Browse Articles

Anatomic compartmentalization of a cytokine buffer system promotes anti-viral immune defense 2257966

Abstract Introduction The circulating concentration of the proinflammatory cytokine IL-6 is regulated by a blood buffer system formed by molar excess of the soluble forms of the IL-6 receptor (sIL-6R) and co-receptor gp130 (sgp130). These buffer components serve to rapidly capture free IL-6 released following immune challenge, preventing systemic proinflammatory signaling. How then can IL-6 accumulate at mucosal sites as needed for immune defense? Methods Post-sublethal H1N1 infection, lungs and sera were collected on Day 0 and Day7 from B6 (control mice) and transgenic sgp130fc mice that overexpress sgp130 in the lung fluid. IL-6 and buffer agents (sIL-6R and sgp130) were measured in the sera and the lung homogenate by ELISA. scRNA-seq was performed on non-infected and infected lung cells to define intrinsic capacity of lung cells to generate buffer agents. High resolution confocal imaging at millimeter special scale was used to measure IL-6 induced signaling in the presence and absence of forced buffer expression in the lung. Influenza-based RT-PCR was used to measure viral load in the lung after sublethal H1N1 infection and 1xLD50 dose was used to evaluate survivorship with and without IL-6 buffer activity in the lung tissue. Results We find that the IL-6 buffer system is anatomically compartmentalized, and is substantially reduced within lung interstitial fluid, enabling IL-6 to accumulate in the lung mucosa within a mouse model of influenza virus infection. Genetic transplantation of IL-6 capture activity into lung tissue limits spatial diffusion of this cytokine and lowers immune protection against influenza virus. Conclusion Our results point to anatomic compartmentalization of biological buffer systems as a homeostatic mechanism, in this case, enabling mucosal immune defense without dangerous systemic delivery of the proinflammatory signal. Funding Source R01AI155447 Topic Categories Cytokines and Chemokines and their Receptors (CCR)

Gestational Stage—Specific Regulation of NK and T cell Compositions by Trafficking and Proliferation 2254964

Abstract Introduction Decidual natural killer (NK) and T cells undergo compositional changes during pregnancy, yet the mechanisms regulating their origin and maintenance remain unclear.Using T-bet fate mapping mice(B6.RosaRFP;Tbx21-Cre) with serial intravascular labeling (SIVL) and BrdU incorporation, we tracked how trafficking and local proliferation coordinate lymphocyte homeostasis across gestation Methods Non-pregnant and pregnant mice at GD7-8 and GD12-14, received BrdU intraperitoneally and sequential αCD45 tail-vein injections (AF488 at 24 hours and AF647 at 5 minutes) before sacrifice. Decidual Leukocytes were isolated, stained with αCD45 (APC/Fire810) and lineage markers for B, T, NK, and classified as continuously circulating (CC), recent emigrant (RE), recent immigrant (RI) or unlabeled cells as tissue localized (TL) Results SIVL showed that at GD7-8, TL fraction of CD4+, CD8+ and NKs declined (P = 0.001, P = 0.0007, P = 0.001) with increased CC CD4+andCD8+ T cells (P = 0.01,0.02), and RI NKs (P = 0.0001), versus virgin. TL reduction was smaller for NK than CD4+ and CD8+ T cells (P = 0.008, 0.001). TL NKs showed elevated proliferation(P = 0.004, vs virgin) limited to decidua and absent in splenic NKs or decidual T cells, suggesting local expansion may sustain early TL NK pool. By GD12-14, NK proliferation sharply decreased, coinciding with further reduction of TL NK fraction (P < 0.0001,P=.004 vs GD7-8), while CD4+ and CD8+ T cells began proliferating(P = 0.006, 0.01,vs virgin), with stronger CD4+ expansion (P = 0.03) and a higher CD4+/CD8+ ratio(P < 0.0001,vs virgin). Interestingly, proliferation at this stage involved T-bet independent NK and CD8+ cells, suggesting a shift to less cytotoxic profile. However, CC, RI, TL and RE fractions within CD4+andCD8+T cells remain comparable. Conclusion Our findings reveal a gestational stage-specific coordination of trafficking and proliferation that maintains decidual immune homeostasis, marked by early NK proliferation and mid-gestation T cell expansion reflecting on CD4+/CD8+ ratio. Funding Source ECEB and R21AI175753 Topic Categories Mucosal and Regional Immunology (MUC)

Metabolic Injury Niche Suppresses Macrophage Efferocytosis and Delays Recovery in Acute Kidney Injury 2258243

Abstract Introduction Efferocytosis, the clearance of apoptotic cells by macrophages, is essential for resolving inflammation and restoring tissue homeostasis following acute kidney injury (AKI). While impaired efferocytosis exacerbates injury, how the metabolic microenvironment modulates this function remains poorly defined. Given that AKI is characterized by metabolic reprogramming, identifying metabolic regulators of macrophage efferocytosis may reveal therapeutic targets for enhancing inflammation resolution and tissue repair. Methods We used a murine model of ischemia/reperfusion (I/R)-induced AKI to examine how local metabolic cues regulate macrophage efferocytosis. Single-cell RNA sequencing, lipidomic profiling, and biochemical assays were applied to identify transcriptional and signaling alterations. Efferocytic capacity and renal recovery were evaluated following genetic deletion and peptide inhibition of Regulator of G-protein Signaling 1 (RGS1). Results Post-injury accumulation of extracellular fatty acids emerged as a major driver of impaired macrophage efferocytosis. These lipids activated PPARα and induced RGS1 expression in a distinct efferocytosis-exhausted macrophage subset. Fatty acids also promoted RGS1 palmitoylation, enhancing its inhibition of Rac1, a key efferocytic GTPase. Genetic deletion of RGS1 restored Rac1 activity, rescued efferocytosis, and improved renal repair. Notably, a novel RGS1 palmitoylation-blocking peptide reproduced these effects, increasing efferocytosis, reducing proinflammatory cytokines, and accelerating kidney function recovery. Conclusion We identify a metabolic regulatory axis in which fatty acids transcriptionally and post-translationally suppress macrophage efferocytosis through RGS1. RGS1 functions as a metabolic checkpoint controlling inflammation resolution in AKI. Targeting RGS1 palmitoylation represents a promising strategy to restore efferocytosis and promote kidney repair. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)

Multi-omic Signatures of Vaccine Responses in Healthy Early Adolescents 2308797

Abstract Introduction Early adolescence represents a distinct phase of immune maturation between childhood and adulthood, yet this age window has rarely been profiled in depth at a systems level. This study examines how vaccine-induced immune responses are shaped during this critical developmental window. Methods We followed 11—13-year-olds for up to two years with repeated PBMC collection, including visits before and after combination (Tdap/MCV4/HPV/influenza), stand-alone influenza, and COVID-19 (prime/booster) vaccination. We generated scRNA-seq, Olink plasma proteomics, flow cytometry, influenza-specific IgG, and HAI titers. These readouts were analyzed across adolescent vaccine exposures, and influenza responses were compared to young and older adult influenza vaccine cohorts. Results Adolescents mounted distinct humoral and transcriptional responses to influenza vaccination versus adults. At the humoral level, adolescents displayed an age-associated pattern of strain-specific influenza IgG and HAI titers, with less cross-reactive memory IgG than adults. At the transcriptional level, adolescents showed strong activation of naïve T cells, NK cells, and monocytes, whereas adults had greater vaccine-responsive changes in the B cell compartment. Across four adolescent visits, we observed naïve T cell activation with minor variation in magnitude and distribution of responding cell types. We searched for non-naïve, clonally expanded cells within phenotypically naïve T cells and found no TCR clonotype expansion across vaccination visits, suggesting that activation signaling in this population is not primarily driven by TCR-specific responses. Conclusion Early adolescent immune responses demonstrate non-specific transcriptional activation across lineages and across vaccine visits - highlighting early adolescence as a unique period of immunity with distinct vaccine-mediated responses compared to adults. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)

Contemplating immunology: using contemplative pedagogy practices to build critical thinking skills and confidence in data analysis and interpretation 2259675

Abstract Introduction Time is precious in immunology courses. With so much ground to cover in the span of only a few weeks, learners are expected to quickly absorb new knowledge with little time to process, much less be curious or dig deep into topics. Furthermore, in courses where building abilities in data analysis and interpretation are central learning goals, in-class activities designed to practice these skills are often rushed. Contemplative pedagogy (CP), teaching methods designed to deepen awareness, concentration, and insight, are one potential mechanism to help students access learning at a slower pace and greater depth. While CP approaches are commonly used in the humanities, they are rare in STEM. Methods Here I report on the development and use of contemplative practices in graduate Immunology and upper-level undergraduate/graduate Host-Pathogen Interactions courses. Following the style of a Lectio Devina, an ancient tool for deep understanding of religious texts, students were guided through close “readings” of data (in class) or journal articles (self-study). This STEM-adapted CP approach provides a framework for students to both practice and build confidence in their critical thinking, observational, and analytical skills. Results Students self-reported increased confidence in their ability to analyze and interpret data and to read and understand journal articles. Anecdotally, students report enhanced attention to detail, self-awareness, and confidence in being ablet to draw their own conclusions. Conclusion While not a common method in the STEM instructional playbook, CP approaches, like Lectio Devina, can provide a new tool to support the development of young scientists in the classroom. Funding Source University of Massachusetts Lowell Center for Excellence in Learning and Teaching Topic Categories Immunology Education and Communication (EDU)

Why HIV Controllers Control: Force-Stabilized TCR—pMHC Interactions Boosts Sensitivity in Elite Controllers and Protective HLA Alleles 2267511

Abstract Introduction CD8+ T cells from HIV elite controllers (ECs) have TCRs with higher antigen sensitivity than those from vaccinees (VACs). However, within protective HLA alleles (B27:05, B57:01), standard functional avidity do not separate EC from VAC, and why B27:05/B57:01 are protective has remained unclear. Methods We applied single-molecule biophysical measurement–micropipette assay for 2D TCR affinity and biomembrane force probe for TCR catch-bond–to test whether TCR—pMHC interaction mechanics explain cohort differences and predict high sensitivity at low antigen dose. Results Across Gag-specific TCRs, we observed allele-specific discrimination. For B57:01, EC and VAC TCRs differ by higher 2D TCR affinity in ECs. For B27:05, 2D affinity overlaps, and catch bond lifetime uniquely separates EC from VAC TCRs. Dose-controlled activation with pMHC-coated beads at known site densities showed that TCRs with stronger catch bonds generate higher peak Ca²+ flux, which correlates directly with bond lifetime at the optimal force and also translates to higher CD69 expression, especially at low antigen densities. To probe allele effects, we coupled mechanics with structural modeling and molecular dynamics, revealing force-favorable contact consistent with the measurements. Protective-allele TCRs–especially B*27:05–exhibit markedly stronger catch bonds and longer lifetimes than TCRs restricted by non-protective alleles (A02:01, A03:01, B*08:01), including some TCRs from ECs, indicating that enhanced stability is allele-specific (restricted to protective allele), not universal. Conclusion Our findings identify TCR mechanics as the missing discriminator: B57:01 separates by higher 2D affinity; B27:05 separates by stronger catch-bond, and these features predict superior activation at low antigen density. Such mechanics is supported by structure/MD simulation which provides a mechanistic basis for EC and protective-allele advantage and offers practical measures for TCR selection in vaccines and T cell therapies. Funding Source n/a Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Nucleation‐Controlled Synthesis and a Unified Descriptor for Rational Interlayer Design of Vanadium‐Oxide Cathodes toward High‐Performance Zinc‐Ion Batteries

ABSTRACT Aqueous zinc‐ion batteries (AZIBs) are promising for large‐scale energy storage, yet their development is constrained by the cathode that suffers from energy‐intensive synthesis and poorly understood interlayer‐ion chemistry. NH 4 V 4 O 10 (NVO) exemplifies these challenges, as hydrothermal preparation hampers scalability and the stabilizing role of intercalated cations remains ambiguous. Here, by revisiting vanadium‐oxide synthesis history and nucleation mechanisms, we establish a nucleation‐kinetics–driven, pH‐controlled supersaturation strategy that enables mild and scalable NVO synthesis. Moreover, this method provides a reliable platform for systematic interlayer chemistry studies. A comparative investigation of cations‐intercalated NVO establishes a unified descriptor, weighted ionic potential, δ = Z/r × EN( (valence/radius) × electronegativity), which quantifies the effective polarizing power and metal–oxygen interaction of interlayer cations. Experimental correlation and theory analysis identify the most effective stabilizing species. To further enhance capacity without sacrificing stability, redox‐active molecules are co‐intercalated into Al 3+ ‐stabilized NVO. The resulting cathode exhibits accelerated Zn 2+ transport, modified redox chemistry, and additional charge storage, delivering high specific capacities of ∼420 mAh g −1 at 0.1 A g −1 , 248 mAh g −1 at 5 A g −1 , and ∼83% retention over 8000 cycles. Overall, this work integrates scalable synthesis and descriptor‐guided interlayer design to advance high‐performance vanadium‐oxide cathodes toward practical AZIBs.

Ruxolitinib prevents irreversible autoimmune endocrinopathies in APECED

Abstract Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED/APS-1) is a monogenic disorder of failed central tolerance. Interferon-γ-driven inflammation in APECED underlies multiorgan autoimmunity and chronic mucocutaneous candidiasis and is targetable with JAK1/2 inhibition. Whether early cytokine blockade can avert irreversible endocrine failure is currently unknown. Here, we describe two individuals with APECED who developed evolving autoimmune hypoparathyroidism and hypergonadotropic hypogonadism. Treatment with the JAK1/2 inhibitor ruxolitinib halted progression and reversed biochemical and clinical abnormalities, preserving parathyroid and gonadal function. These findings provide clinical evidence that timely JAK-STAT pathway inhibition can intercept evolving endocrine autoimmunity in APECED. More broadly, they advance a disease-interception paradigm in which early, pathway-directed cytokine blockade may alter the natural history of autoimmune endocrinopathies.

Characterizing Import of RNA Polymerase into a Phage Nucleus 2310316

Abstract Introduction Jumbo bacteriophages in the ϕKZ-like family have shown great potential as a therapeutic to treat infections from the human pathogen Pseudomonas aeruginosa, known for its high level of antibiotic resistance. ϕKZ-like phages form a proteinaceous “phage nucleus” upon infection that compartmentalizes and protects phage DNA replication and transcription mechanisms from host defenses. Transcription occurs within the phage nucleus, requiring RNA polymerase and other transcriptional components to be imported into the compartment. Selective import of phage-encoded proteins into this nucleus is critical for successful infection, yet the mechanisms governing this specificity remain incompletely understood. Methods In this work I investigated how the ϕKZ-encoded non-virion RNA polymerase (nvRNAP) is selectively imported. Previously, a series of genetic selections identified the genes imp1 as the major import factor and imp7 as a nvRNAP-specific import factor. Therefore, we hypothesized that Imp1 or 7 may directly interact with nvRNAP. We then purified and mixed Imp7 with nvRNAP, in both its active and inactive forms (with and without sigma factor, respectively). Results We discovered that Imp7 does not directly bind to nvRNAP in vitro. Preliminary data also suggests Imp1 may bind to the catalytically inactive nvRNAP and not the active nvRNAP in the presence of Imp7. Conclusion These findings suggest multiple potential models for nvRNAP import, including the independent and separate import of catalytically inactive nvRNAP and sigma factor, forming the catalytically active nvRNAP only when both are successfully imported. Our results highlight a complex import system for the phage nvRNAP and lay the groundwork for further mechanistic dissection of protein trafficking across the phage nuclear barrier. This knowledge could uncover new principles of protein trafficking across novel biological barriers and inform the development of phage-based therapeutics against antibiotic-resistant pathogens. Funding Source NIH Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)

Lag3-KIEELE domain plays a key role in Lag3-dependent Treg function 2267565

Abstract Introduction Lymphocyte activation gene 3 (Lag3) is a co-inhibitory receptor expressed on activated T cells and Foxp3+ regulatory T cells (Tregs). However, the mechanisms underlying its inhibitory function remain largely unclear. We previously demonstrated that Lag3 expression in Tregs constrains glycolytic activity by limiting Myc-PI3K-LDHA pathway activation, thereby supporting Treg-mediated suppression of autoimmune inflammation. Here, we report that the conserved intracellular KIEELE motif of the Lag3 is critical for its ability to regulate Treg suppressive function and metabolic programming. Methods We utilized a novel Treg-specific Lag3-KIEELE motif—deficient mouse model to test the importance of Lag3’s highly conserved KIEELE motif and Lag3 immunoprecipitation—mass spectrometry analysis to identify potential cytosolic proteins potentially mediating the Lag3 functions. Results We found that loss of this KIEELE motif specifically in Tregs significantly impairs their suppressive function and alters their metabolic profiles. Lag3-deficient Tregs displayed elevated glycolysis with Myc expression, phenotypes similar to Lag3-deficient Tregs. Lag3 IP-MS experiment further identified cytosolic proteins interacting with the KIEELE motif, suggesting potential mediators of Lag3 signaling. Conclusion Collectively, these findings provide the first mechanistic insight into how Lag3 modulates intracellular pathways to control both Treg suppressive activity and effector T cell responses. Funding Source NIAID Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Tunable Immune Imprinting of Memory B Cells to SARS-CoV-2 Variants 2255300

Abstract Introduction Immune imprinting, historically termed “original antigenic sin”, biases memory B cell (MBC) recall toward cross-reactive epitopes of ancestral strains, limiting vaccine adaptability to rapidly evolving variants. Whether immune imprinting is a fixed outcome of antigen exposure or can be modulated by host immune factors remains unclear. Chronic inflammatory and immunosuppressive conditions in systemic lupus erythematosus (SLE) patients affect antibody-secreting cell formation during MBC recall responses, but whether these host-intrinsic conditions can modulate MBC epitope targeting and immune imprinting in response to an antigenically distant variant remains unknown. Methods We recruited tightly time-matched cohorts of healthy individuals and SLE patients who had received three doses of ancestral inactivated vaccine and subsequently experienced synchronized Omicron BA.5/BF.7 breakthrough infection. We characterized their MBC responses through monoclonal antibody (mAb) epitope mapping, deep mutational scanning (DMS), spectral flow cytometry, and antigen-linked single-cell multi-omics. Results Healthy individuals displayed strong immune imprinting, characterized by robust recall of high-affinity cross-reactive MBCs. In contrast, SLE patients exhibited markedly reduced imprinting, with DMS revealing enhanced recognition of variant-specific neutralizing epitopes. Antigen-linked single-cell profiling showed attenuated MBC recall in SLE, associated with reduced MBC reactivation, diminished BCR signaling, and heightened inflammatory signatures. Concurrently, naïve and IgM MBCs were recruited and matured into variant-specific IgG MBCs, accompanied by a decline in early self- and polyreactivity. Conclusion Our findings demonstrate that immune imprinting in MBCs is plastic, and modulation of inflammatory and B cell activation signaling can rebalance recall versus de novo responses to promote variant-adaptable immunity. Funding Source National Natural Science Foundation of China Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Investigating the Role of A2A Signaling in Caffeine-Induced EL4 T-Cell Lymphoma Growth 2258175

Abstract Introduction Adenosine A2A receptor signaling suppresses T-cell activation and promotes tumor immune evasion by dampening anti-tumor responses. Preliminary observations suggested that caffeine enhances EL4 lymphoma cell growth, indicating a receptor-mediated mechanism. This study investigates whether caffeine modulates T-cell lymphoma proliferation through A2A receptor signaling. Methods EL4 lymphoma cells and JURKAT T cells were treated with caffeine and with the selective A2A antagonist ZM241385, individually and in combination. Cell proliferation was measured using standard viability assays. In silico docking with SwissDock was performed to compare caffeine and ZM241385 binding affinities for the A2A receptor. Results Caffeine exposure increased proliferation in both EL4 and JURKAT cells, while ZM241385 alone had minimal effect. Co-treatment partially blocked caffeine-induced proliferation, suggesting involvement of A2A receptor signaling. Docking analysis predicted moderate caffeine binding to A2A, supporting a receptor-mediated interaction. Conclusion Caffeine promotes EL4 and JURKAT T-cell lymphoma proliferation through mechanisms consistent with A2A receptor signaling. These findings highlight the importance of evaluating naturally occurring compounds that can alter tumor immune signaling pathways and potentially influence lymphoma progression. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)

Nanobody-STING Agonist Reprogram the Tumor Microenvironment and Improve Adoptive Cell Therapy for Solid Tumors 2309144

Abstract Introduction Adoptive cell therapy (ACT) has demonstrated efficacy in hematologic malignancies but remains limited in solid tumors due to an immunosuppressive tumor microenvironment (TME) that restricts T cell infiltration, activation, and persistence. Activation of the stimulator of interferon genes (STING) pathway can reprogram the TME toward inflammation; however, systemic STING agonist delivery is hindered by poor tumor accumulation and dose-limiting toxicity. We hypothesized that targeted systemic delivery of a STING agonist using an albumin-hitchhiking nanobody platform could safely enhance ACT efficacy in solid tumors by reversing the immunosuppressive TME. Methods We developed albumin-hitchhiking nanobody—STING agonists (AHNSA) and evaluated them as an adjuvant to ACT in a TCR-transgenic OTI T cell transfer model using MC38-OVA tumors. Dosing and timing of AHNSA relative to ACT were optimized. Tumor-infiltrating immune cells and transferred T cells were analyzed by flow cytometry and IHC to assess activation, proliferation, exhaustion, and cytotoxic potential, as well as global changes in TME composition. Results Systemic AHNSA administration following OTI T cell transfer significantly improved survival compared to ACT alone. AHNSA treatment increased infiltration of both innate immune cells and adoptively transferred T cells into tumors. Transferred T cells displayed enhanced activation and proliferation with reduced expression of exhaustion markers. Bulk tumor immune profiling revealed enrichment of pro-inflammatory populations, including M1 macrophages, dendritic cells, and CD8+ T cells, alongside depletion of immunosuppressive subsets such as myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells. These findings indicate effective reversal of TME immunosuppression. Ongoing studies are extending this approach to a fully immunocompetent CAR-T model. Conclusion AHNSA represents a promising strategy to overcome TME-mediated resistance and enhance ACT efficacy in solid tumors. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Cancer-associated metabolites stimulate mucosal-associated invariant T cells for cancer cell killing 2260004

Abstract Introduction Mucosal-associated invariant T (MAIT) cells recognize microbially derived metabolite antigens presented by MHC-related protein 1 (MR1), yet their activation and cytotoxicity against cancer cells are not well defined. We hypothesized that tumor-associated nucleoside adducts serve as MR1 ligands that activate MAIT cells and enable killing of glioblastoma (GBM) and other cancer cells. Methods Here, we examined MR1-dependent MAIT cell killing of various cancer cell lines, including myelogenous leukemia cell K562, and glioblastoma cells U87, U251, and A-172. Human polyclonal MAIT cells (Vα7.2+CD161^hi) were co-cultured with cancer cells, with candidate nucleoside adducts added as putative stimulatory MR1 ligands. MAIT activation was quantified by IFN-γ ELISpot counts. Tumor cell death was assessed in MAIT—GBM co-cultures by fluorescent confocal microscopy using propidium iodide (PI). LC—MS/MS of GBM cell eluates evaluated endogenous presence of the candidate nucleoside adduct. Appropriate vehicle/unstimulated controls and statistical comparisons were included. Results We identified nucleoside adducts and other derivatized metabolites that stimulated MAIT cells, as evidenced by increased IFN-γ ELISpot responses relative to unstimulated controls. MR1-blocking antibodies markedly reduced IFN-γ production, supporting MR1-dependent MAIT cell activation mediated by nucleoside adducts. Functionally, exposure of A-172 glioblastoma cells to polyclonal MAIT cells stimulated by candidate ligands increased tumor cell death as visualized by fluorescent confocal microscopy. Mass spectrometry of GBM cell eluates detected the candidate nucleoside adduct, indicating endogenous production by tumor cells. Conclusion Together, these data implicate an MR1—nucleoside adduct axis in MAIT recognition of cancer-associated metabolites and support the potential of MAIT-directed, MR1-restricted therapeutic strategies for glioblastoma and other cancers. Funding Source National Institute of Allergy and Infectious Diseases (NIAID) Cancer Prevention and Research Institute of Texas (CPRIT) T32 MMI Training Grant (NIH) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Inborn errors of T cell topographic memory underlie organ-selective infectious diseases 2303844

Abstract Introduction Most infections are innocuous in most individuals and most infectious diseases are confined to specific organs. Inborn errors of tissue-intrinsic, non-leukocytic immunity underlie some organ-specific infectious diseases, but most severe infections remain unexplained. We hypothesize that inherited “lacunar” defects of tissue-homing memory T cells can underlie organ-selective infections. Methods We screened >20,000 genomes from patients with severe, unexplained organ-specific infections for candidate variants potentially affecting T-cell trafficking. We then performed extensive functional studies to validate disease-causing mutations and define their impact on memory T-cell compartmentalization and local immune surveillance. Results We identified autosomal recessive deficiency of integrin αL (CD11a), due to biallelic loss-of-function mutations in ITGAL, in otherwise healthy adults of various ancestries with severe, persistent cutaneous lesions due to commensal papillomaviruses. The absence of CD11a does not compromise the development or function of any leukocyte subset, including CD4+ helper and CD8+ cytotoxic T cells. However, the trafficking of skin-tropic memory T cells is severely impaired, resulting in their selective sequestration in the blood and compromising the establishment of tissue-resident memory T cells in the skin. Conversely, alternative integrins mediate the extravasation of other leukocytes, including other T-cell subsets, to other tissues. This leads to a skin-restricted T-cell immunodeficiency characterized by the expansion of the commensal viral flora, including β-HPV, and a predisposition to skin cancers. Conclusion Human integrin αL is essential for steady-state T-cell homing to the skin but largely redundant for protective immunity in other tissues. Our study provides proof-of-concept that severe organ-selective viral diseases can result from lacunar defects in tissue-specific memory T-cell homing in patients whose immunity is otherwise intact. Funding Source n/a Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)

A Recyclable and Sustainable Hydroxypropyl Methylcellulose Electrolyte for Electrochromic Devices

ABSTRACT Gel electrolytes, which supply compensating ions for electrochromic reactions and serve as conductive media, are widely used in electrochromic devices (ECDs). However, the complex preparation processes for gel electrolytes often involve the use of large amounts of organic solvents and hazardous or valuable reagents, limiting their widespread adoption in ECDs. This paper presents a straightforward method for fabricating large‐area hydroxypropyl methylcellulose (HPMC) gel electrolytes using a solution casting technique in an aqueous system. The addition of deep eutectic solvents (DES) and the incorporation of SiO 2 nanoparticles significantly improve the conductivity of the gel electrolytes. The resulting HPMC/DES‐SiO 2 gel electrolyte exhibits high transparency (over 92% transmittance), high ionic conductivity (7.55 × 10 −4 S/cm), wide electrochemical window (±3 V), and outstanding thermal stability. The W 18 O 49 /NiO ECD assembled with HPMC/DES‐SiO 2 gel electrolyte shows excellent cycling stability (maintained 94.8% of initial optical modulation after 1000 cycles) and can perform electrochromic response over a wide temperature range from −50°C to 200°C. Furthermore, the entire HPMC and up to 82.7% of LiTFSI and NMA can be recycled and reprocessed into new gel electrolytes, offering a promising solution for the future development of environmentally friendly and efficient ECDs.

Small Cemetery Within

This piece reflects on the unseen emotional burden carried within oncology, where each clinical encounter leaves a lasting imprint beyond measurable outcomes.

LINE-1 insertion intermediates recombine with one another or with DNA breaks to form genome rearrangements

Collateral Immune Cell Signaling Compromises the Efficacy of T-cell Engaging Therapies for Cardiac Fibrosis 2327789

Abstract Introduction Cardiac fibrosis is a major driver of heart-failure progression, yet no approved therapies directly target fibrotic remodeling. Recent work has identified a population of activated, non-myofibroblast cardiac fibroblasts marked by fibroblast activation protein (FAP). These FAP+ fibroblasts arise after injury through inflammatory signaling and contribute to pathological fibrosis. Methods We utilized an echo guided model of cardiac ischemia reperfusion injury to investigate the effects of of FAP+ fibroblast depletion. We also evaluated the therapeutic feasibility of FAP-directed bispecific T-cell—engaging antibodies (BiTE® molecules) to eliminate FAP+ fibroblasts and profiled downstream signaling pathways. Finally, we investigated strategies for reducing harmful collateral inflammation from BiTE® molecule treatment while preserving the cardioprotective effects of FAP+ fibroblast depletion. Results We demonstrate the potential benefits of FAP+ fibroblast depletion following myocardial infarction. Unexpectedly, while FAP targeted bispecific T-cell engaging antibodies (BiTE® molecules) effectively eliminate FAP+ fibroblasts from the heart, they surprisingly lead to accelerated deterioration of cardiac function, enhanced adverse remodeling, and increased scar size. FAP BiTE® molecules elicit a robust cytokine response within the heart with prominent activation of interferon gamma (IFNg) and CD40 ligand pathways. Target cell killing was independent of IFNg and CD40L signaling and blockade of these pathways was sufficient to unmask the protective therapeutic effects of FAP+ fibroblast depletion. Conclusion We reveal that IFNg signaling to fibroblasts drives the differentiation of an independent lineage of activated fibroblasts not typically found in the infarcted heart, which are responsible for the harmful effects of FAP BiTE® molecules. Collectively, these findings highlight a previously unrecognized cardiac liability of BiTE® molecules and inform the design of the next generation of therapeutics. Funding Source NHLBI Topic Categories Translational and Interventional Immunology (TI)

Lysosomal solute carriers promote pro-inflammatory signaling and MHC-II antigen presentation in dendritic cells 2303674

Abstract Introduction Mutations in lysosomal solute carrier transporters (SLCs) are associated with metabolic and inflammatory diseases. However, the molecular mechanisms that link nutrient sensing and transport with pro-inflammatory immune responses are unclear. Our data suggest that nutrient-dependent responses mediated by the lysosomal SLC15A4 and SLC29A3, which are associated with human inflammatory disorders, are required for optimal phagosomal signaling to the production of pro-inflammatory cytokines and MHC-II antigen (Ag) presentation in murine dendritic cells (DCs). Methods We have investigated the mechanisms of action of SLC15A4 and SLC29A3 in murine DCs by performing biochemical, flow cytometric and immunological assays, as well as live-cell imaging. We have analyzed cytokine secretion by ELISA, transcription factor nuclear translocation by subcellular fractionation and RNA seq, Ag presentation and T cell activation by flow cytometry and biochemical assays, and calcium measurements by live-cell imaging. Results We have found that the histidine transporter SLC15A4 promotes pro-inflammatory responses by activating the master regulator of cell fitness, mechanistic target of rapamycin complex 1 (mTORC1). SLC15A4 also promotes MHC-II Ag presentation after phagocytosis by mechanisms that likely depend on mTORC1. In contrast, the nucleoside transporter SLC29A3 promotes phagosomal signaling and MHC-II Ag presentation by maintaining nucleoside homeostasis and supporting phagosomal acidification and membrane dynamics, as well as the activation of the transcription factor (TF)EB. Conclusion Our findings suggest that SLC15A4 and SLC29A3 regulate phagosomal signaling in murine dendritic cells via differential mechanisms to promote anti-bacterial immunity while preventing excessive inflammation. Funding Source NIH R01 12582389 Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)