title: Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid.
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.
authors: Institute of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, 37073 Göttingen, Germany.
authors: Christian
authors: C
authors: Schläger
authors: Institute of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, 37073 Göttingen, Germany.
authors: Henrike
authors: H
authors: Körner
authors: Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
authors: Martin
authors: M
authors: Krueger
authors: Department of Structural and Geotechnical Engineering, University of Rome La Sapienza, 00185 Rome, Italy.
authors: Stefano
authors: S
authors: Vidoli
authors: Institute of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, 37073 Göttingen, Germany.
authors: Michael
authors: M
authors: Haberl
authors: Department Neurosurgery, University Medical Centre Göttingen, 37075 Göttingen, Germany.
authors: Dorothee
authors: D
authors: Mielke
authors: Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
authors: Elke
authors: E
authors: Brylla
authors: Division of Immunology, Department of Pediatrics Dalhousie University, Halifax B3H 4R2, Canada.
authors: Thomas
authors: T
authors: Issekutz
authors: Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa, 28049 Madrid, Spain.
authors: Carlos
authors: C
authors: Cabañas
authors: Medical Clinic and Policlinic IV, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
authors: Peter J
authors: PJ
authors: Nelson
authors: Department of Neurology, University Hospital, 01307 Dresden, Germany.
authors: Tjalf
authors: T
authors: Ziemssen
authors: Department Neurosurgery, University Medical Centre Göttingen, 37075 Göttingen, Germany.
authors: Veit
authors: V
authors: Rohde
authors: Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
authors: Ingo
authors: I
authors: Bechmann
authors: Institute of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, 37073 Göttingen, Germany.
authors: Dmitri
authors: D
authors: Lodygin
authors: Institute of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, 37073 Göttingen, Germany.
authors: Francesca
authors: F
authors: Odoardi
authors: Institute of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, 37073 Göttingen, Germany.|Max-Planck-Institute for Experimental Medicine, 37075 Göttingen, Germany.
authors: Alexander
authors: A
authors: Flügel
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002555:Cerebrospinal Fluid / Q000166:cytology* / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D002831:Choroid Plexus; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology*; D005260:Female; D039041:Integrin alpha4beta1 / Q000378:metabolism; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008578:Meninges / Q000276:immunology / Q000473:pathology*; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D019713:Receptors, CCR5 / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*
chemical_list: D018925:Chemokines; C515189:Cxcr3 protein, rat; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D003094:Collagen