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

Nature Medicine volume 11, pages 335–339 (2005)Cite this article

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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Figure 1: Naive CFSE-labeled PLP139–151-specific transgenic cells proliferate in the CNS, but not in the peripheral lymph organs, of PLP178–191-primed mice.
Figure 2: PLP139–151-specific transgenic cells show an activated phenotype only in the CNS of PLP178–191-primed bone marrow chimeras.
Figure 3: PLP139–151-specific T cells are activated in the CNS, but not the periphery, of TMEV-infected mice.
Figure 4: Differential ability of CNS microglia, macrophages and DCs to present endogenous and exogenous peptide to naive and activated CD4+ T cells.

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Acknowledgements

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.

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  1. Eileen J McMahon

    Present address: Biology Department, Westmont College, 955 LaPaz Road, Santa Barbara, California, 93108, USA

Authors and Affiliations

  1. Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, 60611, Illinois, USA

    Eileen J McMahon, Samantha L Bailey, Carol Vanderlugt Castenada & Stephen D Miller

  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, 02115, Massachusetts, USA

    Hanspeter Waldner

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Correspondence to Stephen D Miller.

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Supplementary information

Supplementary Fig. 1

PLP139–151 reactivity in PLP178–191-primed mice. (PDF 113 kb)

Supplementary Fig. 2

FACS purification of CNS antigen presenting cell populations. (PDF 124 kb)

Supplementary Fig. 3

CD11c+ DCs are found in the same areas as CD4+ T cells in the CNS of mice with both R-EAE and TMEV-IDD. (PDF 161 kb)

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McMahon, E., Bailey, S., Castenada, C. et al. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 11, 335–339 (2005). https://doi.org/10.1038/nm1202

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