The Journal of Experimental Medicine
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Published 20 January 2004. doi:10.1084/jem.20031064
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 2, 185-197
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The Activation Status of Neuroantigen-specific T Cells in the Target Organ Determines the Clinical Outcome of Autoimmune Encephalomyelitis

Naoto Kawakami1, Silke Lassmann1, Zhaoxia Li1, Francesca Odoardi1, Thomas Ritter2, Tjalf Ziemssen1, Wolfgang E.F. Klinkert1, Joachim W. Ellwart3, Monika Bradl4, Kimberly Krivacic5, Hans Lassmann4, Richard M. Ransohoff5, Hans-Dieter Volk2, Hartmut Wekerle1, Christopher Linington1, and Alexander Flügel1

1 Department of Neuroimmunology, Max-Planck Institute for Neurobiology, 82152 Martinsried, Germany
2 Institute of Medical Immunology, Charité, Humboldt-University, 10098 Berlin, Germany
3 Institute for Molecular Immunology, GSF-National Research Center for Environment and Health, 81377 Munich, Germany
4 Neurological Institute, University of Vienna, 1090 Vienna, Austria
5 Department of Neurosciences, The Lerner Research Institute, Cleveland, OH 44195

Address correspondence to Alexander Flügel, Dept. of Neuroimmunology, Max-Planck Institute for Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany. Phone: 49-89-8578-3550; Fax: 49-89-8578-3790; email: Fluegel{at}neuro.mpg.de

The clinical picture of experimental autoimmune encephalomyelitis (EAE) is critically dependent on the nature of the target autoantigen and the genetic background of the experimental animals. Potentially lethal EAE is mediated by myelin basic protein (MBP)–specific T cells in Lewis rats, whereas transfer of S100ß- or myelin oligodendrocyte glycoprotein (MOG)–specific T cells causes intense inflammatory response in the central nervous system (CNS) with minimal disease. However, in Dark Agouti rats, the pathogenicity of MOG-specific T cells resembles the one of MBP-specific T cells in the Lewis rat. Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue. Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein+ T cells into the CNS were similar. However, exclusively highly pathogenic T cells were significantly reactivated within the CNS. Without local effector T cell activation, production of monocyte chemoattractants was insufficient to initiate and propagate a full inflammatory response. Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

Key Words: autoimmunity of the CNS • disease model • retroviral gene transfer • reactivation in the CNS • multiple sclerosis

The online version of this article includes supplemental material.

The present address of S. Lassmann is the Institute of Pathology, University of Freiburg, 79104 Freiburg, Germany.

The present address of C. Linington is the Dept. of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.

Abbreviations used in this paper: BBB, blood brain barrier; CNS, central nervous system; DA, Dark Agouti; EAE, experimental autoimmune encephalomyelitis; GFP, green fluorescent protein; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; PPD, purified protein derivative; TCL, T cell line; tEAE, adoptive transfer EAE.


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