title: Melanoma cell adhesion molecule-positive CD8 T lymphocytes mediate central nervous system inflammation.
abstract: OBJECTIVE
  Although Tc17 lymphocytes are enriched in the central nervous system (CNS) of multiple sclerosis (MS) subjects and of experimental autoimmune encephalomyelitis (EAE) animals, limited information is available about their recruitment into the CNS and their role in neuroinflammation. Identification of adhesion molecules used by autoaggressive CD8(+) T lymphocytes to enter the CNS would allow further characterization of this pathogenic subset and could provide new therapeutic targets in MS. We propose that melanoma cell adhesion molecule (MCAM) is a surface marker and adhesion molecule used by pathogenic CD8(+) T lymphocytes to access the CNS.
  
  
  METHODS
  Frequency, phenotype, and function of MCAM(+) CD8(+) T lymphocytes was characterized using a combination of ex vivo, in vitro, in situ, and in vivo approaches in humans and mice, including healthy controls, MS subjects, and EAE animals.
  
  
  RESULTS
  Herein, we report that MCAM is expressed by human effector CD8(+) T lymphocytes and it is strikingly upregulated during MS relapses. We further demonstrate that MCAM(+) CD8(+) T lymphocytes express more interleukin 17, interferon γ, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor than MCAM(-) lymphocytes, and exhibit an enhanced killing capacity toward oligodendrocytes. MCAM blockade restricts the transmigration of CD8(+) T lymphocytes across human blood-brain barrier endothelial cells in vitro, and blocking or depleting MCAM in vivo reduces chronic neurological deficits in active, transfer, and spontaneous progressive EAE models.
  
  
  CONCLUSIONS
  Our data demonstrate that MCAM identifies encephalitogenic CD8(+) T lymphocytes, suggesting that MCAM could represent a biomarker of MS disease activity and a valid target for the treatment of neuroinflammatory conditions.
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.|Multiple Sclerosis Clinic, Division of Neurology, Centre Hospitalier de l'Université de Montréal (CHUM)-Notre Dame Hospital, Montreal, Quebec, Canada.|Department of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, Quebec, Canada.
authors: Catherine
authors: C
authors: Larochelle
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
authors: Marc-André
authors: MA
authors: Lécuyer
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
authors: Jorge Ivan
authors: JI
authors: Alvarez
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
authors: Marc
authors: M
authors: Charabati
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
authors: Olivia
authors: O
authors: Saint-Laurent
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
authors: Soufiane
authors: S
authors: Ghannam
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
authors: Hania
authors: H
authors: Kebir
authors: Prothena Biosciences, South San Francisco, CA, USA.
authors: Ken
authors: K
authors: Flanagan
authors: Prothena Biosciences, South San Francisco, CA, USA.
authors: Ted
authors: T
authors: Yednock
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.|Multiple Sclerosis Clinic, Division of Neurology, Centre Hospitalier de l'Université de Montréal (CHUM)-Notre Dame Hospital, Montreal, Quebec, Canada.|Department of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, Quebec, Canada.
authors: Pierre
authors: P
authors: Duquette
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.|Department of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, Quebec, Canada.
authors: Nathalie
authors: N
authors: Arbour
authors: Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.|Multiple Sclerosis Clinic, Division of Neurology, Centre Hospitalier de l'Université de Montréal (CHUM)-Notre Dame Hospital, Montreal, Quebec, Canada.|Department of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, Quebec, Canada.
authors: Alexandre
authors: A
authors: Prat
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism*; D051929:CD146 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000378:metabolism*; D009836:Oligodendroglia; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D051929:CD146 Antigen; D020381:Interleukin-17; C497902:MCAM protein, human; C497903:Mcam protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor