title: Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation.
abstract: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56(bright) NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4β1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4(+) T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4(+) T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor's ligand CD155 on CD4(+) T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4(+) T cells and the cytolytic activity of NK cells.
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany; catharina.gross@ukmuenster.de heinz.wiendl@ukmuenster.de.
authors.forename: Catharina C
authors.initials: CC
authors.lastname: Gross
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulte-Mecklenbeck
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany;
authors.forename: Anna
authors.initials: A
authors.lastname: Rünzi
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Muenster D-48149, Germany;
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany;
authors.forename: Anita
authors.initials: A
authors.lastname: Posevitz-Fejfár
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Schwab
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany;
authors.forename: Tilman
authors.initials: T
authors.lastname: Schneider-Hohendorf
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Herich
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University of Munich, Planegg-Martinsried D-82152, Germany;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Held
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University of Munich, Planegg-Martinsried D-82152, Germany;
authors.forename: Matea
authors.initials: M
authors.lastname: Konjević
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany;
authors.forename: Marvin
authors.initials: M
authors.lastname: Hartwig
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University of Munich, Planegg-Martinsried D-82152, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich D-81377, Germany;
authors.forename: Klaus
authors.initials: K
authors.lastname: Dornmair
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University of Munich, Planegg-Martinsried D-82152, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich D-81377, Germany;
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.affiliation: Department of Neurology, University Hospital Dresden, Dresden D-01307 Germany;
authors.forename: Tjalf
authors.initials: T
authors.lastname: Ziemssen
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany;
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany; Cluster of Excellence EXC 1003, Cells in Motion, Westfälische Wilhelms-University, 48149 Muenster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: Department of Neurology, University Hospital Münster, Muenster D-48149, Germany; Cluster of Excellence EXC 1003, Cells in Motion, Westfälische Wilhelms-University, 48149 Muenster, Germany catharina.gross@ukmuenster.de heinz.wiendl@ukmuenster.de.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D000069442:Natalizumab / Q000008:administration & dosage; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D011991:Receptors, Virus / Q000276:immunology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D000069442:Natalizumab; D015375:Receptors, Interleukin-2; D011991:Receptors, Virus; C066100:poliovirus receptor
keywords: DNAM-1; IL-2 receptor; NK cells; daclizumab; multiple sclerosis