Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis
Abstract
Chronic progression of two T cell-mediated central nervous system (CNS) demyelinating models of multiple sclerosis, relapsing EAE (R-EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is dependent on the activation of T cells to endogenous myelin epitopes (epitope spreading). Using transfer of carboxyfluorescein succinyl ester (CFSE)-labeled T-cell receptor (TCR)-transgenic T cells and mixed bone marrow chimeras, we show that activation of naive proteolipid protein (PLP)139-151-specific T cells in SJL mice undergoing PLP178-191-induced R-EAE or TMEV-IDD occurs directly in the CNS and not in the cervical lymph nodes or other peripheral lymphoid organs. Examination of the antigen-presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with PLP178-191-induced R-EAE shows that only F4/80-CD11c+CD45hi dendritic cells (DCs) efficiently present endogenous antigen to activate naive PLP139-151-specific T cells in vitro. In contrast, DCs as well as F4/80+CD45hi macrophages and F4/80+CD45lo microglia activate a PLP139-151-specific helper T cell line. The data suggest that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.
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Elucidation of the temporal dynamics of immune cell recruitment in the brains of mice with EAE provides a valuable tool for studying the contribution of leukocyte trafficking to cytokine signalling and sickness/depression-like behaviour.
“Elucidation of the temporal dynamics of immune cell recruitment in the brains of mice with EAE90,91 provides a valuable tool for studying the contribution of leukocyte trafficking to the activation of cytokine signalling in the brain and to the development of sickness and depression-like behaviour in this model.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [90]
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- Authors
- McMahon, E. J., Bailey, S. L., Castenada, C. V., Waldner, H., & Miller, S. D.
- Affiliations
- Northwestern University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Miller, Stephen D
- Venue
- Nature Medicine
- Published
- 2005-02-27
- Volume
- 11
- Issue
- 3
- Pages
- 335-339
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1981688486
- Cited by
- 694
- References
- 30
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 23 · 2023: 13 · 2022: 19 · 2021: 22 · 2020: 18 · 2019: 18 · 2018: 21 · 2017: 28 · 2016: 34 · 2015: 47 · 2014: 44 · 2013: 38 · 2012: 44
- FWCI
- 40.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI07476, T32AI007476)
- National Institute of Neurological Disorders and Stroke (NS30871, NS-23349, P01NS023349, R01NS030871)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- epitope spreading, multiple sclerosis, T cell activation, dendritic cells, antigen presentation, microglia, macrophages, naive T cells, neuroinflammation, T cell receptor transgenic T cells, bone marrow chimeras
- MeSH terms
- Animals, Epitopes, Central Nervous System, Demyelinating Diseases, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Multiple Sclerosis, T-Lymphocytes, Theilovirus, Antigen Presentation, Cardiovirus Infections, Adoptive Transfer, Mice
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