Browse Articles
Discover research articles across all indexed journals
Caging Lithium Deposition: High‐Entropy Metal–Organic Framework Interfaces for Anode‐Free Batteries
ABSTRACT Anode‐free lithium metal batteries (AF‐LMBs) offer high energy density systems and simplified design through the complete elimination of excess lithium. However, their practical development is hindered by sluggish lithium‐ion (Li + ) transport and uneven lithium deposition at the anode interface. Here, we introduce a nanoconfined ion‐regulator based on a high‐entropy metal–organic framework (HE‐MOF). The simulation results demonstrate that the multi‐metal channels provide heterogeneous local coordination environments, broadening the distribution of Li + binding sites, facilitating Li + migration, suppressing local ion retention, and regulating interfacial electrolyte decomposition, ultimately leading to the formation of a thin LiF‐rich SEI layer. As a result, the Li||HE‐MOF/C half‐cell delivers an initial Coulombic efficiency of 97.74% at 0.5 mA cm −2 , the HE‐MOF/C@Li symmetric cell exhibits stable cycling for over 10000 h at 60 mA cm −2 /1 mAh cm −2 , and the anode‐free HE‐MOF/C||NCM‐811 full cell remains stable for 2300 cycles with a capacity decay rate per cycle of 0.026%. This work provides a proof‐of‐concept high‐entropy MOF interfacial strategy for regulating Li deposition in AF‐LMBs.
Epigenetic Tumor Suppressor KMT2D Shapes the Immune Landscape in Pancreatic Cancer 2335260
Abstract Introduction KMT2D (known as Mll4 in mice) is a histone methyltransferase and a critical epigenetic regulator frequently mutated across a range of cancers. TCGA data indicate alterations in KMT2D, including mutations and changes in expression, in approximately 11% of pancreatic cancer patients. Our previous research showed that KMT2D loss in human pancreatic cancer cells induces epithelial-to-mesenchymal transition (EMT), promoting aggressive disease progression. We hypothesized that KMT2D loss not only drives intrinsic tumor changes but also remodels the immune microenvironment. Methods We performed bulk RNA sequencing on Mll4 knockdown mouse pancreatic cancer cells (KPC7940) and proteomic profiling of their conditioned media to identify changes in secreted proteins. Pathway analysis focused on TNF-alpha/NF-kB, IL-6/JAK/STAT3, and IL-2/STAT5 signaling. A pancreas-specific Mll4 knockout model (KPCM: KrasG12D/+; Trp53R172H/+; Ptf1a-Cre; Mll4SETflox/flox) was generated to assess tumor progression in vivo. Tumor proliferation was evaluated by Ki-67 immunohistochemistry. Single-cell RNA sequencing was used to characterize the immune microenvironment in KPC and KPCM tumors. Results KPCM mice developed pancreatic cancer by 3 weeks compared to 16—20 weeks in KPC controls, with median survival of 24 vs 126.5 days. Ki-67 staining confirmed higher proliferation in KPCM tumors. Bulk RNA-seq and proteomic analysis revealed altered expression of secreted proteins enriched in inflammatory and immunomodulatory pathways. Single-cell RNA sequencing showed increased myeloid populations and NK/T cells expressing immunosuppressive markers, including CTLA4, CD274, and PDCD1, in KPCM tumors. Conclusion KMT2D plays a pivotal role in orchestrating both tumor-intrinsic and microenvironmental processes that drive pancreatic cancer progression. Understanding how KMT2D loss reprograms the immune landscape may uncover novel immunomodulatory therapeutic targets for pancreatic cancer. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Effects of dietary fiber on the intestinal humoral immune response via interactions with the microbiota 2260105
Abstract Introduction The Western diet, rich in fats and low in fermentable fibers, has been associated with a range of immune-mediated inflammatory diseases. Dietary fiber is the main energy source for gut bacteria, promoting a rich microbial diversity. We have previously demonstrated that microbiota changes induced by a low-fermentable fiber diet (LFF) impair the development of several intestinal T cell populations. However, the importance of dietary fiber for the intestinal humoral immune system is less understood. Secretory IgA (sIgA) is essential for maintaining gut microbiota homeostasis. Methods Here, we show that sIgA is significantly reduced in the small intestinal and fecal contents of mice fed a low fiber diet compared to mice fed a standard chow (SC). Results IgA secretion by PC is not impaired, as shown by ELISA of culture media from sorted IgA+ PC from SC and LFF-fed mice. However, flow cytometry and ELISpot assays revealed that low IgA levels are due to a reduction in numbers of small intestinal lamina propria IgA+ PC in LFF-fed mice, while other isotypes are not affected. Using T cell deficient mice, we demonstrate that LFF diet reduces T-dependent, but not T-independent, sIgA. Conclusion Future studies will elucidate how changes in the microbiota and dietary fiber result in the loss of IgA+ PCs. To this end, time-stamping of PC will allow to track survival and turnover rate in LFF and control mice. These results provide insight into the interactions between fiber, the microbiota, and B cell responses, and further our understanding on how diet modulates the mucosal immune response. Funding Source 5R01DK129950 Topic Categories Mucosal and Regional Immunology (MUC)
T cells play a protective role in maintaining spinal health after intervertebral disc injury 2308705
Abstract Introduction The intervertebral disc (IVD) is an essential joint of the spine that is prone to injury and exhibits limited regenerative capacity, leading to degeneration and chronic back pain. While T cells are known mediators of tissue repair, the specific T cell subtypes that infiltrate the IVD following injury remain poorly defined. We previously demonstrated a temporally oscillatory T cell response after IVD injury in C57BL/6J mice, with reduced degeneration associated with γδ T cell infiltration in females only (Clayton et al., 2024). In other tissues, γδ T cells promote repair following injury; however, their presence and role in the IVD have not been explored. We hypothesize that T cells, particularly γδ T cells, are essential for IVD repair. Methods Using a mouse model of accelerated IVD degeneration, control (non-injured) and injured (needle puncture) IVDs were harvested from the same female, 4-month-old female C57BL/6J wildtype (WT) mice, WT mice treated with TCRγγ-depleting or IgG control antibodies, and T cell knockout (TCRβγKO) mice (n = 3/group). IVDs were analyzed by Safranin O/Fast Green histology (n = 3—4) and flow cytometry (n = 3). Deidentified human IVD tissue was collected from female patients undergoing spinal fusion surgery (n = 3). Results Histological analyses revealed significantly increased injury-induced degeneration in TCRβγKO mice compared to WT controls. Depletion of TCRγγ more severely exacerbated degeneration relative to IgG-treated and TCRβγKO injured mice. Comparative analyses of WT mouse and human samples showed similar proportions of infiltrating CD3+ T cells following injury, with CD4⁻CD8⁻ double-negative T cells comprising the largest population; γδ T cells represented the majority of this subset. Conclusion Collectively, these data demonstrate that γδ T cells infiltrate the injured IVD and play a protective role against degeneration. Loss of γδ T cells worsens injury-induced degeneration, indicating a key immunomodulatory function in maintaining IVD integrity following injury. Funding Source Burroughs Wellcome Fund PDEP Award, Skeletal Disorders Training Program T32 AR060719 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)
CD1d Modulation Influences Tumor Immune Crosstalk in Triple-Negative Breast Cancer (TNBC) through NKT and Macrophage Interaction 2257312
Abstract Introduction TNBC remains an aggressive malignancy with immunosuppressive microenvironment. The lipid antigen-presenting molecule CD1d, a key regulator of Natural Killer T (NKT) cell activation, was found to be overexpressed in TNBC and can be a useful therapeutic target. Methods TNBC cells (MDAMB231 and MDAMB468) and monocytes (THP-1) were treated with CD1d modulators Zerumbone (ZER), α-Galactosylceramide (AGC), and Thymosin Alpha 1 (TA). We employed Immunofluorescence, flow cytometry and western blotting to assess CD1d. Cell adhesion, proliferation assays were performed using the RTCA method. For the NKT cell isolation from human PBMCs, we have used NKT isolation kit. Coculture assays were performed with NKT cells and TNBC cells as well as THP-1. The ELISA technique was used to assess cytokine secretion and correlated with NKT activation. Results Our findings identified differential CD1d isoform expression between the two TNBC cell lines and demonstrated that CD1d modulators ZER, AGC, and TA significantly alter tumor proliferation, migration, and angiogenesis in vitro. We compared CD1d expression in TNBC cell lines, revealing differential CD1d (37 kDa) and (48 kDa) isotypes. CD1d siRNA knockdown in both cell lines reduced these oncogenic phenotypes (proliferation, EMT and angiogenesis), confirming CD1d’s tumor-intrinsic effects. To further investigate the immunological context of CD1d modulation, co-culture of TNBC cells with human NKT cells and macrophages (THP-1 derived). CD1d upregulation by AGC and TA enhanced IFN-γ release in NKT co-cultures with TNBC cells, whereas ZER reduced IFN-γ secretion. Conclusion CD1d modulation differentially regulates TNBC immune interactions. ZER acts as a CD1d antagonist and may be beneficial in immunosuppressive TNBC with low NKT activity. In contrast, AGC and TA can be useful in killing TNBC cells through NKT mediated cytotoxicity through CD1d upregulation. CD1d modulators may therefore serve as novel therapeutic agents to reshape the TNBC immune microenvironment. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Enhancing Immunology Learning through Team-Based Learning (TBL): A Multi-Cohort Study in Undergraduate Medical Education 2267327
Abstract Introduction Immunology is perceived as a challenging subject in medical education due to its abstract concepts, cross-disciplinary integration, and evolving clinical relevance. Traditional lectures may not effectively support the development of higher-order thinking or clinical reasoning. Team-Based Learning (TBL) offers a structured, active learning strategy designed to foster critical thinking, collaboration, and applied understanding. This study evaluated the impact of TBL on student performance in immunology across the preclinical years of a six-year undergraduate medical program. Methods Data were collected from four student cohorts (2019—2023). Weekly TBL sessions were integrated into years 2—4, covering foundational topics (innate/adaptive immunity) and system-based modules (e.g., respiratory, renal, gastrointestinal, hematologic, and body defense). All sessions and assessments were administered via ExamSoft. Students were grouped as Regular Attendees (≥80% TBL attendance) or Non-Regular Attendees (< 60%). Performance was assessed using internal end-of-semester immunology assessments and the IFOM exam at year 4.5, focusing on immunology-specific items. Statistical analyses included t-tests and multivariate regression. Results Among 362 students (132 Regulars, 230 Non-Regulars), Regular Attendees scored significantly higher across internal assessments and showed >30% higher immunology scores on IFOM (p < 0.001). Their IFOM performance also exceeded the global average for international medical graduates. TBL participation was an independent predictor of improved performance, even after adjusting for GPA and prior academic achievement. Conclusion Structured TBL significantly improves immunology understanding, as evidenced by higher internal assessment scores and superior outcomes on the standardized IFOM examination. These findings support the use of TBL as a pedagogical approach to improve comprehension in complex and concept-heavy disciplines like immunology in medical education. Funding Source n/a Topic Categories Immunology Education and Communication (EDU)
ScRNA-seq Analysis of Olfactory Epithelium in Chronic Rhinosinusitis with Nasal Polyps 2261022
Abstract Introduction Olfactory epithelium inflection is associated with olfactory dysfunction, but the specific target cells and regulatory mechanisms in chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear. Methods To explore cellular and molecular mechanism underlying olfactory dysfunction in CRSwNP, we performed single-cell RNA sequencing (scRNA-seq) on superior turbinate tissues from 4 control subjects and 3 CRSwNP patients following endoscopic sinus surgery. Results We profiled 32,367 cells and distinguished key epithelial cell types, including olfactory epithelium cells (sustentacular, Bowman’s glands, horizontal basal cells, microvillar, and olfactory sensory neuron-like cells) and respiratory epithelium cells (ciliated, seromucous glandular, goblet, ionocytes, and tuft cells). Immune cells such as B cell, T cell, NK, myeloid, mast cells were also identified. Lipocalin 15 (LCN15) and other target proteins were significantly decreased in CRSwNP and may be associated with olfaction dysfunction. GSEA indicated revealed distinct signaling pathway enriched in CRSwNP, suggest disease-specific molecular dysregulating affecting olfactory function. Conclusion scRNA-seq of CRSwNP tissues reveals diverse epithelial populations and highlights altered pathways potentially driving olfactory dysfunction. These findings offer new insight into disease mechanisms and may inform future therapeutic strategies. Funding Source R01 AI134952, R01 DC016645, P01 AI145818 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
Measurement of the Reduction of OC-43 Coronavirus Production by Natural Killer Cell Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) 2260991
Abstract Introduction The expression of OC-43 coronaviral proteins in the plasma membranes of infected cells [that are needed to support antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells] occurs at the same time that virions begin to be released from infected cells. The viral production in the absence of ADCC or cytotoxic T cell death will continue for many days more. We queried the impact of early ADCC on unaffected total viral production. Methods We utilized the cold-causing, endemic human coronavirus OC-43, a virus in the same subfamily as SARS-CoV-2. We used NK-92-CD16A lymphocytes as killer cells, OC-43 from BEI Resources at an moi of 2, plasma antibodies from infected children, and infected lung A549 cells as ADCC ‘targets’. Viral production was monitored by PCR of virions released into the cell-free supernatants and by virions remaining inside cells. We used a Taqman probe from ThermoFisher for a propriety site within the positive RNA OC-43 virus, calibrating assays with genomic OC-43 RNA from BEI. Results We found that PCR products began to appear in the cell-free supernatants on day 2 post infection (pi) and increased on subsequent days. These viral RNA signals coincided with our previous times for first susceptibility to ADCC and first detection of plasma membrane viral protein in the A549 cells. At day 3 pi, ADCC could eliminate most infected cells. OC-43 gene copies in the supernatants were 16.8 million on day 3 and 24.2 million on day 5 post infection, indicating that some virion production can be curtailed by early ADCC. Conclusion While substantial viral production before day 3 is observed, ADCC on day 3 reduced the subsequent production by over 75%. Additional conclusions are premature without assessment of infectious virions (by plaque forming units or other means) but the data indicate that early ADCC will substantially reduce the spread of coronaviral infections. Funding Source This poster was made possible by a grant from the National Institute of General Medical Sciences (GM103440) from the National Institutes of Health and by the T34 GM145539 grant awarded to the University of Nevada, Reno Institute for Neuroscience (MARC program), and the UNR foundation. Topic Categories Viral Immunology (VIR)
Strong Adhesives Mediated by Dynamic Phase‐Locking
ABSTRACT Nature has long inspired the design of reversible smart adhesives; however, achieving both high adhesion strength and switchability remains a significant challenge, particularly for emerging applications (e.g., soft robotics and wearable electronics). Herein, we introduce switchable phase‐locking‐mediated adhesives (SPAs) that leverage high‐density hydrogen bonds to deliver ultrahigh adhesion (up to 15 MPa). The underlying mechanism involves dynamic phase‐locking mediation that harmonizes interfacial adhesion with bulk cohesion through interfacial mechanical locking and strain‐induced phase separation. This strategy optimizes performance across the complete adhesion lifecycle, including spreading, adhering, and debonding via temperature/force‐mediated phase‐locking. Through detailed molecular analysis of the SPA system, we uncover the mechanistic basis of ultrahigh adhesion and establish design guidelines applicable to future smart adhesive development.
IFNαR1/R2 heterodimer recombinant protein significantly enhanced Type 1 IFN binding and induced diverse antibody responses in mice 2260333
Abstract Introduction Type I interferons play a crucial role in regulating immune responses through the IFNα/β receptor (IFNαR). IFNαR is a heterodimer complex composed of IFNαR1 and IFNαR2 subunits on the cell surface. Binding of the ectodomains (ECDs) of the dimeric receptor is critical for the cytokine to initiate signaling cascade. To mimic the dimeric receptor conformation, we engineered a novel cis-heterodimer IFNαR1/R2 protein for human IFNαR using the ECDs of IFNαR1 and IFNαR2. Methods IFNαR1 and IFNαR2 ECDs were fused with a heterodimer motif at the C-terminus of each chain. The recombinant IFNαR1/R2 heterodimer protein was expressed/purified from HEK293 cells. The IFNαR1/R2 protein bioactivities were evaluated for binding of specific antibodies and Type I interferon by ELISA and surface plasmon resonance (SPR). To evaluate the immunogenicity, mice were immunized with IFNαR1/R2 protein. The IFNαR1/R2-specific antibody responses in mice were measured by ELISA. IFNαR1/R2-specific monoclonal antibodies (mAbs) were generated by hybridoma technology. Results The IFNαR1/R2 heterodimer protein could potently bind to the IFNαR1 and IFNαR2 specific antibodies and Type I interferon as measured by ELISA and SPR. Notably, the dimeric form of IFNαR1/R2 dramatically enhanced the binding to the interferon by > 50 fold as indicated by EC50 and KD values, compared to the monomeric receptor proteins. Mouse immunogenicity study demonstrated that the IFNαR1/R2 heterodimer protein induced high titers of antibody responses against both IFNαR1 and IFNαR2 subunits. The mAbs generated from immune mouse B cells exhibited diverse IgG profiles and binding specificities against both IFNαR1 and IFNαR2 subunits and heterodimer alone. Conclusion The engineered IFNαR1/R2 heterodimer mimics the IFNα/β receptor native conformation with better bioactivities and can generate diverse antibodies by immunization. This innovative IFNαR1/R2 heterodimer protein is a valuable new molecule for basic immunology research and drug discovery. Funding Source n/a Topic Categories Cytokines and Chemokines and their Receptors (CCR)
Dysregulated Myelopoiesis and Altered Neutrophil Metabolism in Obese Adults: A Role for Glutaminase in Hypoxia-Induced Cell Survival 2260130
Abstract Introduction Obesity is associated with myelopoietic dysfunction, metabolic abnormalities, and low-grade inflammation. This study investigated myeloid cell subpopulations and neutrophil behavior in obese versus non-obese adults, correlating findings with metabolic and inflammatory markers. Methods Blood was collected from obese (BMI 32-51 kg/m², n = 12) and normal weight (BMI 21-24 kg/m², n = 9) participants aged 45-65 years (76% female), excluding those with diabetes, acute infection, or overt kidney/liver disease. Complete blood counts, hemoglobin A1c (A1c), c-reactive protein (hs-CRP), and metabolic panels were performed. Myeloid cell populations were analyzed by flow cytometry, quantifying absolute numbers and surface expression of toll-like receptor 4 (TLR4) and interleukin-1 receptor (IL1R). Neutrophils were cultured under normoxia (18% O2) or hypoxia (1% O2), with/without metabolic inhibitors, to assess the impact of obesity on spontaneous neutrophil death. Results Obese participants exhibited increased monocytes associated with a higher percentage of HLA-DRlow monocytes. After excluding adults over 60 years, eosinophil counts and TLR4 expression on immature CD10- neutrophils were elevated in obese individuals, as was IL-1R expression on total and classical monocytes. Increased A1c (5.9±0.1% vs. 5.3±0.1%), hs-CRP (9.01±3.33 vs. 0.69±0.17 mg/L), and alkaline phosphatase were observed in obese participants. In vitro, hypoxia reduced neutrophil death in both groups; however, this effect was more pronouncedly blunted by glutaminase inhibition in neutrophils from obese participants. Conclusion This study demonstrates dysregulated myelopoiesis in obesity — characterized by altered IL-1R expression on monocytes, increased HLA-DRlow monocytes, and elevated TLR4 expression on immature neutrophils — alongside metabolic differences. Ex vivo neutrophil culture suggests an enhanced role for glutaminase in regulating neutrophil death under hypoxic conditions in obese individuals. Funding Source NIGMS Topic Categories Immune Mechanisms of Human Disease (HUM)
Self-reactive CD4+ T cells display diverse differentiation in health and gain stem-like features in rheumatoid arthritis 2308930
Abstract Introduction Self-reactive T cells have long been associated with autoimmune diseases, yet they are also a physiological component of the peripheral immune repertoire in healthy individuals. Beyond regulatory T cells, little is known about the phenotypic and functional features that restrain self-reactive T cells in healthy and how these features change in disease, which is critical for understanding immune tolerance failure in rheumatoid arthritis (RA). Methods We used a ferritin-based peptide—MHC II multimer platform (spheromers) to capture rare self-reactive T cells and performed high-dimensional phenotypic analyses comparing them with SARS-CoV-2 spike- and influenza hemagglutinin (HA)-specific T cells in pre-2021 blood samples from healthy donors (HD). Phenotypic and functional comparisons between HD and RA patients were assessed using in vitro T cell and antigen-matured dendritic cell co-culture assays. Results Spheromers captured significantly more self-reactive cells than conventional tetramers. In HD, self-reactive CD4+ T cells displayed predominantly memory phenotypes enriched for Tregs and CXCR5⁻PD-1+TIGIT+ Tph-like cells, distinct from pre-exposure spike- and post-exposure HA-specific populations. To examine pathologic changes, we identified self-reactive T cells in RA patients and compared them to HD. Although overall frequencies were similar, self-reactive T cells in RA were enriched for naïve-like subsets, suggesting increased stemness. Consistent with this, naïve T cells responded to the autoantigen citrullinated +-Enolase. +-Enolase—reactive T cells from the naïve pool exhibited greater differentiation plasticity than non-naive counterparts and proliferated more robustly, generating proinflammatory TIGIT+ cytokine-producing cells in RA compared to HD. Conclusion Together, these data reveal diverse states of self-reactive CD4+ T cells in health and identify stem-like self-reactive T cells in RA that give rise to inflammatory progeny and may sustain pathologic self-reactivity. Funding Source n/a Topic Categories Basic Autoimmunity (BA)
Dietary Reversal of Dyslipidemia Ameliorates CD1b-Autoreactive T Cell-Mediated Skin Inflammation 2257438
Abstract Introduction Unconventional group 1 CD1 (CD1a, b, and c)-restricted T cells recognize self/microbial lipid antigens and play important roles in autoimmunity and host defense. Dyslipidemia, characterized by abnormal plasma lipid levels, can modulate conventional T cell responses by altering their metabolism and effector functions. We hypothesis that dyslipidemia may also affect the function of CD1-restricted self-lipid-reactive T cells through changes in the quantity and quality of various lipid species. Methods We utilized a double-transgenic mouse model expressing human group 1 CD1 and CD1b-restricted autoreactive TCR (HJ11Tg) on a Rag-deficient and LDL receptor (LDLR)-deficient background (HJ1Tg/hCD1Tg/Rag-/-/LDLR-/-) to investigate the impact of diet-induced dyslipidemia on CD1b-autoreactive T cells. Mice were fed either a normal chow (NC) or a high fat diet (HFD) for eight weeks. In the diet-switch group, HFD-fed mice were returned to NC for an additional three weeks. Results Diet-induced dyslipidemia markedly enhanced HJ1 T cell activation, proliferation, IL-17A production, leading to neutrophil-mediated skin inflammation. Switching from HFD to NC significantly alleviated skin inflammation, accompanied by reduced HJ1 T cell activation, proliferation, and IL-17A-driven neutrophil infiltration. RNA-seq analysis of skin tissues revealed up-regulation of genes associated with inflammation, neutrophil chemotaxis, cell cycle, and wound healing in HFD-fed mice, as compared with NC and diet-switch groups. Conclusion These findings demonstrate that CD1b-restricted autoreactive T cells mediate a reversible, lipid-driven skin pathology, highlighting the dynamic link between dyslipidemia and immune regulation. Funding Source NIH grants R01 AI057460 and R01 AI180031 Topic Categories Basic Autoimmunity (BA)
Decoding the Role of Resident Tissue Macrophages in Controlling Local Iron Levels and Supporting Organ Function 2309623
Abstract Introduction Iron is an essential micronutrient for nearly all organisms, yet how its balance and distribution are maintained at the tissue level remains poorly understood. We propose that vasculature-associated macrophages (VAMs), a specialized population of resident macrophages, centrally regulate iron homeostasis within adipose tissue. Although traditionally associated with host defense, resident macrophages–including VAMs–likely perform important non-immune functions that are not yet fully appreciated. Gene expression profiling reveals that VAMs possess the full molecular machinery for iron import, export, processing, and storage. These findings support our hypothesis that VAMs act as key regulators of adipose tissue iron content, sensing local metabolic demand and adjusting iron availability to maintain tissue homeostasis. Methods We use macrophage-specific mouse models, along with flow cytometry, confocal imaging, inductively coupled plasma mass spectrometry, and physiological stimuli that induce lipolysis and thermogenesis in visceral adipose tissue. Results Our preliminary data indicate that VAMs are the most efficient adipose tissue cell type for importing transferrin-bound iron from the circulation and serve as major intracellular iron reservoirs. When adipose tissue undergoes high bioenergetic activity, VAMs increase their uptake of transferrin-bound iron and enhance iron mobilization to support elevated tissue demands. Conversely, disrupting iron storage in VAMs reduces iron availability to neighboring stromal cells and diminishes their capacity to activate during energetically demanding processes such as lipolysis. Conclusion This work expands our understanding of how the immune system contributes to tissue physiology beyond classical host defense, specifically by defining the mechanistic roles of resident tissue macrophages in upholding iron homeostasis at tissue level. Funding Source Howard Hughes Medical Institute Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
Tbet+CD11c+ B cells depend on CD36 for expansion and effector function during obesity 2258257
Abstract Introduction CD21- CD23- CD11c+ Tbet+ B cells expand in primary immune and peripheral tissues during chronic conditions such as aging, autoimmune diseases, and obesity. These antigen experienced B cells largely produce IgG2a/c autoantibodies which exacerbate autoimmunity and metabolic dysfunction, positioning them as a promising therapeutic target. Typically, Tbet+ CD11c+ B cells expand in vitro and in vivo in response to a combination of TLR agonists, cytokines, and CD4+ T cell help, but the nature and coordination of signals involved in their expansion and effector function remain poorly understood. We have discovered that Tbet+ CD11c+ B cells express high levels of class B scavenger receptor and fatty acid translocase CD36. CD36 is capable of innate signaling, antigen uptake and metabolic reprogramming, all of which could be contributing to B cell activity. Methods This project combines unique mouse strains engineered to lack CD36 selectively in B cells with high fat diet-induced obesity or bm12 autoimmune mouse models. We are determining the relative contribution of CD36 to Tbet+CD11c+ B cell expansion and effector function. Results Mice lacking CD36 in B cells fail to expand inflammatory CD11c+Tbet+ B cells or accompanying splenic TFH/TPH cells to the same level as BWT controls during high fat diet-induced obesity. HFD-fed obese mice lacking CD36 on B cells also develop significantly lower levels of anti-oxLDL and anti-dsDNA IgG2c autoantibodies than WT control mice. This effect may extend to additional effector functions including antibodies and cytokine production. We will also determine if Tbet+ B cell dependence on CD36 extends to cGVHD lupus mice. Conclusion Elaborating a better understanding of signals employed by CD36 during expansion and function of CD11c+Tbet+ B cells will allow targeted clinical interventions and could improve immune responses to vaccination or infection for patients with obesity, autoimmunity, or related chronic inflammatory conditions. Funding Source The Flow Cytometry Shared Resource at UT Health San Antonio is supported by the National Cancer Institute (P30CA054174) through the Mays Cancer Center, the Cancer Prevention and Research Institute of Texas (CPRIT) (RP210126), the National Institutes of Health (S10OD030432), and the Office of the Vice President for Research at UT Health San Antonio. This work was also supported by critical funding from the National Institutes of Health: R01 AI32789-01A1 (EAL), R21 AI183125-01A1 (EAL), K12 GM111726 (BTE), T32 DE014318 (EC). Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)
Discordant Anti-SARS-COV-2 IgA Responses In Blood, Saliva, and Tears 2261177
Abstract Introduction To determine whether anti-SARS CoV-2 IgA responses in blood reflected the expression of anti-SARS CoV-2 IgA in mucosal tissues, anti-SARS-CoV-2 IgA antibodies in blood plasma, tears and saliva were measured by indirect ELISA before and after SARS-CoV-2 exposure or COVID-19 vaccination. Methods SARS-CoV-2 RBD of Wuhan (R&D Systems; Cat #10534CV) or Omicron (Proteogenix; PX-CoV-P080) were used to coat ELISA plates. Blood, tear or saliva specimens were added at 1:100, 1:40, and 1:5 dilutions respectively. Human anti-SARS-CoV-2 RBD (Wuhan) IgA monoclonal antibody (Proteogenix; Cat # PTXCOV-569) was used as a standard to determine the concentration of anti-SARS-CoV-2 RBD IgA antibody . Results Blood plasma was available from fourteen individuals before and after SARS-CoV-2 exposure or COVID-19 vaccination. Seroconversion for anti-SARS-CoV-2 IgG antibodies was observed in all individuals whereas only six of fourteen (43%) demonstrated anti-SARS-CoV-2 IgA antibodies. In a larger cohort of 39 participants that were anti-SARS-CoV-2 RBD IgG positive, 16 (41%), 9 (23%), and 11(28%) were positive for anti-SARS-CoV-2 RBD IgA in blood, saliva and tears respectively. Forty four percent of individuals positive for anti-SARS-CoV-2 RBD IgA in blood were also IgA positive in saliva or tears. Thirty percent of individuals negative for anti-SARS-CoV-2 RBD IgA in blood were IgA positive in saliva or tears. In a pilot study three individuals with anti-SARS-CoV-2 IgA antibodies directed against Wuhan and Omicron variants demonstrated anti-SARS-CoV-2 IgA antibodies in the tears from both eyes. Conclusion Our data indicate that anti-SARS-CoV-2 IgA responses in blood, tears, and saliva are variable in SARS-CoV-2 exposed and COVID-19 vaccinated individuals with discordant responses in blood and mucosal tissues. Equivalent antibody responses in tears of both eyes suggests equal seeding of both lacrimal glands by antibody-producing B cells. Funding Source Franciscan Institute of Science and Health Topic Categories Mucosal and Regional Immunology (MUC)
Dual‐Functional Alumina Additive Enabling Efficient, Volumetric Mechanoluminescence for Nighttime Safety Footwear
ABSTRACT Visualizing mechanical force distribution through mechanoluminescent foams allows real‐time optical monitoring of human motion for energy, sensing, and safety applications. However, conventional polymer‐based mechanoluminescent composites often suffer from inefficient stress transmission in thick structures due to their high elasticity, resulting in surface‐confined emission and weak luminescence in the global regions. In this study, Al 2 O 3 is introduced as a simple additive that performs dual functional roles in both structural and electrical aspects. During fabrication, surface‐adsorbed species on Al 2 O 3 , such as oxygen and moisture, induce spontaneous bubble formation, generating a sponge‐like porous architecture that enhances force dispersion and consequently improves mechanoluminescent performance in the global region of the foam. Moreover, the intrinsically strong positive triboelectricity of Al 2 O 3 strengthened the interfacial triboelectric field, leading to highly bright emission even with a low loading ratio of ML particles. When applied to shoe soles, the foam enables not only full‐area signal monitoring but also spatially resolved detection of dynamic loading during human motion. This study reveals the dual structural and triboelectric enhancements induced by a simple additive and highlights its potential for realizing practical self‐luminous platforms in smart footwear, healthcare monitoring, and wearable stress sensing.
Schistocephalus solidus suppresses melanomacrophages, IgM+, and CD4+ cells but not IL-17 expression in threespine stickleback (Gasterosteus aculeatus) 2260422
Abstract Introduction Immunoregulation is critical for maintaining an organism’s health, as excessive or deficient immune responses can lead to pathology. Research on humans and other mammals has shown that parasites can affect immune regulation by manipulating their hosts’ immune responses in their favor by suppressing lymphocyte cell survival, activation and/or differentiation. The extent and mechanisms by which parasites modulate fish immunity remains vastly understudied. To address this gap in knowledge, we utilized an emerging immunoparasitological model system: the parasitic tapeworm Schistocephalus solidus, and its host, the threespine stickleback (Gasterosteus aculeatus) fish. Methods We evaluated the presence of melanomacrophage centers (MMCs), lymphocytes (IgM and CD4) and pro-inflammatory cytokine Interleukin-17 (IL-17) expression in the spleen of infected and uninfected stickleback. We hypothesized that S. solidus would downregulate stickleback immune response, causing a reduction in splenic MMCs, lymphocytes, and IL-17+ cells. Results The results of these studies showed a significant reduction in the size of MMC aggregates and the frequency of IgM+ and CD4+ cells, suggesting S. solidus is capable of suppressing both myeloid and lymphocyte development, recruitment, and/or activation. However, we found no significant difference in IL-17 expression between infected and uninfected fish. Conclusion These preliminary findings indicate S. solidus has broad effects on host immunity, expanding our limited knowledge of the mechanisms underlying parasite-mediated immunomodulation in fish and laying the foundation for future work studying local vs systematic immune responses. Funding Source NIH Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)
Clonal Persistence of Tissue-Adapted CD4+ T Cells Drives Recurrent Oral Mucosal Inflammation 2309294
Abstract Introduction The oral mucosa is a major immunological barrier and a primary site of interaction between the host immune system and the oral microbiome. Periodontitis is a highly prevalent, recurrent inflammatory disease of the gingiva characterized by tissue destruction; however, the immunological mechanisms driving disease relapse remain poorly understood. We hypothesized that recurrence is driven by clonally expanded, antigen-experienced CD4+ memory T cells that persist in the tissue after microbial challenge resolution and retain effector programs biased toward Th1 and Th17 lineages. Methods We used imaging mass cytometry of human gingival samples and a mouse model of recurrent periodontitis that combined transient regulatory T cell (Treg) depletion to enhance CD4+ T cell recruitment without altering antigen specificity. Disease resolution was confirmed by alveolar bone micro-CT. We next performed integrated single-cell RNA sequencing, paired with T cell receptor (TCR) sequencing, of gingival cells to define transcriptional states and clonal architecture of gingival CD4+ T cells in disease recovery and recurrence. Results In human gingival samples, we identified enrichment of peri-epithelial CD45RO+ CD4+ T cells in periodontitis, consistent with retention of antigen-experienced cells. In recovered mice, there was a significant increase in gingival CD4+ T cell retention (p < 0.05) compared with controls. Clonally expanded CD4+ T cells displayed transcriptional signatures of tissue-resident memory and expression of inhibitory checkpoints associated with chronic activation. Highly expanded clonotypes persisted across recovery and recurrence and maintained stable Th1 effector programs, while acquiring Th17 features. Conclusion These findings implicate tissue-adapted, clonally expanded CD4+ T cells as potential drivers of recurrent oral mucosal inflammation and highlight adaptive immune memory as a therapeutic target for preventing periodontitis and peri-implantitis. Funding Source NIDCR 4R00DE032704-03 Topic Categories Mucosal and Regional Immunology (MUC)
Uncovering T cell antigens in sarcoidosis 2308956
Abstract Introduction Sarcoidosis is characterized by the accumulation of clonally expanded CD4+ T cells within affected tissues, strongly implicating antigen-specific immune responses in granulomatous inflammation. However, the identity of antigens recognized by pathogenic T cells remains unknown, limiting understanding of disease mechanisms and opportunities for targeted therapies. Here, we undertook a systematic approach to identify CD4+ T cell antigens in sarcoidosis, focusing on subjects expressing HLA-DRB1*11:01, a risk allele associated with disease susceptibility. Methods CD4+ T cells from the bronchoalveolar lavage of HLA-DR11 sarcoidosis and beryllium-sensitized control subjects were single-cell sorted and paired TRA/TRB sequences identified using 10x Genomics to define TCR repertoires for each subject. A set of five related TCRs exhibiting hallmarks of antigen-stimulation and derived from three sarcoidosis patients were expressed as T cell hybridomas. Their specificity was probed using an unbiased decapeptide positional-scanning library (PSL) to define amino acid preferences at each peptide position contributing to activation. Results Initial PSL screens revealed repeated glycine and isoleucine preferences at multiple peptide positions, suggesting stimulatory peptides enriched for these residues, but also possible register-shifting of peptides within the HLA-DR11 binding groove. Deconvolution steps using dual-defined peptide mixtures and a biased PSL fixing glycine at position p5 and isoleucine at p7 led to the discovery of mimotopes and naturally-occurring peptides that activated all T cell hybridomas. The most stimulatory peptide was a specific conserved epitope of non-histone chromosomal protein 6, expressed by a variety of fungi. Conclusion These findings of antigen recognition by DR11-restricted T cells highlight a potential role for fungal antigens in disease, consistent with prior findings in acute sarcoidosis. Ongoing studies aim to define the breadth and disease specificity of these responses. Funding Source R01HL136137 Topic Categories Immune Mechanisms of Human Disease (HUM)