Laminin-411 Is a Vascular Ligand for MCAM and Facilitates TH17 Cell Entry into the CNS
Open accessAbstract
TH17 cells enter tissues to facilitate pathogenic autoimmune responses, including multiple sclerosis (MS). However, the adhesion molecules involved in the unique migratory capacity of TH17 cells, into both inflamed and uninflamed tissues remain unclear. Herein, we characterize MCAM (CD146) as an adhesion molecule that defines human TH17 cells in the circulation; following in vitro restimulation of human memory T cells, nearly all of the capacity to secrete IL-17 is contained within the population of cells expressing MCAM. Furthermore, we identify the MCAM ligand as laminin 411, an isoform of laminin expressed within the vascular endothelial basement membranes under inflammatory as well as homeotstatic conditions. Purified MCAM-Fc binds to laminin 411 with an affinity of 27 nM, and recognizes vascular basement membranes in mouse and human tissue. MCAM-Fc binding was undetectable in tissue from mice with targeted deletion of laminin 411, indicating that laminin 411 is a major tissue ligand for MCAM. An anti-MCAM monoclonal antibody, selected for inhibition of laminin binding, as well as soluble MCAM-Fc, inhibited T cell adhesion to laminin 411 in vitro. When administered in vivo, the antibody reduced TH17 cell infiltration into the CNS and ameliorated disease in an animal model of MS. Our data suggest that MCAM and laminin 411 interact to facilitate TH17 cell entry into tissues and promote inflammation.
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MCAM+ effector T cells migrate more efficiently across the BBB than MCAM-negative counterparts through homotypic binding with MCAM on vascular endothelial cells and interactions with laminin-411.
“MCAM+ effector T cells migrate more efficiently across the BBB than their MCAM-negative counterparts and appear to do so through homotypic binding with MCAM expressed on vascular endothelial cells (123) and through interactions with laminin-411 (124).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [124]
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- [25]Dagur PK Biancotto A Wei L Nida Sen H Yao M 2011 MCAM-expressing CD4(+) T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases. J Autoimmun 37(4) 319 327 21959269 PMC3223259
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- Authors
- Flanagan, K., Fitzgerald, K., Baker, J., Regnstrom, K., Gardai, S., Bard, F., Mocci, S., Seto, P., You, M., Larochelle, C., Prat, A., Chow, S., Li, L., Vandevert, C., Zago, W., Lorenzana, C., Nishioka, C., Hoffman, J., Botelho, R., Willits, C., Tanaka, K., Johnston, J., & Yednock, T.
- Affiliations
- Elan Pharmaceuticals, Inc. (Ireland) (IE)
- Université de Montréal (CA)
- Corresponding author
- Flanagan, Ken
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-07-06
- Volume
- 7
- Issue
- 7
- Pages
- e40443
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3391262
- OpenAlex
- W1981126128
- Cited by
- 134
- References
- 53
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 11 · 2021: 9 · 2020: 8 · 2019: 11 · 2018: 9 · 2017: 14 · 2016: 5 · 2015: 17 · 2014: 13 · 2013: 11 · 2012: 3
- FWCI
- 10.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Karolinska Institutet
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- laminin-411, CD146, Th17 cells, T cell adhesion, T cell migration, multiple sclerosis, vascular basement membrane, IL-17, autoimmune inflammation
- MeSH terms
- Interleukin-22, Animals, Cell Movement, Choroid Plexus, Encephalomyelitis, Autoimmune, Experimental, Extracellular Matrix, Female, Cricetinae, Humans, Interleukins, Laminin, Ligands, Protein Binding, CHO Cells, Cell Polarity, Mice, Knockout, Interleukin-17, Cell Proliferation, Mice, CD146 Antigen, Interleukin-1beta, Th17 Cells
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