Functional tolerance of CD8+ T cells induced by muscle-specific antigen expression.
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.
Institut National de la Santé et de la Recherche Médicale, Unité 905, University of Rouen, and Department of Immunology, Rouen University Hospital, Rouen, France. sebastien.calbo@univ-rouen.fr
Sébastien
S
Calbo
Héloïse
H
Delagrèverie
Christophe
C
Arnoult
François-Jérome
FJ
Authier
François
F
Tron
Olivier
O
Boyer
D000818:Animals; D000941:Antigens / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002645:Chickens; D051858:Forkhead Transcription Factors / Q000276:immunology; D015870:Gene Expression; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D019076:Transgenes / Q000235:genetics; D015854:Up-Regulation
D000941:Antigens; D000943:Antigens, Differentiation; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin