Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis

Eileen J. McMahon, Samantha L. Bailey, Carol Vanderlugt Castenada, Hanspeter Waldner, Stephen D. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

548 Scopus citations


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 PLP 139-151-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.

Original languageEnglish (US)
Pages (from-to)335-339
Number of pages5
JournalNature Medicine
Issue number3
StatePublished - Mar 2005

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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