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Immunity. 2015 Dec 15;43(6):1160-73. doi: 10.1016/j.immuni.2015.11.010.

Integration of Th17- and Lymphotoxin-Derived Signals Initiates Meningeal-Resident Stromal Cell Remodeling to Propagate Neuroinflammation.

Author information

1
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
2
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.
3
Department of Cancer Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
4
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.
5
Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
6
EPIRUS Biopharmaceuticals Netherlands, BV Yalelaan 46, 3584 CM Utrecht, the Netherlands.
7
Department of Medicine, University of Toronto and St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
8
Neuroimmunology Research Laboratory, Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montreal, QC H2L 4M1, Canada.
9
Department of Genome Analysis, Academic Medical Center, Noord-Holland 1105AZ, the Netherlands.
10
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
11
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jen.gommerman@utoronto.ca.

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.

PMID:
26682987
DOI:
10.1016/j.immuni.2015.11.010
[Indexed for MEDLINE]
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