Nature Medicine11, 335 - 339 (2005)
Published online: 27 February 2005; | doi:10.1038/nm1202
Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis
Eileen J McMahon1, 3, Samantha L Bailey1, Carol Vanderlugt Castenada1, Hanspeter Waldner2
& Stephen D Miller1
1
Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
2
Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, HIM Rm 786, Boston, Massachusetts 02115, USA.
3
Current address: Biology Department, Westmont College, 955 LaPaz Road, Santa Barbara, California 93108, USA.
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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