Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment
Abstract
Activated CD4 Th1 lymphocytes can enter the brain in the absence of an inflammatory focus. However, the molecular mediators that regulate this early migration of lymphocytes into the brain have remained unclear. We hypothesized that the entry of these 'pioneer' lymphocytes into the brain is regulated by a set of molecular events that are distinct from those used once inflammation has been established. Using cells fluorescently labelled with the lipophilic dye DiI, myelin basic protein (MBP)-specific CD4 lymphocytes that expressed low or high levels of very late antigen-4 (VLA-4) and non-antigen-specific activated splenocytes homed to mouse brain in similar quantities 2 h after adoptive transfer. However, antigen specificity and VLA-4 expression were required for more robust recruitment by 24 h. Immunocytochemistry revealed endothelial and microenvironmental upregulation of vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule 1 (ICAM-1), MHC class II and interferon-gamma 48 h after transfer of MBP-specific cells. In contrast, expression of meningeal and choroid plexus-associated P selectin was upregulated 2 h after adoptive transfer, but not at 48 h. Monoclonal antibody to P selectin, but not to VLA-4, inhibited early migration of high VLA-4-expressing MBP-specific lymphocytes. These results suggest that early migration occurs independent of the lymphocyte integrin VLA-4 and endothelial VCAM, but does require increased surface expression of endothelial P selectin.
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Subarachnoid and pial vessels restrict extravasation of leukocytes, but migration across these vessels is more efficient relative to parenchymal vessels because meningeal endothelial cells constitutively express P-selectin during steady state.
“Subarachnoid and pial vessels also restrict extravasation of leukocytes; however, migration across these vessels is more efficient relative to parenchymal vessels (86). This is because meningeal, unlike parenchymal, vascular endothelial cells constitutively express P-selectin during steady state, which is stored in Weibel-Palade bodies, allowing rapid release to the endothelial surface (79, 86).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [86]
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- Authors
- Carrithers, M. D., Visintin, I., Kang, S. J., & Janeway, C. A.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Carrithers, Michael D.
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-06
- Volume
- 123
- Issue
- 6
- Pages
- 1092-1101
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2009355727
- Cited by
- 220
- References
- 34
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 7 · 2022: 12 · 2021: 8 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 6 · 2015: 10 · 2014: 7 · 2013: 10 · 2012: 11
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Multiple Sclerosis Society
- Multiple Sclerosis Society
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI/AR36529)
- National Institute of Neurological Disorders and Stroke (KO8 NS 02124-01, K08NS002124)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- lymphocyte homing, CD4+ T cells, VLA-4, P-selectin, VCAM-1, ICAM-1, MHC class II, interferon-gamma, myelin basic protein, adoptive transfer, neuroinflammation, immune surveillance, choroid plexus, adhesion molecules
- MeSH terms
- Animals, Antibodies, Monoclonal, Histocompatibility Antigens Class II, Brain, Brain Chemistry, Carbocyanines, Cell Movement, Myelin Basic Protein, Encephalomyelitis, Autoimmune, Experimental, Female, Fluorescent Dyes, Immunologic Surveillance, Interferon-gamma, Mice, Inbred Strains, Pancreas, Spleen, CD4-Positive T-Lymphocytes, Integrins, Receptors, Lymphocyte Homing, Th1 Cells, Intercellular Adhesion Molecule-1, Anti-Allergic Agents, P-Selectin, Vascular Cell Adhesion Molecule-1, Integrin alpha4beta1, Mice
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