Biology subjects

Bopp, T.

Publications and source records attributed to Bopp, T..

7 recordsLinked to original sources

bioRxiv2026

Oligodendrocyte subtype diversity underlines clinical progression in Parkinsons disease

Despite growing evidence for glial involvement in Parkinsons disease, oligodendrocyte dysfunction remains poorly defined. To address this gap, we compared single-cell RNA sequencing from a mouse model of -synuclein aggregation pathology with fresh human brain tissue from deep brain stimulation surgery to build a cross-species framework of disease progression. In total, we profiled over 200,000 cortical transcriptomes, including 55,000 oligodendrocytes. Early disease in mice was characterized by inflammatory activation, while advanced stages in both species converged on metabolic dysfunction, including impaired ribosomal output, chaperone stress responses, ubiquitination deficits, and lysosomal perturbation. In patients, APLP1 was upregulated and correlated with clinical disease progression and increased levodopa demand, linking -synuclein spread in oligodendrocytes to disease severity. APP and CNTN pathways emerged as key signalling axes, with CNTN reflecting weakened reparative communication and reduced resilience. Together, these findings define oligodendrocyte subtype dynamics as shared and clinically relevant features of PD progression.

neuroscience↗

bioRxiv2025

Single-cell chromatin landscape and DNA methylation patterns reveal shared molecular programs in human tumor and non-tumor tissue CCR8+ Treg cells

Regulatory T (Treg) cells, a subset of CD4+ T cells, play a crucial role in immunoregulation. Notably, CCR8-expressing Treg cells in tissues also contribute to organ homeostasis and repair. To determine whether these tissue-regenerative programs are active in the tumor microenvironment, we employed single-cell chromatin accessibility and genome-wide DNA methylation analyses to investigate CCR8+ tissue Treg cells isolated from human tumor and adjacent tumor-free tissues. Our findings indicate that CCR8+ tissue Treg cells from tumor and corresponding tumor-free tissues exhibit a high degree of similarity, suggesting that the tumor microenvironment may harbor highly activated tissue Treg cells. This observation was consistent across various tumor types and origins, including primary tumors and metastases. Using quantitative proteomics, we identified several candidate factors associated with the regenerative and suppressive programs of Treg cells, which may serve as potential reservoir of druggable targets for future therapeutic interventions.

immunology↗

bioRxiv2025

B cells maintain the homeostasis of splenic marginal zone antigen-presenting cells to promote the anti-viral CD8+ T cell response

Natural killer and CD8+ T cells are critical in the elimination of blood-borne viruses such as cytomegalovirus (CMV); however, the role of B cells in this process is less clear. Here, using the murine CMV (MCMV) infection model, we demonstrated that the B cell-deficient mice mounted a weaker primary virus-specific CD8+ T cell response than their wild-type counterparts, which was associated with increased viral transcription. Notably, we found that the contribution of B cells to the CD8+ T-cell-mediated anti-viral response was not associated with their ability to generate antibodies but with their ability to sustain Langerin+ type 1 conventional dendritic cells (cDC1s), a dendritic cells (DC) subset known for being involved in viral and bacterial clearance in the marginal zone of the spleen. Furthermore, we found that the presence of Langerin+ cDC1s is dependent on B cells expressing lymphotoxin (LT{beta}) to maintain CD169+ marginal metallophilic macrophages (MMMs). We further discovered, using ligand-receptor interaction analyses, that the communication between MMMs and Langerin+ cDC1s was mediated via VCAM1 - ITGA4/ITGB1 interaction. Thus, our data reveals that B cell regulate the development of MMMs in the spleen via LT{beta} expression and consequently sustain Langerin+ cDC1s homeostasis for effective initiation of an anti-viral CD8+ T cell response. Overall, our study offers a new perspective on how B cells maintain the homeostasis of antigen-presenting cells in the splenic marginal zone and thus indirectly affect the virus-specific CD8+ T cell response, which could potentially be extended to other infectious and autoimmune diseases as well as tumors.

immunology↗

bioRxiv2024

Non-invasive visualization of pH changes within the tumor-micro-environment by positron emission tomography

Slight changes in the pH value of the tumor microenvironment (TME) have crucial effects on host defense, metastatic behavior, immune regulation and cellular metabolism. Due to the high metabolic activity and insufficient perfusion of tumors, acidic metabolites often accumulate in tumors and can influence the pH of the TME. Several studies have shown that the acidity of the interstitial space and the relatively stable intracellular pH can influence the functions of cancer and stromal cells and their interaction with the extracellular matrix. We describe radiopharmaceutical probes for positron emission tomography (PET) that exploits the increasingly used concept of pH-dependent intratumorally cleavage of PET-tracer to release functional moieties. The radiopharmaceuticals are based on [18F]FDG, a PET tracer, routinely used, and substituents that are pH-dependently cleaved. Utilizing preclinical models, we were able to visualize small pH differences in the acidic TME of different tumors with [18F]FDG-4-methoxybenzylamine ([18F]FDG-4MBA). In vivo studies were in line with in vitro results and showed that the hemiaminal bond between FDG and a substitute is cleaved at slightly acidic pH and leads to pH dependent radiotracer uptake. In vivo neutralization of the acidic extracellular tumor pH by sodium bicarbonate treatment prevents pH-dependent cleavage of [18F]FDG-4MBA and a resulting decrease of uptake. The determination of pH differences in acidic TME may serve as a novel marker for various questions such as regulation of the response to immunotherapies. Notably, even small pH differences in the acidic TME of different tumors, in the same in vivo model, could be visualized. This is the first preclinical study to show that it is possible to visualize small pH differences in the TME of different tumors in the same mouse using hemiaminal bound [18F]FDG. Due to the facile tracer synthesis and application, this system could be well suited for translation into clinical studies to develop new strategies of pH regulation to improve the efficacy of immunotherapy in cancer patients. graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/624628v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1c338c8org.highwire.dtl.DTLVardef@1c4fc67org.highwire.dtl.DTLVardef@197036aorg.highwire.dtl.DTLVardef@1613fa2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

CREB determines the expression of ST2 in Tregs and mediates the balance between type 1 and type 2 immune responses

Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. Here we demonstrate that in mice with a Foxp3-specific knockout of CREB, enhanced numbers of Tregs are found in vivo in spleen, lung and colon. These Tregs display a reduced Foxp3 expression, but enhanced expression of the IL-33 receptor (ST-2), IL-10, IL-13, and CREM. CREB deficient Tregs were highly suppressive in vitro and prevented disease activity in CD4 T cell mediated transfer colitis in an IL-10 dependent way. Mechanistically CREB fulfils dual roles in Tregs. First it downregulates Foxp3 expression, however in cooperation with CREM, CREB expression in Tregs alters chromatin accessibility to the ST-2 region and thereby influences T cell specific immune responses mediated by IL-10. Brief summary: Mice with a Foxp3-specific knockout of CREB display enhanced expression of IL-13, IL-10, ST-2 and CREM, which prevents gut inflammation GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/601312v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@a2d341org.highwire.dtl.DTLVardef@1db6852org.highwire.dtl.DTLVardef@19e024borg.highwire.dtl.DTLVardef@a8c84d_HPS_FORMAT_FIGEXP M_FIG C_FIG Created by Biorender

immunology↗

bioRxiv2023

Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

The transcription factor interferon regulatory factor 4 (IRF4) is crucial for the differentiation and fate determination of pro-inflammatory T helper (Th)17 and the functionally opposing group of immunomodulatory regulatory T (Treg) cells. However, molecular mechanisms of how IRF4 steers diverse transcriptional programs in Th17 and Treg cells are far from being definitive. To unveil IRF4-driven lineage determination in Th17 and Treg cells, we integrated data derived from affinity-purification and full mass spectrometry-based proteome analysis with chromatin immune precipitation sequencing (ChIP-Seq). This allowed the characterization of subtype-specific molecular programs and the identification of novel, previously unknown IRF4 interactors in the Th17/Treg context, such as ROR{gamma}t, AHR, IRF8, BACH2, SATB1, and FLI1. Moreover, our data reveal that most of these transcription factors are recruited to IRF composite elements for the regulation of cell type-specific transcriptional programs providing a valuable resource for studying IRF4-mediated gene regulatory programs in pro- and anti-inflammatory immune responses.

immunology↗

bioRxiv2022

IRF4 deficiency vulnerates B cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity

The processes leading from disturbed B cell development to adult B cell progenitor acute lymphoblastic leukemia (BCP-ALL) are poorly understood. Here, we describe Irf4-/- mice as prone to developing BCP-ALL with age. Irf4-/- preB-I cells exhibited impaired differentiation but enhanced proliferation in response to IL-7, along with reduced retention in the IL-7 providing bone marrow niche due to decreased CXCL12 responsiveness. Thus selected, preB-I cells acquired Jak3 mutations, probably following irregular AID activity, resulting in malignant transformation. We demonstrate heightened IL-7 sensitivity due to Jak3 mutants, devise a model to explain it and describe structural and functional similarities to Jak2 mutations often occurring in human Ph-like ALL. Finally, targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4-/- leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. In this work, we present spontaneous leukemogenesis following IRF4 deficiency with potential implications for high-risk BCP-ALL in adult humans.

cancer biology↗