Biology subjects

Pasciuto, E.

Publications and source records attributed to Pasciuto, E..

7 recordsLinked to original sources

bioRxiv2025

The Alzheimer's therapeutic Lecanemab induces an amyloid-clearing program in microglia

Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-A{beta} antibody, mediates amyloid clearance by triggering effector functions in the microglia. Using a human microglia xenograft model, we show that Lecanemab significantly reduces A{beta} pathology and associated neuritic damage, while neither Fc-inactivated Lecanemab nor microglia deficiency elicit this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon gamma genes, and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting A{beta} clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through Fc fragment, providing critical insights for optimizing anti-amyloid therapies in AD.

neuroscience↗

bioRxiv2025

Probabilistic migration events drive transient tissue residency of lymphocytes during homeostasis

Tissue-resident lymphocytes form a phenotypically and functionally distinct analog to the corresponding circulatory lymphocyte populations. Residential CD8 T cells, in particular, are identified as having prolonged residence in the tissues and key functions in recall responses at tissue-environmental interfaces, although the dwell time in individual tissues has yet to be resolved. Residential CD4 T cells, regulatory T cells, B cells, and NK cells have been demonstrated to share phenotypic properties with residential CD8 T cells, but the migratory kinetics are even more poorly defined. Here we used probabilistic modelling on a large parabiosis dataset, covering multiple time-points and tissues, to calculate migration kinetics and dwell times of multiple lymphocyte subsets across a diverse set of tissues. Markov chain modelling identified distinct cell type-specific and tissue-specific residency patterns. The liver and gut were prone to prolonged residency compared to other tissue types, and a hierarchy of residency was observed with CD8 T cells and NK cells demonstrating longer residency than CD4 conventional T cells and regulatory T cells, which in turn resided in tissues longer than B cells. With few exceptions, however, average residency was at least an order of magnitude shorter than the life-span of the mouse, indicating a more dynamic form of steady-state tissue residency than usually assumed. Together these data provide a comprehensive model of a pan-tissue shared program in lymphocyte tissue residence, as well as identifying cell type- and organ-specific modification of the migratory kinetics.

immunology↗

bioRxiv2024

A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases

BackgroundRecent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation for the development and testing of medication that targets human microglia. MethodsWe developed the hCSF1Bdes mouse line suitable as new transplantation model available to be crossed to any disease model of interest. The hCSF1Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additional we crossed this model with two humanized App KI mice, the AppHu and the AppSAA . Flow cytometry, immunohistochemistry and bulk sequencing was used to study the response of microglia in the context of Alzheimers disease. ResultsOur results demonstrate the successful transplantation of iPSC-derived human microglia into the brains of hCSF1Bdes mice without triggering a NK-driven immune response. Furthermore we confirmed the multipronged response of microglia in the context of Alzheimers disease. The hCSF1Bdes and the crosses with the Alzheimers disease knock-in model AppSAA and the humanized App knock-in control mice, AppHu are deposited with EMMA and fully accessible to the research community. Conclusionthe hCSF1Bdes mouse is available for both non-profit and for-profit organisations, facilitating the use of the xenotransplantation paradigm for human microglia to study complex human disease.

neuroscience↗

bioRxiv2023

The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program

The tissues are the site of many of the most important immunological reactions, yet the immunology of the tissues has remained relatively opaque. Recent studies have identified Foxp3+ regulatory T cells (Tregs) in several non-lymphoid tissues. These tissue-resident populations have been ascribed unique characteristics based on comparisons to lymphoid Tregs. Here we performed a systematic analysis of the Treg population residing in non-lymphoid organs throughout the body, revealing shared phenotypes, transient residency and common molecular dependencies. Further, tissue Tregs from different non-lymphoid organs shared T cell receptor (TCR) sequences, with functional capacity to drive multi-tissue Treg entry. Finally, tissue Tregs extracted from non-lymphoid organs were tissue-agnostic on re-entry, without homing preference for their tissue of origin. Together these results demonstrate that the tissue-resident Treg pool in most non-lymphoid organs, other than the gut, is largely constituted by broadly self-reactive Tregs, characterised by transient multi-tissue migration and a common residency program.

immunology↗

bioRxiv2022

The AppNL-G-F mouse model of Alzheimer's disease is refractory to regulatory T cell treatment

BackgroundAlzheimers Disease is a neurodegenerative disease with a neuroinflammatory component. Due to the multifunctional capacity of regulatory T cells to prevent and reverse inflammation, regulatory T cells have been proposed as a potential therapeutic in Alzheimers Disease, either as a direct cell therapy or through the use of IL2 as a biologic to expand the endogenous population. MethodsHere we characterize the longitudinal immunological changes occurring in T cells in the AppNL-G-F mouse model of Alzheimers disease. ResultsAge-dependent immunological changes, in both the brain and periphery, occurred in parallel in both AppNL-G-F mice and control AppNL mice. As the endogenous IL2 axis was disturbed with age, we sought to determine the effect of IL2 supplementation on disease progression. Using a genetic model of IL2 provision in the periphery or in the brain, we found that expanding regulatory T cells in either location was unable to alter the progression of key pathological events or behavioral changes. ConclusionThese results suggest that either the AppNL-G-F mouse model does not recapitulate key regulatory T cell-dependent process of Alzheimers disease, or that regulatory T cell therapy is not a promising candidate for APP-mutation-driven Alzheimers disease.

immunology↗

bioRxiv2022

Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain

Cognitive decline is a common pathological outcome during aging, with an ill-defined cellular or molecular basis. Among the cellular changes observed with age are alterations to neuronal plasticity, changes in the glial compartment and the decline of the neurogenic niche. In the recent years, the concept of inflammaging, defined as a low-grade inflammation increasing with age, has emerged as a nexus for age-related diseases. This increase of basal inflammation is also observed in the central nervous system. While not classically considered a neurological cell type, infiltrating T cells increase in the brain with age, and may be responsible for amplification of inflammatory cascades and disruptions to the neurogenic niche. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2-mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here we test a brain-specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments, and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age-induced defect in spatial learning, without improving the general decline in motor skill or arousal. These results identify immune modulation as a potential path to preserving cognitive function for healthy ageing.

neuroscience↗

bioRxiv2022

Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune-modulation and a delivery system capable of crossing the blood-brain-barrier. The recent identification and characterization of a small population of regulatory T cells (Tregs) resident in the brain presents one such potential therapeutic target. Here we identified brain IL2 levels as a limiting factor for brain-resident Tregs. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially-direct delivery to inflammatory sites. Mice with brain-specific IL2 delivery were protected from traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL2 gene-delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.

immunology↗