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.
Calbo
Sébastien
S
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
Delagrèverie
Héloïse
H
Arnoult
Christophe
C
Authier
François-Jérome
FJ
Tron
François
F
Boyer
Olivier
O
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