Publication Date:
2016-02-11
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schlager, Christian -- Korner, Henrike -- Krueger, Martin -- Vidoli, Stefano -- Haberl, Michael -- Mielke, Dorothee -- Brylla, Elke -- Issekutz, Thomas -- Cabanas, Carlos -- Nelson, Peter J -- Ziemssen, Tjalf -- Rohde, Veit -- Bechmann, Ingo -- Lodygin, Dmitri -- Odoardi, Francesca -- Flugel, Alexander -- England -- Nature. 2016 Feb 18;530(7590):349-53. doi: 10.1038/nature16939. Epub 2016 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Centre Gottingen, 37073 Gottingen, Germany. ; Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany. ; Department of Structural and Geotechnical Engineering, University of Rome La Sapienza, 00185 Rome, Italy. ; Department Neurosurgery, University Medical Centre Gottingen, 37075 Gottingen, Germany. ; Division of Immunology, Department of Pediatrics Dalhousie University, Halifax B3H 4R2, Canada. ; Departamento de Biologia Celular e Inmunologia, Centro de Biologia Molecular Severo Ochoa, 28049 Madrid, Spain. ; Medical Clinic and Policlinic IV, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany. ; Department of Neurology, University Hospital, 01307 Dresden, Germany. ; Max-Planck-Institute for Experimental Medicine, 37075 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863192" target="_blank"〉PubMed〈/a〉
Keywords:
Adoptive Transfer
;
Animals
;
Cell Adhesion
;
*Cell Movement
;
Cerebrospinal Fluid/*cytology/immunology
;
Chemokines/metabolism
;
Choroid Plexus
;
Collagen/metabolism
;
Disease Models, Animal
;
Encephalomyelitis, Autoimmune, Experimental/immunology/*pathology
;
Female
;
Integrin alpha4beta1/metabolism
;
Lymphocyte Activation
;
Lymphocyte Function-Associated Antigen-1/metabolism
;
Macrophages/immunology/metabolism
;
Male
;
Meninges/immunology/*pathology
;
Multiple Sclerosis/immunology/*pathology
;
Rats
;
Rats, Inbred Lew
;
Receptors, CCR5/metabolism
;
Receptors, CXCR3/metabolism
;
T-Lymphocytes/immunology/*pathology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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