Biology subjects

Gasteiger, G.

Publications and source records attributed to Gasteiger, G..

7 recordsLinked to original sources

bioRxiv2026

Mite-induced migratory skin-like CD103+ ILC2s establish lung residency and impact immunity

Tissue-resident immune cells are critical for lung homeostasis and protection against inflammation. Here, we describe a novel population of migratory inflammatory CD103+ skin ILC2s (skILC2s) that accumulate in the lung vasculature following transient infestation with ubiquitous Demodex mites, hair follicle commensals that drive local skILC2 proliferation and entry into blood. With time, ex-skILC2s become tissue resident in the lung, occupy previously described immune cell adventitial niches and respond earlier to lung perturbations than endogenous lung ST2+ ILC2s to alter the trajectories of a subsequent immune response. Thus, like transiting ex-gut ILC2s described after small intestinal infection by helminths and protists, ex-skILC2s migrate post-birth in response to pathobionts to change the inflammatory milieu of the lung, revealing a common paradigm by which internal mucosal responses become shaped by ILC2s from barrier epithelia colonized post-birth. HighlightsO_LIDemodex mites infestation drives local expansion of CD103+ skin ILC2s that egress and enter the circulation C_LIO_LIMigratory CD103+ skin-like ILC2s infiltrate into lung, adapt to the local environment and establish long-term residency C_LIO_LIPrior Demodex mite exposure re-organizes the lung ILC2 landscape C_LIO_LIThe distinct cytokine and receptor repertoire of ex-skILC2 alters lung immunity C_LI

immunology↗

bioRxiv2025

Immunological liver-skin axis: a systemic Vγ4+ γδT17 cell responselinks psoriasis-like inflammation and MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) and psoriasis frequently co-occur and share interleukin-17 (IL-17)-mediated inflammatory mechanisms. Using a murine model combining Western-diet-induced early MASLD with chronic imiquimod-triggered psoriasis-like dermatitis, we observed exacerbated skin inflammation with increased cellularity and systemic IL-17-driven immune activation. In mice with psoriasis-like skin inflammation, hepatic {gamma}{delta}T cells shifted from IFN-{gamma}-producing {gamma}{delta}T1 toward IL-17-secreting {gamma}{delta}T17 cells, accompanied by an acute-phase response and induction of hepatic lipogenic gene expression. Single-cell RNA sequencing revealed an expansion of V{gamma}4 {gamma}{delta}T17 cells engaged in IL-17 and TGF-{beta} signaling, consistent with early fibrogenic responses. Together, these findings identify V{gamma}4 {gamma}{delta}T17 cells as a mechanistic link between psoriasis and MASLD, promoting systemic inflammation and early hepatic remodeling. Consistently, in a clinical cohort of patients with moderate-to-severe psoriasis and co-morbid MASLD, IL-17-targeted therapy improved hepatic steatosis, underscoring the translational relevance of this immunological axis.

immunology↗

bioRxiv2025

Changes in peripheral blood leukocyte composition precede development of heart-reactive autoantibodies in patients hospitalised for acute heart failure

In a retrospective pilot study, we showed that the induction of heart-reactive autoantibodies (HRA) in the wake of acutely decompensated heart failure predicts worse outcomes. To gain deeper insights into the immunological mechanisms causing induction of HRA after heart failure decompensation we initiated the prospective Acute Heart Failure-Immunomonitoring Cohort Study (AHF-ImmunoCS). For this study, 380 patients were enrolled and will be followed up, including serial collection of biomaterials, for a period of 18 months after the index hospitalisation for AHF. Analysis of AHF-ImmunoCS samples obtained at baseline and at 6-month follow-up from 110 patients showed de novo induction of HRA - as detected by indirect immunofluorescence (IFT) - in 21% of patients (previously published percentage: 32%). The IFT results did not reflect induction of broad anti-heart autoimmunity as autoantibodies against other cardiac antigens like Troponin I3 or Myosin Light Chain 7 were not induced in parallel. To understand what drives HRA induction in these patients we longitudinally immunophenotyped peripheral blood leukocytes at baseline, 6-week and 6-month follow-up by high-resolution spectral flow cytometry. Among lymphocytes, induction of HRA in the wake of acute decompensation of heart failure was associated with a higher proportion of CD4+ T cells among lymphocytes, more CD45RA+ CCR7+ naive conventional, i.e. non-regulatory, and more CXCR3+ CCR4- Th1 cells among CD4+ T cells at baseline. Among myeloid cells, there were no differences at baseline between patients going on to develop HRA and those that did not. However, patients developing HRA had higher proportions of eosinophils (six-month follow-up) and lower proportions of Arginase+ HLA-DR- polymorphnuclear myeloid-derived suppressor cells among myeloid cells (six-week and six-month follow-up). Our data, thus, implicate that alterations in the composition of both the lymphoid and the myeloid compartments might drive HRA induction which impacts disease progression and prognosis in AHF.

immunology↗

bioRxiv2025

STAT3 operates as an inflammation-dependent transcriptional switch

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of immune cell function, but its role in lymphocytes remains incompletely understood. Here, we show that STAT3 has a context-dependent function in antiviral natural killer (NK) cells, either promoting or impairing adaptive NK cell responses dependent on the level of inflammation. STAT3 is recruited to distinct genomic sites under homeostatic versus inflammatory environments, where it drives different transcriptional programs. Through this re-localization, STAT3 regulates downstream transcription factors MYB and BLIMP-1 in an inflammation-dependent manner to shape NK cell differentiation under homeostasis and during infection. Thus, STAT3 acts as a transcriptional switch that integrates cytokine signals to control lymphocyte adaptation to different environments. This mechanism highlights how therapeutic interventions targeting STAT3 can result in different outcomes depending on the degree of inflammation. HIGHLIGHTS- STAT3 exerts a context-dependent role on adaptive NK cells during viral infection - STAT3 modulates IL-15 signaling by competing with STAT5 and regulating MYB - Homeostatic versus inflammatory cytokines relocate STAT3 to distinct genomic sites - Downstream transcription factors MYB and BLIMP-1 govern STAT3-dependent differentiation

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↗

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↗

bioRxiv2022

A novel lineage of RORγt+Aire+ antigen presenting cells promotes peripheral generation of intestinal regulatory T cells and tolerance during early life

Establishing and maintaining tolerance to self- or innocuous foreign antigens is vital for preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing AutoImmune Regulator, Aire, play a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery, upon exposure to dietary and commensal microbiota derived antigens, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells are not known. Here we identified a new class of ROR{gamma}t+ antigen-presenting cells (APC), dubbed Thetis cells (TCs), with transcriptional features of both mTECs and dendritic cells (DCs), comprising 4 major sub-groups (TC I-IV). We uncovered a developmental wave of TCs within intestinal lymph nodes during a critical early life window, coincident with the wave of pTreg cell differentiation. While TC I and III expressed the signature mTEC nuclear factor Aire, TC IV lacked Aire expression and were enriched for molecules required for pTreg generation, including the TGF-{beta} activating integrin v{beta}8. Loss of either MHCII or Itgb8 expression by TCs led to a profound impairment in intestinal pTreg differentiation, with onset of intestinal inflammation. In contrast, MHCII expression by ROR{gamma}t+ group 3 innate lymphoid cells (ILC3) and classical DCs was neither sufficient nor required for pTreg generation, further implicating TCs as the tolerogenic ROR{gamma}t+ APC with an essential early life function. Our studies reveal parallel pathways for establishment of tolerance to self and foreign antigen within the thymus and periphery, marked by involvement of shared cellular and transcriptional programs.

immunology↗