title: Integration of Th17- and Lymphotoxin-Derived Signals Initiates Meningeal-Resident Stromal Cell Remodeling to Propagate Neuroinflammation.
abstract: Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin αβ (LTαβ) on Th17 cells and LTβR on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTβR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Pikor
authors.affiliation: Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Astarita
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Leslie
authors.initials: L
authors.lastname: Summers-Deluca
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Georgina
authors.initials: G
authors.lastname: Galicia
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Joy
authors.initials: J
authors.lastname: Qu
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Ward
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Armstrong
authors.affiliation: Department of Cancer Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Claudia X
authors.initials: CX
authors.lastname: Dominguez
authors.affiliation: Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Deepali
authors.initials: D
authors.lastname: Malhotra
authors.affiliation: Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Heiden
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Kay
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Valera
authors.initials: V
authors.lastname: Castanov
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Hanane
authors.initials: H
authors.lastname: Touil
authors.affiliation: EPIRUS Biopharmaceuticals Netherlands, BV Yalelaan 46, 3584 CM Utrecht, the Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Department of Medicine, University of Toronto and St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: O'Connor
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.affiliation: Neuroimmunology Research Laboratory, Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montreal, QC H2L 4M1, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Noord-Holland 1105AZ, the Netherlands.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ramaglia
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Ludwin
authors.affiliation: Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jen.gommerman@utoronto.ca.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gommerman
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000276:immunology*; D008297:Male; D008578:Meninges / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D008233:Lymphotoxin-alpha