Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment

Piehl, Natalie; Olst, Lynn van; Ramakrishnan, Abhirami; Teregulova, Victoria; Simonton, Brooke; Zhang, Ziyang; Tapp, Emma; Channappa, Divya; Oh, Hamilton; Losada, Patricia Morán; Rutledge, Jarod; Trelle, Alexandra N.; Mormino, Elizabeth C.; Elahi, Fanny M; Galasko, Douglas; Henderson, Victor W.; Wagner, Anthony D.; Wyss‐Coray, Tony; Gate, David

doi:10.1016/j.cell.2022.11.019

Cited by 55 publications

(41 citation statements)

References 57 publications

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“…Meanwhile, CXCL16 was detected in CD8 + T cell enrichment area using RNA in situ hybridization and its transcription level was increased in pSS (Figure 6I, Supplementary Figure 6G). These results indicated that CXCR6-CXCL16 axis might be involved in the infiltration and colonization of CXCR6 + GZMK + CD8 + T cells in LGs, which was consistent with a very recent report that also showed, utilizing a cell-cell communication algorithm, that CXCL16-secreting cells signal to clonal CD8 + T cells via CXCL16-CXCR6 in cognitively impaired cerebrospinal fluid to promote their aggregation to the lesion site (27). Thus, our results suggested that disease-associated CD8 + TRM cells in LG were originated from CD122-expressing CD8 + T cells.…”

Section: Il-15 Prime Cd8 + T Cell Into Trm Precursor In Psssupporting

confidence: 92%

Single-cell profiling reveals pathogenic role and differentiation trajectory of granzyme K+CD8+ T cells in primary Sjögren’s syndrome

Xu¹,

Zhu²,

You³

et al. 2023

JCI Insight

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Primary Sjogren's syndrome (pSS) is a systemic autoimmune inflammatory disease mainly defined by T cell-dominated destruction of exocrine glands. Currently, CD8 + T cells were closely related to the pathogenesis of pSS. However, the single-cell immune profiling of pSS and molecular signatures of pathogenic CD8 + T cells have not been well elucidated.Our multiomics investigation identified that both T cell and B cell, especially CD8 + T cells, were undergoing significant clonal expansion in pSS patients. TCR clonality analysis revealed that peripheral granzyme (GZM) K + CXCR6 + CD8 + T cells had higher proportion of shared clones with CD69 + CD103 -CD8 + tissue resident memory T (TRM) cells in labial glands in pSS. CD69 + CD103 -CD8 + TRM cells featured by high expression of GZMK were more active and cytotoxic in pSS compared with their CD103 + counterparts. Peripheral GZMK + CXCR6 + CD8 + T cells with higher CD122 expression were increased and harbored a gene signature similar to TRM cells in pSS. Consistently, IL-15 was significantly elevated in pSS plasma and showed the capacity to promote differentiation of CD8 + T cells into GZMK + CXCR6 + CD8 + T cells in a STAT5 dependent manner. Taken together, we depicted the immune profile of pSS and further conducted comprehensive bioinformatics analysis and in vitro experimental investigation to characterize the pathogenic role and differentiation trajectory of CD8 + TRM cells in pSS.

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Section: Il-15 Prime Cd8 + T Cell Into Trm Precursor In Psssupporting

confidence: 92%

Single-cell profiling reveals pathogenic role and differentiation trajectory of granzyme K+CD8+ T cells in primary Sjögren’s syndrome

Xu¹,

Zhu²,

You³

et al. 2023

JCI Insight

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“…One of the ways T cells can lead to defects in the CNS structure and function is prompting axon degeneration in a TCR and granzyme B-dependent manner, causing cognitive and motor impairments in the brain of aging mice (Groh et al, 2021). The role of cytotoxic T cells in cognitive decline is further supported by the observations of Piehl et al (2022), which found an increased expression of C-X-C motif chemokine receptor 6 (CXCR6) in the CD8 + T cells within the CSF of cognitively impaired individuals, together with an accumulation of its ligand, C-X-C motif chemokine ligand 16 (CXCL16), suggesting that this damaging subset of T cells is being recruited in the brain.…”

Section: T Cells and Age-related Cognitive Impairmentmentioning

confidence: 75%

“…The ratio of CD4 + T cells to CD8 + T cells is estimated to be around 3.1 to 1. (Piehl et al, 2022;Ransohoff & Engelhardt, 2012). .…”

Section: T Cells and Where To Find Themmentioning

confidence: 99%

Update on the Role of T Cells in Cognitive Impairment

Ruiz-Fernandez

Sánchez-Díaz

Ortega-Sollero

et al. 2023

Preprint

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The central nervous system (CNS) has long been considered an immune-privileged site, with minimal interaction between immune cells, particularly of the adaptive immune system. Previously, the presence of immune cells in this organ was primarily linked to events involving disruption of the blood-brain barrier (BBB) or inflammation. However, current research has shown that immune cells are found patrolling CNS under homeostatic conditions. Specifically, T cells of the adaptive immune system are able to cross the BBB and are associated with aging and cognitive impairment. In addition, T-cell infiltration has been observed in pathological conditions, where inflammation correlates with poor prognosis. Despite ongoing research, the role of this population in the aging brain under both physiological and pathological conditions is not yet fully understood. In this review, we provide an overview of the interactions between T cells and other immune and CNS parenchymal cells, and examine the molecular mechanisms by which these interactions may contribute to normal brain function and the scenarios in which disruption of these connections lead to cognitive impairment. A comprehensive understanding of the role of T cells in the aging brain and the underlying molecular pathways under normal conditions could pave the way for new research to better understand brain disorders.

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“…The CSF immune system dysregulates during healthy brain aging and especially during neurodegenerative processes. Monocytes upregulate lipid processing genes with age in cognitively normal CSF, and particularly in neurodegeneration [ 30 ]. The release of aggregated pathogenic proteins such as Aβ, tau, α-synuclein, mSOD1, and TDP-43 into the extracellular space, drives the changes of microglia and astrocytes into their pro-inflammatory phenotypes ( Figure 1 B).…”

Section: The Bbb the Csf And The Neurodegenerative Diseasesmentioning

confidence: 99%

“…The release of aggregated pathogenic proteins such as Aβ, tau, α-synuclein, mSOD1, and TDP-43 into the extracellular space, drives the changes of microglia and astrocytes into their pro-inflammatory phenotypes ( Figure 1 B). The pro-inflammatory-phenotype astrocytes and activated microglia release pro-inflammatory factors, such as interleukins and tumor necrosis factor α (TNF-α), which act as mediators dysregulating the synaptic function, the BBB, the metabolic function, and CSF and blood flow [ 5 , 29 , 30 , 31 , 32 , 33 , 34 ]. Altogether, the predominance of the pro-inflammatory state results in the increase of pro-inflammatory factors and in a decrease in the protein clearance; and ultimately in disease progression.…”

Section: The Bbb the Csf And The Neurodegenerative Diseasesmentioning

confidence: 99%

Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications

et al. 2023

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Intrathecal pseudodelivery of drugs is a novel route to administer medications to treat neurodegenerative diseases based on the CSF-sink therapeutic strategy by means of implantable devices. While the development of this therapy is still in the preclinical stage, it offers promising advantages over traditional routes of drug delivery. In this paper, we describe the rationale of this system and provide a technical report on the mechanism of action, that relies on the use of nanoporous membranes enabling selective molecular permeability. On one side, the membranes do not permit the crossing of certain drugs; whereas, on the other side, they permit the crossing of target molecules present in the CSF. Target molecules, by binding drugs inside the system, are retained or cleaved and subsequently eliminated from the central nervous system. Finally, we provide a list of potential indications, the respective molecular targets, and the proposed therapeutic agents.

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Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment

Cited by 55 publications

References 57 publications

Single-cell profiling reveals pathogenic role and differentiation trajectory of granzyme K+CD8+ T cells in primary Sjögren’s syndrome

Single-cell profiling reveals pathogenic role and differentiation trajectory of granzyme K+CD8+ T cells in primary Sjögren’s syndrome

Update on the Role of T Cells in Cognitive Impairment

Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications

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