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

EJ McMahon, SL Bailey, CV Castenada, H Waldner… - Nature medicine, 2005 - nature.com
EJ McMahon, SL Bailey, CV Castenada, H Waldner, SD Miller
Nature medicine, 2005nature.com
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 …
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 F4/80CD11c+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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