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Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions


The tissues of the central nervous system are effectively shielded from the blood circulation by specialized vessels that are impermeable not only to cells, but also to most macromolecules circulating in the blood. Despite this seemingly absolute seclusion, central nervous system tissues are subject to immune surveillance and are vulnerable to autoimmune attacks1. Using intravital two-photon imaging in a Lewis rat model of experimental autoimmune encephalomyelitis, here we present in real-time the interactive processes between effector T cells and cerebral structures from their first arrival to manifest autoimmune disease. We observed that incoming effector T cells successively scanned three planes. The T cells got arrested to leptomeningeal vessels and immediately monitored the luminal surface, crawling preferentially against the blood flow. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying leptomeningeal (pial) membrane. There, the T cells encountered phagocytes that effectively present antigens, foreign as well as myelin proteins. These contacts stimulated the effector T cells to produce pro-inflammatory mediators, and provided a trigger to tissue invasion and the formation of inflammatory infiltrations.

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Figure 1: Intravital two-photon recording of T MBP–GFP cells entering the leptomeninges.
Figure 2: T MBP–GFP cell locomotion within meningeal CNS structures.
Figure 3: Effector T cells leaving the leptomeningeal vessels encounter perivascular/meningeal antigen-presenting cells.
Figure 4: Brain-antigen-ignorant effector T cells invade the CNS tissue after antigen-driven activation.

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We thank S. Kosin, I. Haarmann, C. Federle, T. H. Ngugen and K. Nispel for technical assistance. We thank M. Krumbholz for help in statistical analysis, M. Hübener for support in 3D analysis software, and K. Dornmair, E. Meinl and E. Lütjen-Drecoll for critical comments on the paper. We are grateful to V. Staiger for providing software and R. Schorner for help with the artwork. This work was supported by the Deutsche Forschungsgemeinschaft (SFB455 project A8 and SFB571 project C6) and the Hertie foundation (Hertie no.1.01.1/04/010).

Author Contributions I.B., N.K. and C.S. performed most of the imaging experiments. N.K., F.O. and D.M. performed the experiments testing the antigen presentation capacity of meningeal/perivascular macrophages. F.O. performed the transcriptome analyses, EAE studies and cytofluorometric characterizations. W.E.F.K. and J.W.E. performed cell sorting. C.F.-K. contributed to the immunohistochemical studies. T.B.I. provided a monoclonal antibody. A.F. coordinated the experimental work. A.F. and H.W. designed the study and wrote the manuscript with inputs from co-authors.

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Correspondence to Hartmut Wekerle or Alexander Flügel.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12 with Legends and Legends for Supplementary Movies 1-9. (PDF 15004 kb)

Supplementary Movie 1

This movie file shows TMBP-GFP cell motility within leptomeningeal vessels during early EAE - see file s1 for full Legend. (MOV 7815 kb)

Supplementary Movie 2

This movie file shows rolling of TMBP-GFP cells in vascular beds of peripheral organs - see file s1 for full Legend. (MOV 7734 kb)

Supplementary Movie 3

This movie file shows intraluminal crawling and detachment of TMBP-GFP cells in vessels of the CNS - see file s1 for full Legend. (MOV 11037 kb)

Supplementary Movie 4

This movie file shows diapedesis of TMBP-GFP cells - see file s1 for full Legend. (MOV 7458 kb)

Supplementary Movie 5

This movie file shows intravascular crawling is abolished by integrin neutralization - see file s1 for full Legend. (MOV 8599 kb)

Supplementary Movie 6

This movie file shows meningeal infiltration by encephalitogenic effector T cells - see file s1 for full Legend. (MOV 10134 kb)

Supplementary Movie 7

This movie shows perivascular movement and subsequent diffuse distribution of TMBP-GFP cells in the Meninges - see file s1 for full Legend. (MOV 14018 kb)

Supplementary Movie 8

This movie file shows Location and locomotion of perivascular and meningeal phagocytes - see file s1 for full Legend. (MOV 4165 kb)

Supplementary Movie 9

This movie file shows TMBP cells in contact to perivascular /meningeal phagocytes - see file s1 for full Legend. (MOV 25825 kb)

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Bartholomäus, I., Kawakami, N., Odoardi, F. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94–98 (2009).

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