Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration

Hobson, Ryan; Levy, Samuel H.S.; Flaherty, Delaney; Xiao, Harrison; Ciener, Benjamin; Reddy, Hasini; Singal, Chitra; Teich, Andrew F.; Shneider, Neil A.; Bradshaw, Elizabeth M.; Elyaman, Wassim

doi:10.1101/2023.07.13.548931

Cited by 5 publications

(2 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A presentation of mitochondrial antigens has also been implicated in adaptive immunity in animal models of PD 17,18 . Finally, T-cells have been shown to adopt reactive phenotypes in PD, and to contribute to neurodegeneration alongside microglia 19,20 .…”

Section: Introductionmentioning

confidence: 99%

The spatial landscape of glial pathology and T-cell response in Parkinson’s disease substantia nigra

Jakubiak,

Paryani,

Kannan

et al. 2024

Preprint

View full text Add to dashboard Cite

Parkinson’s Disease (PD) is a progressive neurodegenerative disease that leads to debilitating movement disorders and often dementia. Recent evidence, including identification of specific peripheral T-cell receptor sequences, indicates the adaptive immune response is associated with disease pathogenesis. However, the properties of T-cells in the brain regions where neurons degenerate are uncharacterized. We have analyzed the identities and interactions of T-cells in PD in post-mortem brain tissue using single nucleus RNA sequencing, spatial transcriptomics and T-cell receptor sequencing. We found that T-cells in the substantia nigra of PD brain donors exhibit a CD8+ resident memory phenotype, increased clonal expansion, and altered spatial relationships with astrocytes, myeloid cells, and endothelial cells. We also describe regional differences in astrocytic responses to neurodegeneration. Our findings nominate potential molecular and cellular candidates that allow a deeper understanding of the pathophysiology of neurodegeneration in PD. Together, our work represents a major single nucleus and spatial transcriptional resource for the fields of neurodegeneration and PD.

show abstract

Section: Introductionmentioning

confidence: 99%

The spatial landscape of glial pathology and T-cell response in Parkinson’s disease substantia nigra

Jakubiak,

Paryani,

Kannan

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The brain’s lymphatics system, hosted by the meninges, may also be a source of non-resident immune cells in the brain, although this remains to be experimentally supported. Immune cell surveillance in the brain’s lymphatic spaces appears to be a constitutive phenomenon[ 18 , 24 ], and cerebrospinal fluid (CSF) immunity appears to influence neuroinflammation[ 25 – 27 ], but migration of immune cells from CSF to parenchyma is not a well-established occurrence. As such, our study focuses on the relationship between the brain and blood-borne immune cells in response to an inflammatory stimulus in the periphery.…”

Section: Introductionmentioning

confidence: 99%

Peripheral endotoxin exposure in mice activates crosstalk between phagocytes in the brain and periphery

Boles,

Huarte,

Tansey

2024

Preprint

View full text Add to dashboard Cite

Background Inflammation is a central process of many neurological diseases, and a growing number of studies suggest that non-brain-resident immune cells may contribute to this neuroinflammation. However, the unique contributions of specific immune cell subsets to neuroinflammation are presently unknown, and it is unclear how communication between brain-resident and non-resident immune cells underlies peripheral immune cell involvement in neuroinflammation.Methods In this study, we employed the well-established model of lipopolysaccharide (LPS)-induced neuroinflammation and captured brain-resident and non-resident immune cells from the brain and its vasculature by magnetically enriching cell suspensions from the non-perfused brain for CD45 + cells. Then, we identified immune subtype-specific neuroinflammatory processes using single-cell genomics and predicted the crosstalk between immune cell subtypes by analyzing the simultaneous expression of ligands and receptors.Results We observed a greater abundance of peripheral phagocytes associated with the brain in this model of neuroinflammation, and report that these professional phagocytes activated similar transcriptional profiles to microglia during LPS-induced neuroinflammation. And, we observed that the probable crosstalk between microglia and peripheral phagocytes was activated in this model while homotypic microglial communication was likely to be decreased.Conclusions Our novel findings reveal that microglia signaling to non-brain-resident peripheral phagocytes is preferentially triggered by peripheral inflammation, which is associated with brain infiltration of peripheral cells. Overall, our study supports the involvement of peripheral immune cells in neuroinflammation and suggests several possible molecular signaling pathways between microglia and peripheral cells that may facilitate central-peripheral crosstalk during inflammation. Examining these molecular mediators in human disease and other rodent models may reveal novel targets that modify brain health, especially in comorbidities characterized by peripheral inflammation.

show abstract

A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis

Boles,

Krueger,

Jernigan

et al. 2023

Preprint

View full text Add to dashboard Cite

The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases (IBDs) displaying an ever-expanding list of neurological comorbidities. To identify molecular systems that underpin this gut-brain connection and thus discover therapeutic targets, experimental models of gut dysfunction must be evaluated for brain effects. In the present study, we examine disturbances along the gut-brain axis in a widely used murine model of colitis, the dextran sodium sulfate (DSS) model, using high-throughput transcriptomics and an unbiased network analysis strategy coupled with standard biochemical outcome measures to achieve a comprehensive approach to identify key disease processes in both colon and brain. We examine the reproducibility of colitis induction with this model and its resulting genetic programs during different phases of disease, finding that DSS-induced colitis is largely reproducible with a few site-specific molecular features. We focus on the circulating immune system as the intermediary between the gut and brain, which exhibits an activation of pro-inflammatory innate immunity during colitis. Our unbiased transcriptomics analysis provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a process vulnerable to increased intestinal permeability, and identifies a possible role for oxidative stress and brain oxygenation. Overall, we provide a comprehensive evaluation of multiple systems in a prevalent experimental model of intestinal permeability, which will inform future studies using this model and others, assist in the identification of druggable targets in the gut-brain axis, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction.

show abstract

Clonal CD8 T cells in the leptomeninges are locally controlled and influence microglia in human neurodegeneration

Cited by 5 publications

References 51 publications

The spatial landscape of glial pathology and T-cell response in Parkinson’s disease substantia nigra

The spatial landscape of glial pathology and T-cell response in Parkinson’s disease substantia nigra

Peripheral endotoxin exposure in mice activates crosstalk between phagocytes in the brain and periphery

A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis

Contact Info

Product

Resources

About