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* Institut National de la Santé et de la Recherche Médicale, Unité 277, Institut Pasteur, Paris, France;
University of Paris Sud, Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Unité Mixte de Recherche 8619, Centre National de la Recherche Scientifique, Orsay, France;
Immune Regulation Group, Deutsches Rheuma-Forschungszentrum, Berlin, Germany;
Antiviral Immunity, Biotherapy and Vaccine Unit, Institut Pasteur, Paris, France; and
¶ Unité Mixte de Recherche 546, Institut National de la Santé et de la Recherche Médicale, Paris, France
Comparison of TCR
repertoires of myelin oligodendrocyte glycoprotein (MOG)-specific T lymphocytes in C57BL/6 and TdT-deficient littermates (TdT–/–) generated during experimental autoimmune encephalomyelitis (EAE) highlights a link between a diversified TCR repertoire and EAE relapses. At the onset of the disease, the EAE-severity is identical in TdT+/– and TdT–/– mice and the neuropathologic public MOG-specific T cell repertoires express closely similar public V-J and V-J rearrangements in both strains. However, whereas TdT+/+ and TdT+/– mice undergo successive EAE relapses, TdT–/– mice recover definitively and the lack of relapses does not stem from dominant regulatory mechanisms. During the first relapse of the disease in TdT+/– mice, new public V-J and V-J rearrangements emerge that are distinct from those detected at the onset of the disease. Most of these rearrangements contain N additions and are found in CNS-infiltrating T lymphocytes. Furthermore, CD4+ T splenocytes bearing these rearrangements proliferate to the immunodominant epitope of MOG and not to other immunodominant epitopes of proteolipid protein and myelin basic protein autoantigens, excluding epitope spreading to these myelin proteins. Thus, in addition to epitope spreading, a novel mechanism involving TCR repertoire diversification contributes to autoimmune progression.
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1 This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, the Pasteur Institute, l’Association de Recherche contre le Cancer (to N.F. and J.M.K.), Pasteur-Weizmann (to N.F.), Association de Recherche sur la Sclérose en Plaques (to C.D., D.P.-D., and J.M.K.), the European Leukodystrophy Association (to D.P.-D.), and European grant for AUTOROME STREP (to M.-L.G.).
2 N.F. and C.D. have contributed equally to this work.
3 Current address: Institute for Childhood and Neglected Diseases-120, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
4 Address correspondence and reprint requests to Dr. Jean M. Kanellopoulos, Unité Mixte de Recherche, 8619 Centre National de la Recherche Scientifique, Université Paris 11, Orsay, France. E-mail address: Jean.Kanellopoulos{at}ibbmc.u-psud.fr
5 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; ID, immunodominant; LNC, lymph node cell; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; PPD, purified protein derivative; SD, subdominant; wt, wild type; SI, stimulation index.
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