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

568 Scopus citations

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 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
Volume11
Issue number3
DOIs
StatePublished - Mar 2005

Funding

We thank J. Marvin at the University of Chicago for FACS-sorting expertise and A. Kohm for critical reading of the manuscript. The authors acknowledge the contribution of discussion with colleagues at the Myelin Repair Foundation. Supported in part by grants from the US National Institutes of Health (NS-30871 and NS-23349) and the Myelin Repair Foundation. E.J.M. was supported by National Institutes of Health Training Grant AI-07476 and S.L.B. by National Multiple Sclerosis Society Postdoctoral Fellowship Grant FG 1563 A-1.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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