Biology subjects

Grimm, A.

Publications and source records attributed to Grimm, A..

10 recordsLinked to original sources

bioRxiv2026

CD19 CAR Engineered T Regulatory Cells Promote Durable Immune Tolerance in Experimental Systemic Lupus Erythematosus

While the immune reset induced by CD19 CAR T therapies has shown striking promise in systemic lupus erythematosus (SLE), the nature and duration of benefit mediated by B cell depletion remains unclear. Loss of tolerance in SLE is driven by extrafollicular and germinal center interactions between dendritic cells and self-reactive T and B cells. We hypothesized that CD19 CAR-engineered regulatory T cells (CAR19 EngTreg), capable of suppressing multiple autoimmune effector cell types, might promote long-term tolerance without producing high-levels of inflammatory mediators. To generate CAR19 EngTreg, we combined CD19 CAR delivery with homology directed repair at the FOXP3 locus to drive constitutive, stable FOXP3 expression in CD4 T cells. CAR19 EngTreg expressed canonical Treg markers; exhibited minimal inflammatory cytokine production; and blocked human B cell differentiation into antibody secreting plasma cells. In humanized mouse models, transfer of CAR19 EngTreg led to a reduction in B cell numbers with low inflammatory cytokine production relative to CD19 CAR Teff, and reduced tissue inflammation. In a short-term, in vivo imiquimod-induced inflammatory model, murine CAR19 EngTreg reduced skin pathology, spleen size, and inflammatory cytokines. Finally, in two distinct mouse models of lupus, CAR19 EngTreg persisted for >4 months leading to reduced autoimmune T and B effector populations, sustained reduction in multiple autoantibodies and improved renal function and histopathology. Thus, CAR19 EngTreg may offer a promising and durable therapeutic avenue for B cell-mediated autoimmune disorders capable of long-term regulation of both autoreactive B and T cells.

immunology↗

bioRxiv2026

An extraglomerular relay circuit for multimodal integration within the Drosophila antennal lobe

The central integration of sensory information within and between brain hemispheres is critical for efficient behavioral responses, but at which level of information processing multimodal integration occurs is poorly understood. In olfactory systems an array of receptor-specific synaptic glomeruli with corresponding projection neurons (PNs) form separate sensory channels within each hemisphere, which run in parallel with other sensory modalities to converge at higher brain regions. We recently identified a small cluster of commissural pioneer neurons (cPINs) in the Drosophila olfactory system, which controls the formation of bilateral sensory circuits to support interhemispheric integration at the first synaptic layer. Here we show that cPINs also mediate the integration of sensory channels by relaying class-specific input within the antennal lobe. Functional studies showed that medial cPINs converge olfactory amine/ammonia input with a class of non-olfactory PNs to trigger attraction. During olfactory circuit formation, growing cPINs specify separate dendritic input/output domains, which merge into distinct glomeruli of different sensory modalities. Mutant analysis of the Wnt5 pathway revealed that cPINs display an initial PN-related growth pattern, which becomes redirected to organize lateral relay between sensory channels. These results identified a small cluster of olfactory interneurons as a central coordinator for fast convergence of sensory information, providing a mechanistic model of neural circuit evolution.

neuroscience↗

bioRxiv2025

Cryo-EM structure of a cell-free synthesized full-length human β1-adrenergic receptor in complex with Gs

The third intracellular loop (ICL3) of the {beta}1-adrenergic receptor ({beta}1AR) plays a critical role in regulating G protein coupling, yet the structural basis has remained unclear due to truncations of ICL3 in all available structures of the {beta}1AR in complex with Gs or a G protein mimetic nanobody. To address this, we used cell-free cotranslational insertion of full-length human {beta}1AR into nanodiscs and determined its cryo-EM structure in complex with Gs. In this structure, ICL3 extends transmembrane helix 5, resulting in enhanced interactions with Gs and in a slight rotation of the engaged G protein. This repositioning enables new polar interactions between Gs, ICL2 and helix 8, while ICL1 and helix 8 form additional contacts with G{beta}. These structural insights, supported by mutational analysis, demonstrate that ICL3 enhances G protein activation and downstream cAMP signaling by promoting more extensive interactions between the receptor and the heterotrimeric G protein.

biochemistry↗

bioRxiv2025

Abnormal Tau Protein Influences Intercellular Mitochondrial Transfer Between Astrocytic and Neuronal Cells

Tauopathies are a group of neurodegenerative diseases characterized by the pathological accumulation of abnormal tau protein. A consequence of tau pathologies is mitochondrial dysfunctions, which affect essential processes such as mitochondrial transport, bioenergetics, and dynamics. Given the high energy demands of neurons, tau-induced mitochondrial impairment significantly contributes to neuronal vulnerability and degeneration. Recent studies have revealed that cells can transfer mitochondria between them to help energy-deficient cells. This process, known as intercellular mitochondrial transfer, occurs through two different pathways: an indirect transfer via extracellular vesicles and a direct transfer via tunneling nanotubes and gap junctions. Given the known impact of abnormal tau protein on mitochondrial transport and actin filament dynamics, we hypothesized that intercellular mitochondrial transfer could be altered in the context of tauopathies. Therefore, this study aimed to investigate mitochondrial transfer between astrocytic and neuronal cells and assess how abnormal tau protein may influence this process. Our results showed that abnormal tau protein enhances mitochondrial transfer from astrocytic to neuronal cells. Notably, this transfer occurs mainly via contact-dependent mechanisms. In both pathological and healthy conditions, the transferred astrocytic mitochondria either fused with the mitochondrial network of recipient cells or were degraded in the lysosomes or remained isolated in the cytosol. Our data highlight a novel pathway by which abnormal tau protein impacts mitochondrial function, namely the transfer of astrocytic mitochondria to neuronal cells.

neuroscience↗

bioRxiv2024

Metabolic enzymes moonlight as selective autophagy receptors to protect plants against viral-induced cellular damage

AbstractRNA viruses co-opt the host endomembrane system and organelles to build replication complexes for infection. How the host responds to these membrane perturbations is poorly understood. Here, we explore the autophagic response of Arabidopsis thaliana to three viruses that hijack different cellular compartments. Autophagy is significantly induced within systemically infected tissues, its disruption rendering plants highly sensitive to infection. Contrary to being an antiviral defense mechanism as previously suggested, quantitative analyses of the viral loads established autophagy as a tolerance pathway. Further analysis of one of these viruses, the Turnip Crinkle Virus (TCV) that hijack mitochondria, showed that despite perturbing mitochondrial integrity, TCV does not trigger a typical mitophagy response. Instead, TCV and Turnip yellow mosaic virus (TYMV) infection activates a distinct selective autophagy mechanism, where oligomeric metabolic enzymes moonlight as selective autophagy receptors and degrade key executors of defense and cell death such as EDS1. Altogether, our study reveals an autophagy-regulated metabolic rheostat that gauges cellular integrity during viral infection and degrades cell death executors to avoid catastrophic amplification of immune signaling.

plant biology↗

bioRxiv2024

Human iPSCs from aged donors retain their mitochondrial aging signature

Aging represents the main risk factor for developing neurodegenerative disorders. One of the hallmarks of aging is mitochondrial dysfunction. Age-related mitochondrial alterations have been shown to affect mitochondrial energy metabolism and redox homeostasis as well as mitochondrial dynamics. In the present study, we addressed the question of whether or not, induced pluripotent stem cells (iPSCs) may be used as a model of "aging in a dish" to identify therapies at alleviating the aging of mitochondria. Notably, we could demonstrate that compared to human iPSCs from young donors, those from aged donors show impaired mitochondrial bioenergetics and exhibit a rise in reactive oxygen species generation. Furthermore, we demonstrate that iPSCs from aged donors present low mitochondrial mass and alterations of the morphology of the mitochondrial network. This study provides evidence that the aging phenotype is present at the mitochondrial level in iPSCs from aged donors, ranging from bioenergetics to dynamics. Thus, this model can be used for high through put screening to identify drugs that improve mitochondrial function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/589733v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@17c5ccorg.highwire.dtl.DTLVardef@bae9aaorg.highwire.dtl.DTLVardef@142d8e6org.highwire.dtl.DTLVardef@1adf519_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Preservation of an Aging-Associated Mitochondrial Signature in Advanced Human Neuronal Models

1.This study investigated whether induced pluripotent stem cell-derived neurons (iPSCsNs) and directly converted neurons (iNs) generated from the same cells of origin (human fibroblasts) represent aging-related characteristics on mitochondrial levels. There is still uncertainty regarding the potential for rejuvenation or preservation of an aging-associated donor signature in aged iPSCsNs upon transition through pluripotent states, while direct conversion retains the aging-associated mitochondrial impairments. Surprisingly, both aged neuronal models exhibited age-associated donor phenotypes, including decreased ATP, mitochondrial membrane potential, mitochondrial respiration, NAD+/NADH ratio, and increased radical levels and mitochondrial mass. Besides, a fragmented mitochondrial network was observed in both aged neuronal models. However, unlike aged iNs, aged iPSCsNs did not show a metabolic shift towards anaerobic glycolysis to compensate for the energy deficit. Moreover, the mRNA expression profile significantly differed between aged iPSCsNs and aged iNs. Our study indicates that aged iPSCsNs may experience rejuvenation in certain parameters, such as transcriptomics and the aging-associated glycolytic shift. Nevertheless, aged iPSCsNs can be a valuable tool for studying neuronal aging of mitochondrial parameters in vitro alongside aged iNs.

neuroscience↗

bioRxiv2022

Tumor Microenvironment Cellular Crosstalk Predicts Response to Adoptive TIL Therapy in Melanoma

Adoptive cell therapy (ACT) using ex vivo expanded tumor-infiltrating T lymphocytes (TILs) can mediate responses in metastatic melanoma, but long-term efficacy remains limited to a fraction of patients. Here we interrogated tumor-microenvironment (TME) cellular states and interactions of longitudinal samples from 13 metastatic melanoma patients treated with TIL-ACT in our clinical study (NCT03475134). We performed single-cell RNA-seq and spatial proteomic analyses in pre- and post-ACT tumor tissues and showed that responders exhibited higher tumor cell-intrinsic immunogenicity. Also, endogenous CD8+ TILs and myeloid cells of responders were characterized by increased cytotoxicity, exhaustion and costimulation and type-I IFN signaling, respectively. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders have rich baseline intratumoral and stromal tumor-reactive T-cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study reveals CD8+ T-cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials. One-Sentence SummaryResponse to adoptive TIL therapy in melanoma is determined by CD8+ TIL-myeloid cell networks

immunology↗

bioRxiv2021

Mutant huntingtin crosses the neuromuscular junction and causes transmission-selective pathological alterations in huntingtin expressing myotubes

A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain of patients with neurodegenerative protein misfolding diseases (PMDs) is cell-to-cell transmission of aggregation-prone, misfolded proteins. Little is known about central to peripheral transmission and its contribution to pathology. We show that transmission of Huntingtons disease- (HD-) associated mutant HTT exon 1 (mHTTEx1) occurs across the neuromuscular junctions in human iPSC cultures and in vivo in wild-type mice. We found that transmission is an active and dynamic process, that happens prior to aggregate formation and is regulated by synaptic activity. Furthermore, we find that transmitted mHTTEx1 causes HD-relevant pathology at a molecular and functional level in human muscle cells, even in the presence of ubiquitous expression mHTTEx1. With this work we uncover a casual-link between mHTTEx1 synaptic transmission and pathology, highlighting the therapeutic potential in blocking toxic protein transmission in PMDs.

neuroscience↗

bioRxiv2018

Tolerogenic transcriptome landscape in CD8+ T lymphocytes after exposure to erythrocyte-targeted antigens

Our group has recently shown induction of antigen-specific T cell tolerance through targeting of the antigen to erythrocytes in situ. The tolerogenic state is characterized by initial proliferation of antigen-specific T cells and subsequent acquisition of signatures associated with both deletional, anergic and regulatory T cell phenotypes. In this study we wished to further understand the molecular mechanisms behind induction of tolerance by erythrocyte-targeted antigens. RNA sequencing was performed to determine how gene expression response is regulated in tolerized ovalbumin-specific CD8+ T cells and which molecular pathways are activated after treatment with this technology. Treatment with erythrocyte-targeted antigens led to the upregulation of genes encoding several TCR co-inhibitory receptors such as CTLA4, PD1, LAG3, TIGIT and CD200R1, and lack of upregulation of cytotoxic and pro-inflammatory signaling molecule genes. Modulation in expression of the master transcription factors Egr2/NFatc1, Nur77 family and E2f1 was also observed, all known to be associated with the natural process of establishment of peripheral tolerance. Expression of these genes differed in response to treatment with soluble ovalbumin or SIINFEKL MHCI peptide, suggesting a specific mechanism of T cell modulation and tolerance induction in response to the erythrocyte-associated forms.

immunology↗