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Integration of Th17- and lymphotoxin-derived signals initiates meningeal-resident stromal cell remodeling to propagate neuroinflammation.
Open accessAbstract
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.
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“The presentation of MS induced leptomeningeal inflammation can be variable, ranging from disorganized collections of immune cells to organized ectopic lymphoid follicle-like structures”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Pikor et al., 2015
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“…cytokines both in vitro and in vivo and that the LT pathway was required for optimal induced expression of Tgfb, a vital factor for Th17 cell differentiation (Veldhoen et al., 2006), we hypothesized that LTbR-dependent signals might influence meningeal CD4+ T cell responses in the CNS.”
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Metadata
- Authors
- Pikor, N. B., Astarita, J. L., Summers-Deluca, L., Galicia, G., Qu, J., Ward, L. A., Armstrong, S., Dominguez, C. X., Malhotra, D., Heiden, B., Kay, R., Castanov, V., Touil, H., Boon, L., O’Connor, P., Bar-Or, A., Prat, A., Ramaglia, V., Ludwin, S., Turley, S. J., & Gommerman, J. L.
- Affiliations
- University of Toronto (CA)
- Harvard University (US)
- Genentech (US)
- Montreal Neurological Institute and Hospital (CA)
- University Medical Center Utrecht (NL)
- Centre Hospitalier de l’Université de Montréal (CA)
- Amsterdam UMC Location University of Amsterdam (NL)
- Queen's University (CA)
- Corresponding author
- Gommerman, Jennifer L.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 43
- Issue
- 6
- Pages
- 1160-1173
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2212030004
- Cited by
- 229
- References
- 31
- Citations by year
- 2026: 21 · 2025: 22 · 2024: 27 · 2023: 16 · 2022: 23 · 2021: 34 · 2020: 17 · 2019: 22 · 2018: 18 · 2017: 14 · 2016: 14 · 2015: 1
- FWCI
- 12.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Multiple Sclerosis Society of Canada
- Multiple Sclerosis Society
- U.S. Public Health Service (P01 AIO45757)
- Canadian Institutes of Health Research (MOG 67157)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074500)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tertiary lymphoid tissue, meninges, Th17 cells, lymphotoxin beta receptor, stromal cells, neuroinflammation, multiple sclerosis, experimental autoimmune encephalitis, demyelination, extracellular matrix, chemokines, leukocyte homing, IL-17
- MeSH terms
- Adult, Animals, Encephalomyelitis, Autoimmune, Experimental, Female, Flow Cytometry, Humans, Immunohistochemistry, Inflammation, Lymphotoxin-alpha, Male, Meninges, Signal Transduction, CD4-Positive T-Lymphocytes, Polymerase Chain Reaction, Stromal Cells, Mice, Knockout, Multiple Sclerosis, Relapsing-Remitting, Mice, Th17 Cells
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