The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid
Open accessAbstract
In multiple sclerosis, brain-reactive T cells invade the central nervous system (CNS) and induce a self-destructive inflammatory process. T-cell infiltrates are not only found within the parenchyma and the meninges, but also in the cerebrospinal fluid (CSF) that bathes the entire CNS tissue. How the T cells reach the CSF, their functionality, and whether they traffic between the CSF and other CNS compartments remains hypothetical. Here we show that effector T cells enter the CSF from the leptomeninges during Lewis rat experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. While moving through the three-dimensional leptomeningeal network of collagen fibres in a random Brownian walk, T cells were flushed from the surface by the flow of the CSF. The detached cells displayed significantly lower activation levels compared to T cells from the leptomeninges and CNS parenchyma. However, they did not represent a specialized non-pathogenic cellular sub-fraction, as their gene expression profile strongly resembled that of tissue-derived T cells and they fully retained their encephalitogenic potential. T-cell detachment from the leptomeninges was counteracted by integrins VLA-4 and LFA-1 binding to their respective ligands produced by resident macrophages. Chemokine signalling via CCR5/CXCR3 and antigenic stimulation of T cells in contact with the leptomeningeal macrophages enforced their adhesiveness. T cells floating in the CSF were able to reattach to the leptomeninges through steps reminiscent of vascular adhesion in CNS blood vessels, and invade the parenchyma. The molecular/cellular conditions for T-cell reattachment were the same as the requirements for detachment from the leptomeningeal milieu. Our data indicate that the leptomeninges represent a checkpoint at which activated T cells are licensed to enter the CNS parenchyma and non-activated T cells are preferentially released into the CSF, from where they can reach areas of antigen availability and tissue damage.
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“Dysfunctional meninges also represent an important contributor to neuroinflammation in neurodegenerative diseases by acting as a checkpoint for T-cell infiltration.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [685]
In the citing paper
“In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, autoreactive effector T cells first infiltrate the leptomeninges via the pial vasculature, are activated by antigen presenting meningeal/perivascular macrophages, and subsequently enter the CNS parenchyma, triggering lesion formation”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Schläger et al., 2016
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Metadata
- Authors
- Schläger, C., Körner, H., Krueger, M., Vidoli, S., Haberl, M., Mielke, D., Brylla, E., Issekutz, T., Cabañas, C., Nelson, P. J., Ziemssen, T., Rohde, V., Bechmann, I., Lodygin, D., Odoardi, F., & Flügel, A.
- Affiliations
- Universitätsmedizin Göttingen (DE)
- Leipzig University (DE)
- Sapienza University of Rome (IT)
- Dalhousie University (CA)
- Centro de Biología Molecular Severo Ochoa (ES)
- Ludwig-Maximilians-Universität München (DE)
- University Hospital Carl Gustav Carus (DE)
- Corresponding author
- Flügel, Alexander
- ORCID
- Venue
- Nature
- Published
- 2016-02
- Volume
- 530
- Issue
- 7590
- Pages
- 349-353
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2261157573
- Cited by
- 372
- References
- 53
- Citations by year
- 2026: 14 · 2025: 35 · 2024: 34 · 2023: 49 · 2022: 45 · 2021: 46 · 2020: 34 · 2019: 33 · 2018: 32 · 2017: 34 · 2016: 15
- FWCI
- 34.54
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- GRO (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- T cell migration, cerebrospinal fluid, leptomeninges, experimental autoimmune encephalomyelitis, multiple sclerosis, autoreactive T cells, integrins, VLA-4, LFA-1, chemokines, T cell activation, Brownian motion, choroid plexus
- MeSH terms
- Animals, Cell Adhesion, Cell Movement, Cerebrospinal Fluid, Choroid Plexus, Collagen, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Lymphocyte Activation, Macrophages, Male, Meninges, Multiple Sclerosis, Rats, Inbred Lew, T-Lymphocytes, Lymphocyte Function-Associated Antigen-1, Chemokines, Adoptive Transfer, Receptors, CCR5, Integrin alpha4beta1, Rats, Receptors, CXCR3
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