Biology subjects

Vaeth, M.

Publications and source records attributed to Vaeth, M..

8 recordsLinked to original sources

bioRxiv2026

MYC/MIZ1 suppression of lysosomal protein degradation drives immune evasion in pancreatic ductal adenocarcinoma

The MYC oncoprotein promotes immune evasion of pancreatic ductal adenocarcinoma (PDAC), but the underlying molecular mechanisms are not fully understood. Here we show that MYC protects PDAC tumors from CD4+ T cell-dependent elimination. Single cell sequencing shows that MYC suppression in tumor cells increases amino acid availability and broadly activates amino acid-responsive gene expression programs in immune cell populations. This occurs because MYC-driven uptake depletes free amino acids from tumor interstitial fluid and plasma, while MYC compromises macropinocytosis and autophagy, both of which depend on lysosomal protein degradation. MYC engages the POZ/BTB transcription factor MIZ1 to suppress lysosomal genes regulated by the TFE3/TFEB/MITF network or by free MIZ1, thereby inhibiting lysosomal protein degradation. An orthogonal genetic model enabling transient, selective inhibition of amino acid uptake in tumor cells recapitulates the effects of MYC depletion on amino acid levels in the tumor microenvironment and induces complete, CD4+ T cell-dependent tumor eradication with long-term survival. We propose that MYC-mediated, cell-autonomous disruption of lysosome function coupled to non-cell-autonomous protection from immune clearance allows MYC-low cells to benefit from MYC-high neighbors, such that intratumoral heterogeneity in MYC expression confers a selective advantage to the entire tumor. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/740267v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@140d2ccorg.highwire.dtl.DTLVardef@cf5f1borg.highwire.dtl.DTLVardef@6d132aorg.highwire.dtl.DTLVardef@10535e6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

The Glucose Transporter GLUT3 Controls Regulatory T Cell Function

Regulatory T (Treg) cells are central mediators of immune tolerance and are generally considered to rely predominantly on mitochondrial metabolism rather than glucose-driven glycolysis. To define the role of glucose metabolism in Treg cells, we investigated the contribution of the hexose transporters GLUT1 and GLUT3. Genetic ablation of GLUT1 in T cells or selectively in Treg cells had minimal impact on Treg cell numbers, phenotype or immune homeostasis, indicating that GLUT1 is largely dispensable in this lineage. By contrast, deletion of GLUT3 in T cells resulted in a marked reduction in Treg cell numbers. However, it remained unclear whether this reduction reflected diminished IL-2 production by GLUT3-deficient conventional T cells or a cell-intrinsic requirement for GLUT3 in Treg cells. To investigate this, we generated mice with Treg cell-specific deletion of GLUT3. These animals developed severe systemic inflammation accompanied by lethal cellular and humoral autoimmunity. Mechanistically, GLUT3-deficient Treg cells exhibited reduced glycolytic activity and mitochondrial respiration, leading to impaired suppressive function and defective effector and follicular Treg cell differentiation. Collectively, our findings demonstrate a non-redundant requirement for GLUT3 in Treg cell metabolic fitness and immune regulation, refining the prevailing view that Treg cells operate largely independently of glucose metabolism. Our data further suggest that therapeutic strategies targeting glucose uptake and glycolysis in autoimmune and inflammatory diseases should account for potential adverse effects on Treg cell-mediated immune tolerance.

immunology↗

bioRxiv2025

Interferon gamma signaling drives cardiac metabolic rewiring

BackgroundIFN-gamma (IFN-{gamma}) signaling influences myocardial inflammation and fibrosis across a wide range of conditions, including ischemic and non-ischemic heart failure (HF). However, the direct effects of IFN-{gamma} on cardiomyocytes remain poorly understood. Here, we developed a novel in vivo model to investigate how IFN-{gamma} impacts myocardial metabolism and function. MethodsMale C57BL/6J mice were injected intravenously with hepatotropic adeno-associated virus (AAV2/8) carrying Ifng and nLuc reporter under the albumin promoter (AAV- Ifng) or empty vector control virus (AAV-ctrl). Cardiac alterations were monitored on day 28 through flow cytometry, bulk RNA sequencing, targeted metabolomics, isolated mitochondrial activity, echocardiography, and in vivo imaging using [18F]fluordeoxyglucose ([18F]FDG) and [18F]fluoro-6-thia-heptadecanoic acid. Additionally, mice lacking IFN-{gamma} receptor expression in cardiomyocytes (Myh6Cre Ifngr1fl/fl) were used to further dissect the cell-intrinsic roles of IFN-{gamma} signaling in cardiomyocyte metabolic reprograming. ResultsAfter confirming liver-specific viral transfection and elevated serum IFN-{gamma} production at physiological levels, we observed cardiac metabolic adaptation and rewiring in animals treated with AAV-Ifng compared to control animals. Myocardial bulk RNA sequencing and gene set enrichment analysis identified an IFN-{gamma} response signature accompanied by marked down-regulations of oxidative phosphorylation and fatty acid oxidation pathways. Functional assessment of isolated cardiac mitochondria showed decreased oxygen consumption, and targeted metabolomics confirmed metabolic shifts toward glycolysis in mice overexpressing IFN-{gamma}. In vivo imaging confirmed increased cardiac glucose uptake following AAV-Ifng treatment. Notably, these metabolic alterations were abrogated in mice with cardiomyocyte-specific deletion of IFN-{gamma} receptors (IFNGR). ConclusionsSystemic IFN-{gamma} induces pronounced metabolic reprogramming in the heart, characterized by increased glucose uptake and reduced oxidative phosphorylation, via direct signaling through cardiomyocyte IFNGR. These alterations mirror those observed in aging and some forms of HF, thereby highlighting that, beyond classical inflammation, this cytokine regulates cardiac metabolism. Novelty and significanceO_ST_ABSWhat is known?C_ST_ABSO_LIImmunological mechanisms can impact myocardial disease progression through complex context-dependent mechanisms. C_LIO_LIIFN-{gamma}, a cytokine primarily secreted by natural killer and T cells, promotes myocardial inflammation and fibrosis in the context of autoimmune myocarditis, pressure-overload-induced heart failure, and Chagas cardiomyopathy. C_LIO_LICytokines exert pleiotropic effects and can influence inflammatory responses through mechanisms involving control of energy metabolism. C_LI What new information does this article contribute?O_LIA novel adeno-associated virus model of systemic IFN-{gamma} elevation allows assessment of cardio-immune-metabolic crosstalk without confounding factors. C_LIO_LIIFN-{gamma} drives cardiac metabolic reprogramming in inflammatory contexts, characterized by enhanced glucose uptake and glycolysis with mitochondrial dysfunction, ultimately altering cardiac metabolic fluxes and function. C_LIO_LIThe IFN-{gamma}-induced cardiac metabolic reprogramming is, at least in part, mediated through direct signaling via receptors on cardiomyocytes. C_LI

immunology↗

bioRxiv2025

Glucose Metabolism Controls Oxidative Burst and Lipid Mediator Production in Neutrophils upon Microbial Challenge

Neutrophils are frontline responders against bacterial and fungal pathogens, requiring rapid energy and biosynthetic precursors to mount effective antimicrobial responses. To meet these demands, they primarily rely on aerobic glycolysis, making glucose uptake essential. Murine and human neutrophils express the glucose transporters GLUT1 and GLUT3; however, their specific roles in neutrophil immunobiology have not yet been fully elucidated. Here, we show that neutrophilic immune responses to Candida albicans and Staphylococcus aureus critically depend on GLUT1/3-dependent glucose uptake and glycolysis. Combined deletion of GLUT1 and GLUT3 almost completely abolished glucose uptake and aerobic glycolysis in murine neutrophils, yet did not impair granulopoiesis, indicating that homeostatic neutrophil development is largely independent of extracellular glucose. By contrast, during microbial challenge, loss of GLUT1/3 severely compromised NADPH-dependent ROS production, oxidative burst and cyclooxygenase-derived lipid mediator (LM) biosynthesis, demonstrating that glucose uptake via GLUT1/3 controls inflammatory effector functions of neutrophils. Moreover, genetic and pharmacologic inhibition of GLUT1/3-mediated glucose utilization reprograms neutrophil metabolism and LM biosynthesis toward an immunomodulatory phenotype. These findings identify a conserved nutrient-sensing metabolic checkpoint that governs neutrophil reprogramming and highlight novel opportunities for therapeutic immunomodulation.

immunology↗

bioRxiv2025

Tafazzin-Mediated Cardiolipin Remodeling Controls Metabolic Stress Response and Effector Function of Inflammatory T Cells

Clonal expansion and effector differentiation of T cells require extensive metabolic reprogramming. This includes the restructuring of the inner mitochondrial membrane (IMM) to enhance respiration by increasing chemiosmotic coupling efficiency. Cardiolipin, a unique phospholipid that is exclusively synthesized and localized in the IMM, modulates the biophysical properties of the electron transport chain (ETC) in tissues with high energy demands, such as cardiomyocytes and skeletal muscle. However, it remains unclear whether cardiolipin is also important for metabolic remodeling during T helper (Th) cell differentiation. In this study, we show that cardiolipin transacylation, catalyzed by the enzyme Tafazzin, supports the clonal expansion and effector function of inflammatory Th1 and Th17 cells in vitro and in models of autoimmune colitis and encephalomyelitis. At the molecular level, we demonstrate that loss of Tafazzin-mediated cardiolipin maturation induces a metabolic and transcriptional stress response in Th cells to compensate for impaired coupling efficiency of the ETC complexes and disrupted cellular redox homeostasis. However, the genetic program that restores cellular homeostasis and mitigates oxidative stress concurrently impairs the effector functions of inflammatory T cells, such as cytokine production. Our findings also provide insights into the complex clinical manifestation of patients with Barth syndrome (BTHS) caused by mutations in the human TAFAZZIN gene. BTHS is characterized by cardiac and skeletal myopathy as well as neutropenia and an increased susceptibility to infections. Although the molecular basis of the immunodeficiency remains poorly understood, our findings suggest that impaired Th cell function contributes to the immunopathology observed in BTHS patients.

immunology↗

bioRxiv2024

Spatio-temporal dynamics of the fibrotic niche in cardiac repair

The heart is one of the least regenerative organs in humans, and ischemic heart disease is the leading cause of death worldwide. Understanding the cellular and molecular processes that occur during cardiac wound healing is an essential prerequisite to reducing health burden and improve cardiac function after myocardial tissue damage. By integrating single-cell RNA-sequencing with imaging-based spatial transcriptomics, we reconstructed the spatio-temporal dynamics of the fibrotic niche after ventricular injury in adult mice. Our analysis reveals dynamic regulation of local cell communication niches over time. We identified interactions that regulate cardiac repair, including fibroblast proliferation silencing by Trem2high macrophages that prevents excessive fibrosis. Moreover, we discovered a rare population of dedifferentiating cardiomyocytes during early post-lesion stages, which was sustained by signals from myeloid and lymphoid cells. Culturing non-regenerative mouse cardiomyocytes or human heart tissue with these niche factors reactivated progenitor gene expression and cell cycle activity. In summary, this spatio-temporal cell type atlas provides valuable insights into the heterocellular interactions that control cardiac repair. HighlightsO_LIscRNA-seq and in situ sequencing reveal spatio-temporal dynamics of heart repair C_LIO_LILocal heterocellular communication niches coordinate overall wound response C_LIO_LIFibroblast cell cycle silencing by Trem2high macrophages suppresses excessive fibrosis C_LIO_LICardiomyocyte plasticity is promoted by myeloid and lymphoid cells C_LI

systems biology↗

bioRxiv2024

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren's Syndrome

ObjectivesSjogrens Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD. MethodsHistological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 (Stim1/2Foxp3), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells from Stim1/2Foxp3mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects. ResultsStim1/2Foxp3 mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation in Stim1/2Foxp3 mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells from Stim1/2Foxp3 mice demonstrates that the SjD-like disease is driven by interferon (IFN)-{gamma} producing autoreactive CD4+ T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD. ConclusionsWe report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-{gamma} producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.

immunology↗

bioRxiv2023

HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells

Functional exhaustion of T cells in cancer and persistent infections is characterized by the upregulation of inhibitory receptors, the progressive decline in cytokine secretion and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex) with phenotypic features of memory T cells and a stem-like capacity to self-renew. However, the metabolic principles of Tpex maintenance and the regulatory circuits that control the exhaustion of their progeny remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics and metabolomic analyses, we here show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the T cell exhaustion program. At the molecular level, we found that diminished mitochondrial respiration and metabolic remodeling cause oxidative stress, which inhibits the proteasomal degradation of hypoxia inducible factor 1 alpha (HIF-1) in Tpex cells. HIF-1 mediates the transcriptional-glycolytic reprogramming of Tpex cells as an initial step towards terminal differentiation and functional exhaustion. Finally, we show that enhancing respiration by limiting the glycolytic activity of CAR T cells is a feasible metabolic intervention strategy to preserve the stemness of Tpex cells during chronic viral infection and cancer immunotherapy.

immunology↗