Cited by 373Multiple Sclerosis Research StudiesT-cell and B-cell ImmunologyCell Adhesion Molecules Research

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Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid

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Schläger, Christian, Körner, Henrike, Krueger, Martin, Vidoli, Stefano, Haberl, Michael, Mielke, Dorothee, Brylla, Elke, Issekutz, Thomas, Cabañas, Carlos, Nelson, Peter J., Ziemssen, Tjalf, Rohde, Veit, Bechmann, Ingo, Lodygin, Dmitri, Odoardi, Francesca, Flügel, Alexander·2016·Nature

DOI 10.1038/nature16939

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Abstract

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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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: Haberl, Michael
Issekutz, Thomas
Cabañas, Carlos
Nelson, Peter J.
Ziemssen, Tjalf
Rohde, Veit
Bechmann, Ingo
Odoardi, Francesca
Flügel, Alexander
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2016-02
Volume: 530
Issue: 7590
Pages: 349-353
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature16939
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: green
resolver.sub.uni-goettingen.de
Licence: cc-by
www.springer.com/tdm (tdm)
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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Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid

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