HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Calbo, S. Articles by Boyer, O. Search for Related Content PubMed PubMed Citation Articles by Calbo, S. Articles by Boyer, O.

Functional Tolerance of CD8⁺ T Cells Induced by Muscle-Specific Antigen Expression¹

Sébastien Calbo^2,*, Héloïse Delagrèverie^*, Christophe Arnoult^*, François-Jérome Authier, François Tron^* and Olivier Boyer^2,*

^* Institut National de la Santé et de la Recherche Médicale, Unité 905, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides, Institute for Biomedical Research, University of Rouen, and Department of Immunology, Rouen University Hospital, Rouen, France; and Institut National de la Santé et de la Recherche Médicale, Unité 841, Institute for Biomedical Research Mondor Créteil, and Assistance Publique-Hôpitaux de Paris, Henri Mondor University Hospital, Créteil, France

Skeletal muscles account for more than 30% of the human body, yet mechanisms of immunological tolerance to this tissue remain mainly unexplored. To investigate the mechanisms of tolerance to muscle-specific proteins, we generated transgenic mice expressing the neo-autoantigen OVA exclusively in skeletal muscle (SM-OVA mice). SM-OVA mice were bred with OT-I or OT-II mice that possess a transgenic TCR specific for OVA peptides presented by MHC class I or class II, respectively. Tolerance to OVA did not involve clonal deletion, anergy or an increased regulatory T cell compartment. Rather, CD4⁺ T cell tolerance resulted from a mechanism of ignorance revealed by their response following OVA immunization. In marked contrast, CD8⁺ T cells exhibited a loss of OVA-specific cytotoxic activity associated with up-regulation of the immunoregulatory programmed death-1 molecule. Adoptive transfer experiments further showed that OVA expression in skeletal muscle was required to maintain this functional tolerance. These results establish a novel asymmetric model of immunological tolerance to muscle autoantigens involving Ag ignorance for CD4⁺ T cells, whereas muscle autoantigens recognized by CD8⁺ T cells results in blockade of their cytotoxic function. These observations may be helpful for understanding the breakage of tolerance in autoimmune muscle diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Fondation pour la Recherche Médicale, the Association Française contre les Myopathies, and the Inserm Avenir Program (to S.C. and O.B.).

² Address correspondence and reprint requests to Dr. Sébastien Calbo or Prof. Olivier Boyer, Institut National de la Santé et de la Recherche Médicale, Unité 905, Faculté de Médecine et de Pharmacie, University of Rouen, 22 boulevard Gambetta, 76183 Rouen Cedex, France. E-mail addresses: sebastien.calbo{at}univ-rouen.fr or olivier.boyer{at}chu-rouen.fr

³ Abbreviations used in this paper: AChR, acetylcholine receptor; PD-1, programmed death-1; PD-L1, PD-1 ligand 1; Tg, transgenic; MCK, muscle creatine kinase; DTH, delayed-type hypersensitivity; Treg, regulatory T cell; LN, lymph node; β-gal, β-galactosidase.