Biology subjects

Yshii, L.

Publications and source records attributed to Yshii, L..

6 recordsLinked to original sources

bioRxiv2026

Cirrhosis-associated immune dysfunction presents with preserved circulating lymphocyte function and altered intestinal intraepithelial lymphocyte profile

Bacterial infections are major drivers of decompensation and mortality in cirrhosis, yet the mechanisms underlying cirrhosis-associated immune dysfunction remain incompletely understood. Although current models frequently invoke adaptive immune exhaustion, intestinal intraepithelial lymphocytes (IELs), a central barrier immune compartment responsible for epithelial surveillance and microbial containment, have remained largely unexplored in cirrhosis. Here, we performed integrated immune profiling of paired duodenal biopsies and peripheral blood from healthy volunteers and patients with compensated or decompensated cirrhosis using spectral flow cytometry, plasma proteomics, immunofluorescence, and single-cell RNA sequencing. The healthy duodenal epithelium was dominated by CD8{beta} IELs, whereas cirrhosis was associated with marked depletion of these cells together with expansion of innate cytotoxic populations. Residual IELs exhibited attenuation of antimicrobial transcriptional programs alongside enrichment of innate-like cytotoxic pathways. Loss of CD8{beta} IELs was associated with coordinated reduction of CCR9 surface expression across circulating and mucosal CD8 T-cell compartments together with persistent systemic elevation of CCL25. In contrast, circulating lymphocytes retained functional competence and lacked enrichment of canonical exhaustion markers despite progressive inflammatory remodeling. Collectively, these findings identify defective intestinal IEL compartmentalization as a central feature of cirrhosis-associated immune dysfunction and implicate dysregulation of the CCL25-CCR9 axis in impaired mucosal immune surveillance. HighlightsO_LICirrhosis-associated immune dysfunction reflects defective mucosal immune compartmentalization rather than global adaptive immune paralysis C_LIO_LICirculating lymphocytes retain effector function and do not exhibit canonical exhaustion phenotypes C_LIO_LICD8{beta} intraepithelial lymphocytes are selectively depleted from the duodenal epithelium in cirrhosis C_LIO_LIPersistent systemic CCL25 elevation is associated with coordinated CCR9 loss across mucosal and circulating CD8 T-cell compartments C_LI

immunology↗

bioRxiv2024

Depletion of skin bacteria by topical antibiotic treatment accelerates onset of Zika virus disease in mice.

Mosquito-borne flaviviruses have emerged as global health threats due to their rapid spread and high disease burden. The initial site of virus replication is the mosquito biting site in the host skin, yet the role of host skin bacteria remains unclear. Here, we observed accelerated progression of Zika virus (ZIKV)-induced disease in mice with depleted skin bacteria by topical antibiotic treatment prior to ZIKV infection. Increased viral loads in the blood, draining lymph node, spleen and brain of antibiotic-treated mice suggested faster ZIKV dissemination. Flow cytometry revealed increased frequencies of T cells in the lymph nodes, along with enhanced activation of T cells in the brain upon antibiotic treatment. The antibiotic-induced phenotype was rescued by restoring the skin bacteria prior to infection. Our findings demonstrate an increased susceptibility to ZIKV infection in mice with depleted skin microbiomes, suggesting a potential role of skin bacteria in modulating the infection outcome.

microbiology↗

bioRxiv2024

Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo

The most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a G4C2 repeat expansion in intron 1 of the C9orf72 gene. This repeat expansion undergoes bidirectional transcription to produce sense and antisense repeat RNA species. Both sense and antisense-derived repeat RNAs undergo repeat-associated non-AUG translation in all reading frames to generate five distinct dipeptide repeat proteins (DPRs). Importantly, toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs. This suggests targeting both sense and antisense repeat RNA may provide the most effective therapeutic strategy. The RNA-targeting CRISPR-Cas13 systems offer a promising avenue for simultaneous targeting of multiple RNA transcripts, as they mature their own guide arrays, thus allowing targeting of more than one RNA species from a single construct. We show that CRISPR-Cas13d originating from Ruminococcus flavefaciens (CasRx) can successfully reduce C9orf72 sense and antisense repeat transcripts and DPRs to background levels in HEK cells overexpressing C9orf72 repeats. CRISPR-CasRx also markedly reduced the endogenous sense and antisense repeat RNAs and DPRs in three independent C9orf72 patient-derived iPSC-neuron lines, without detectable off-target effects. To determine whether CRISPR-CasRx is effective in vivo, we treated two distinct C9orf72 repeat mouse models using AAV delivery and observed a significant reduction in both sense and antisense repeat-containing transcripts. Taken together this work highlights the potential for RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS/FTD.

neuroscience↗

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↗