title: Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin.
abstract: Cerebrospinal fluid (CSF) from healthy individuals contains between 1,000 and 3,000 leukocytes per ml. Little is known about trafficking patterns of leukocytes between the systemic circulation and the noninflamed CNS. In the current study, we characterized the surface phenotype of CSF cells and defined the expression of selected adhesion molecules on vasculature in the choroid plexus, the subarachnoid space surrounding the cerebral cortex, and the cerebral parenchyma. Using multicolor flow cytometry, we found that CSF cells predominantly consisted of CD4+/CD45RA-/CD27+/CD69+-activated central memory T cells expressing high levels of CCR7 and L-selectin. CD3+ T cells were present in the choroid plexus stroma in autopsy CNS tissue sections from individuals who died without known neurological disorders. P- and E-selectin immunoreactivity was detected in large venules in the choroid plexus and subarachnoid space, but not in parenchymal microvessels. CD4+ T cells in the CSF expressed high levels of P-selectin glycoprotein ligand 1, and a subpopulation of circulating CD4+ T cells displayed P-selectin binding activity. Intercellular adhesion molecule 1, but not vascular cell adhesion molecule 1 or mucosal addressin cell adhesion molecule 1, was expressed in choroid plexus and subarachnoid space vessels. Based on these findings, we propose that T cells are recruited to the CSF through interactions between P-selectin/P-selectin ligands and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 in choroid plexus and subarachnoid space venules. These results support the overall hypothesis that activated memory T cells enter CSF directly from the systemic circulation and monitor the subarachnoid space, retaining the capacity to either initiate local immune reactions or return to secondary lymphoid organs.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Millennium Pharmaceuticals, Inc., Cambridge, MA 02142.
authors.forename: Pia
authors.initials: P
authors.lastname: Kivisäkk
authors.forename: Don J
authors.initials: DJ
authors.lastname: Mahad
authors.forename: Melissa K
authors.initials: MK
authors.lastname: Callahan
authors.forename: Corinna
authors.initials: C
authors.lastname: Trebst
authors.forename: Barbara
authors.initials: B
authors.lastname: Tucky
authors.forename: Tao
authors.initials: T
authors.lastname: Wei
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
authors.forename: Espen S
authors.initials: ES
authors.lastname: Baekkevold
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.forename: Susan M
authors.initials: SM
authors.lastname: Staugaitis
authors.forename: James J
authors.initials: JJ
authors.lastname: Campbell
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001099:Arachnoid / Q000098:blood supply / Q000166:cytology / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology* / Q000276:immunology; D002448:Cell Adhesion; D002465:Cell Movement; D002555:Cerebrospinal Fluid / Q000166:cytology / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D002831:Choroid Plexus / Q000098:blood supply / Q000166:cytology / Q000276:immunology*; D019040:E-Selectin / Q000032:analysis; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology* / Q000276:immunology; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000502:physiology*; D008875:Middle Aged; D019007:P-Selectin / Q000032:analysis / Q000502:physiology*; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000032:analysis / Q000502:physiology*; D013346:Subarachnoid Space; D014699:Venules / Q000737:chemistry
chemical_list: C515370:CCR7 protein, human; D019040:E-Selectin; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D018799:Intercellular Adhesion Molecule-1