evasion and viral persistence, highlighting lncRNAs as potential antiviral therapeutic targets Funding Source n/a Topic Categories Viral Immunology (VIR)

Glucose Uptake by Germinal Center B Cells Selectively Sustains Autoimmunity While Sparing Responses to Foreign Antigens 2255581

Abstract Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that features persistent germinal center (GC) formation and pathogenic autoantibody production. While healthy GC B cells rely primarily on fatty acid oxidation for energy, we showed that blocking glycolysis with 2-deoxyglucose (2DG) selectively inhibited autoreactive, but not foreign antigen-specific, GC B cells. Here, we directly tested whether this glycolytic bias corresponds to an intrinsic requirement of autoimmune GC B cells. Methods We generated GC-specific GLUT1-deficient mice (GLUT1 f/f Aicda-Cre) on healthy C57BL/6 (B6-cKO) and autoimmune Sle1b (Sle1b-cKO) backgrounds. B6 and B6-cKO mice were subjected to five weeks of bm12-induced chronic graft-versus-host disease (cGVHD) or immunized once with NP-OVA/alum to model lupus-like and primary foreign-antigen responses, respectively. For recall responses, B6, B6-cKO, Sle1b, and Sle1b-cKO mice were primed and boosted with NP-OVA/alum. Splenocytes were analyzed by flow cytometry and serum anti-NP antibodies were assessed by ELISA. Results GLUT1 loss markedly reduced the expansion of GC B cells and T follicular helper cells, and eliminated autoantibody production in the cGVHD model, while GC and antibody responses to primary immunization with NP-OVA remained intact. In the recall cohort, GLUT1 deletion in Sle1b mice eliminated the expanded NP⁻ (autoreactive) GC B cell subset, reducing it to B6 levels, while NP+ GC B cell frequency and NP-specific antibody titers remained unchanged across B6 and Sle1b backgrounds. Conclusion Across primary and memory NP-OVA responses, GC B-cell GLUT1 is dispensable for foreign-antigen GC B cell frequency, class switching, and affinity maturation. In contrast, GLUT1 is selectively required to sustain autoreactive GC B cells. With current therapies still limited by broad immunosuppression, targeting B-cell metabolism may redefine lupus treatment, silencing autoimmunity while preserving host defense. Funding Source NIH/NIAID R37AI128901; NIH T32GM113896; NIH T32GM145432 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Transcriptional and post-translational regulation of B7-H4 2258098

Abstract Introduction Immune tolerance mechanisms are shared between cancer and pregnancy. By cross-analyzing single-cell RNA sequencing data from multiple human cancer types and the maternal—fetal interface, we found that B7-H4 (VTCN1) is highly expressed in both cancer cells and trophoblasts. Methods Genetic deficiency of B7-H4 led to immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 promoted breast cancer progression, accompanied by CD8+ T cell exhaustion, indicating that B7-H4 functions as an onco-fetal immune tolerance checkpoint. Results We found that progesterone induces B7-H4 expression in placental and breast cancer cells. The progesterone receptor (PR) binds to the -58 kb enhancer of the B7-H4 gene and drives its transcription through the PR—P300—BRD4 axis. Pharmacologic inhibition using a PR antagonist or BRD4 degrader enhanced the efficacy of immunotherapy in a murine B7-H4+ breast cancer model. These findings establish a mechanistic and biological link between the female sex hormone progesterone and onco-fetal immune tolerance via B7-H4, highlighting the PR—P300—BRD4 axis as a targetable pathway in B7-H4+ cancers. We next investigated the post-translational regulation of B7-H4. We discovered that ZDHHC3, a zinc finger DHHC-type palmitoyltransferase, palmitoylates B7-H4 at Cys130 in breast cancer cells, preventing its lysosomal degradation and sustaining B7-H4—mediated immunosuppression. Knockdown of ZDHHC3 elicited robust anti-tumor immunity and suppressed tumor progression in murine models. Moreover, the CDK4/6 inhibitor abemaciclib activated lysosomal pathways and promoted B7-H4 degradation. Abemaciclib treatment led to T cell activation and mitigated B7-H4—mediated immune suppression in preclinical tumor models. Conclusion Our study delineates transcriptional and post-translational mechanisms that regulate B7-H4 expression and stability, and identifies hormonal and lysosomal pathways as therapeutic strategies for targeting B7-H4+ cancers. Funding Source Supported by the NIH/NCI R01 grants (CA217648, CA123088, CA099985, CA193136, and CA152470), and the NIH/NCI through the University of Michigan Rogel Cancer Center (CA46592) to W.Z., and by the UTC-Yale Endowment to L.C.. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Translational control of T cell expansion and autoimmune responses by a non-conventional RNA binding protein 2252845

Abstract Introduction Naïve CD4+ T cells respond to antigenic stimulus and rapidly transition into active state by intensifying clonal expansion. To meet the bioenergetic demand for this energy-intensive process, CD4+ T cells modulate their transcriptional and translational regulatory mechanisms and fuel profound increase in protein production. However, unlike the transcriptional control, the translational layer of regulation that is at work and the molecular mechanisms underpinning the translational control in T cells remain elusive. AT-rich interactive domain 5a (ARID5a) is an unconventional RBP that primarily stabilizes the pro-inflammatory mRNA transcripts to drive the progression of autoimmune diseases such as EAE and rheumatoid arthritis. However, it remains completely unexplored whether Arid5a regulates protein synthesis in CD4+ T cells to drive autoimmune T cell-mediated responses. Methods Naive CD4+ T cells were activated from Wildtype and Arid5a-/- mice and the effect of Arid5a depletion on protein translation, proliferation and metabolism in T cells was assessed upon polyclonal CD4+ T cell activation as well as upon challenge with MOG- autoantigen. We used polysome profiling and molecular biology approaches to identify the mechanisms underlying the translational regulation by Arid5a. Results We uncovered that Arid5a associated with translation initiation factors, eIF4G and poly A binding protein (PABP) to enhance the translation efficiency of Myc and drive CD4+ T cell expansion. Despite the central role of mTORC1 in controlling protein synthesis, the translational control-mediated by Arid5a was mTOR-independent, suggesting an underappreciated pathway of translational regulation in CD4+T cells. Deficiency of Arid5a disrupted Myc protein production and MOG autoantigen-specific CD4+ T cell proliferation. Conclusion Our study reveals that Arid5a acts as an mTOR-independent translation facilitator and drives autoimmune CD4+ T cell responses. Funding Source n/a Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Chain‐Mobility‐Enabled 1D Lanthanide Coordination Polymer Glassy Scintillators for Underwater X‐Ray Videography

ABSTRACT Lanthanide(III) coordination scintillators feature efficient triplet harvesting and narrow‐band emission, making them promising for X‐ray imaging applications. However, their rigid coordination environments hinder melt‐processing into large‐area, transparent glassy scintillator screens. Herein, a “rigid‐node flexible‐linker” molecular design strategy that facilitates chain‐mobility‐enabled glass‐forming in lanthanide coordination scintillators by constructing one‐dimensional (1D) coordination chains is proposed. By integrating dibenzoylmethane antenna with flexible dual‐phosphine‐oxide linkers (OP‐Cn, n = 2, 4, 6, 8), a series of 1D Eu‐OP‐Cn coordination polymers is constructed, enabling the simultaneous realization of efficient ligand‐sensitized radioluminescence and the chain‐mobility required for vitrification, thereby allowing transformation from crystalline powders into glassy states. Benefiting from rigid local coordination environments that suppress nonradiative decay, crystalline Eu‐OP‐C2 exhibits a near‐unity photoluminescence quantum yield (97.5%) and an ultrahigh relative light yield of 70379 photons MeV −1 . Besides, elongating the alkyl‐chain length increases segmental flexibility, allowing Eu‐OP‐C6/C8 to form water‐stable, transparent glassy scintillators via melt‐quenching method. Notably, Eu‐OP‐C8 glass delivers radioluminescence intensity 12.1 times higher than Bi 4 Ge 3 O 12 , enabling high‐resolution X‐ray imaging (> 30 lp mm −1 ) and real‐time underwater X‐ray videography (2K, 60 fps). Moreover, this strategy is readily extendable to Tb 3+ , Sm 3+ and Dy 3+ , establishing a general molecular‐design paradigm for melt‐processable lanthanide coordination glassy scintillators.

Deep-learning-enabled multi-omics analyses for prediction of future metastasis in cancer

Targeting the Adenosine—Adenosine Deaminase-1 Axis to Restore HIV-Specific CD8+ T Cell Function 2309228

Abstract Introduction Despite suppressive antiretroviral therapy (ART), HIV reservoirs rapidly rebound upon treatment interruption, driven in part by progressive dysfunction of HIV-specific CD8+ T cells. Current strategies targting CD8+T cell dysfunction in cancer show limited benefit in people living with HIV (PLWH), underscoring the need for alternative approaches tailored to the unique immunological landscape of HIV infection. Adenosine (ADO) signaling is a potent immunoregulatory pathway regulated by adenosine deaminase-1 (ADA-1) that becomes dysregulated in PLWH and is associated with viral persistence. However, more work is needed to define its direct contribution to HIV-specific CD8+ T-cell dysfunction. Methods Using primary samples from PLWH, we applied three complementary approaches: (1) multi-omic and phenotypic profiling of tetramer-sorted HIV- and CMV-specific CD8+ T cells to assess regulation of ADA and ADO-signaling components; (2) ex vivo functional assays measuring cytokine production and degranulation following ADO or 2-chloroadenosine exposure with ADA-1 inhibition; and (3) CD8-targeted lipid nanoparticles (CD8-ADA-LNPs) to selectively deliver ADA-1 mRNA and assess functional improvement. Results HIV-specific CD8+ T cells exhibited repression of the ADA locus, increased expression of CD39 and the A2a adenosine receptor, indicating potential heightened sensitivity to ADO-mediated suppression. Functionally, ADO-exposure impaired CD8+ T-cell function, dependent on ADA-1. Targeted ADA-1 mRNA delivery via CD8-ADA-LNPs restored ADA-1 expression and improved antigen-specific CD8+ T-cell function in PLWH ex vivo. Conclusion These findings identify dysregulated ADO signaling and ADA-1 deficiency as contributors to HIV-specific CD8+ T-cell dysfunction and establish targeted ADA-1 delivery as a novel strategy to enhance CD8+ T-cell function. This approach provides a framework for targeting ADO-mediated immune suppression of CD8+T cells in HIV and other disease landscapes, including cancer. Funding Source Part of this work was funded by NIH grant to Dr. Elias K Haddad (# U19AI128910-04S1) Topic Categories Translational and Interventional Immunology (TI)

Antibodies in Guillain-Barré syndrome, the immune system’s double-edged sword 2332889

Abstract Introduction Campylobacter jejuni is a leading cause of bacterial gastroenteritis worldwide, and a majority of isolates express an outer layer of lipooligosaccharides (LOS) that mimic human gangliosides. In approximately 1:1,000 cases of C. jejuni infection, there is a breakdown of self-tolerance resulting in antibody generation against the LOS mimics that cross-react with gangliosides found abundantly on human neurons. Opsonized neurons are then destroyed via complement and phagocyte recruitment, leading to the autoimmune paralysis known as Guillain-Barré syndrome (GBS). Our lab has observed a subset of former GBS patients possess high levels of circulating anti-ganglioside IgG one decade after recovery. Methods Serum was collected from GBS patients (acute phase and post-GBS), C. jejuni-only enteritis patients, and healthy donors. We then assessed anti-ganglioside responses via ELISA. Additionally, immune responses were analyzed by western blotting and opsonophagocytosis assays using C. jejuni-expressing ganglioside-mimicking LOS. IgG glycosylation was analyzed via liquid chromatography-mass spectrometry (LC-MS). Results Circulating anti-GM1 antibodies were observed in 10% of GBS recovered donors, 3% of healthy donors, and 0% of enteritis donors. Anti-GM1 positive sera cross-reacted with GM1-mimicking LOS and significantly killed C. jejuni at higher levels than anti-GM1 negative sera. LC-MS analyses indicate a shift towards anti-inflammatory carbohydrate modifications on IgG in the recovered donors. Conclusion Through understanding the differences in immune responses in acute-phase versus recovered GBS patients, improved therapeutics for GBS treatment can be developed. Funding Source NIAID R21AI175925, DoD CDMRP PR181475 Topic Categories Basic Autoimmunity (BA)

Defining the Stress—Gut Microbiome Interplay in Anti-Tumor B Cell Response 2247381

Abstract Introduction Chronic psychological stress is a major driver of cancer progression, yet its effects on anti-tumor B cell immunity remain unclear. Activation of the hypothalamic—pituitary—adrenal axis elevates glucocorticoids that broadly suppress immune responses. Given that the gut microbiota supports germinal center (GC) B cell differentiation, stress-induced dysbiosis may impair B cell—mediated tumor immunity. Methods Mice were subjected to a 21-day chronic unpredictable mild stress (CUMS) regimen. MC38 or B16F10 tumor cells were implanted on day 7, and tumor growth was monitored. Microbiota dependence was tested using broad-spectrum antibiotics, germ-free housing, and monocolonization. Tumor-associated bacteria were isolated and identified by culturomics, 16S rRNA sequencing, and whole-genome analysis to detect prophage activation. CAFs were stimulated with bacterial DNA ± TLR9 antagonist. Interventions included intratumoral TLR9 blockade and localized antibiotic treatment. Human colorectal tumors were analyzed for intratumor corticosterone and GC B cell abundance. Results Chronic stress significantly accelerated tumor growth and suppressed GC B cell responses. These effects were abrogated under antibiotic or germ-free conditions, indicating microbiota dependence. Stress enabled translocation of a gut pathobiont into tumors, where its phage-derived DNA activated TLR9 in cancer-associated fibroblasts, inducing local corticosterone synthesis. This intratumor glucocorticoid suppressed GC B cells and antibody responses. Blockade of the phage—TLR9 pathway restored B cell activity and prevented stress-induced tumor progression. Human colorectal tumors exhibited elevated corticosterone and reduced GC B cells, supporting clinical relevance. Conclusion Chronic stress triggers a microbiota-dependent phage—TLR9—glucocorticoid circuit that suppresses B cell immunity and accelerates tumor growth. Targeting this axis restores anti-tumor B cell function and mitigates stress-driven cancer progression. Funding Source CRI Irvington Fellowship Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Opa1 Regulates iNKT Cell Differentiation Through Control of TCR Signaling 2260028

Abstract Introduction Invariant natural killer T (iNKT) cells are innate-like T cells with rapid effector functions. Distinct metabolic programs support their differentiation and function. We found that iNKT cells exhibit higher mitochondrial content, activity, and a punctate morphology compared to conventional CD4+ T cells. Notably, the mitochondrial fusion regulator Opa1, but not the fission factor Drp1, is specifically required for iNKT cell differentiation: NKT1 and NKT17 subsets are markedly reduced in Opa1-deficient mice, whereas NKT2 cells remain unaffected. Methods We used complementary approaches, including conditional genetic models, flow cytometry, thymic organ culture, confocal imaging, and transcriptomic analyses, to dissect how mitochondrial dynamics influence iNKT cell development and signaling. Results The differentiation defect is cell-intrinsic and not rescued by Bcl-XL overexpression. Opa1 loss leads to increased mitochondrial volume and decreased membrane potential, indicating dysfunction supported by transcriptional changes. Metabolic reprogramming accompanies this defect, with increased Glut1 expression and 2-NBDG uptake, while LDHA appears to compensate for Opa1 loss. TCR signaling is impaired: NF-κB, AP-1, and mTOR activities are reduced, whereas PLZF and Egr2, downstream of Ca²+/NFAT, are elevated. Consistently, TCR-induced Ca²+ flux is altered. Remarkably, simultaneous loss of Opa1 and Drp1, which induces mitochondrial stasis, partially restores iNKT cell homeostasis, proliferation, and TCR signaling in Opa1-deficient cells. Conclusion These findings uncover a critical role for Opa1-mediated mitochondrial dynamics in coordinating TCR signaling and metabolic programs that shape iNKT cell differentiation. Funding Source NIH Topic Categories Hematopoiesis and Immune System Development (HEM)