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

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

Open access
Schläger, Christian, Körner, Henrike, Krueger, Martin, Vidoli, Stefano, Haberl, Michael, Mielke, Dorothee, Brylla, Elke, Issekutz, Thomas +8 more·2016·Nature

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.

Integrity signals

Registry

Crossref · 10.1038/nature16939

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Dysfunctional meninges represent an important contributor to neuroinflammation in neurodegenerative diseases by acting as a checkpoint for T-cell infiltration.

    “Dysfunctional meninges also represent an important contributor to neuroinflammation in neurodegenerative diseases by acting as a checkpoint for T-cell infiltration.”
  • In the 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.

    “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

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
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
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 › Pathology and Forensic Medicine › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review