title: Immunological tolerance to muscle autoantigens involves peripheral deletion of autoreactive CD8+ T cells.
abstract: Muscle potentially represents the most abundant source of autoantigens of the body and can be targeted by a variety of severe autoimmune diseases. Yet, the mechanisms of immunological tolerance toward muscle autoantigens remain mostly unknown. We investigated this issue in transgenic SM-Ova mice that express an ovalbumin (Ova) neo-autoantigen specifically in skeletal muscle. We previously reported that antigen specific CD4(+) T cell are immunologically ignorant to endogenous Ova in this model but can be stimulated upon immunization. In contrast, Ova-specific CD8(+) T cells were suspected to be either unresponsive to Ova challenge or functionally defective. We now extend our investigations on the mechanisms governing CD8(+) tolerance in SM-Ova mice. We show herein that Ova-specific CD8(+) T cells are not detected upon challenge with strongly immunogenic Ova vaccines even after depletion of regulatory T cells. Ova-specific CD8(+) T cells from OT-I mice adoptively transferred to SM-Ova mice started to proliferate in vivo, acquired CD69 and PD-1 but subsequently down-regulated Bcl-2 and disappeared from the periphery, suggesting a mechanism of peripheral deletion. Peripheral deletion of endogenous Ova-specific cells was formally demonstrated in chimeric SM-Ova mice engrafted with bone marrow cells containing T cell precursors from OT-I TCR-transgenic mice. Thus, the present findings demonstrate that immunological tolerance to muscle autoantigens involves peripheral deletion of autoreactive CD8(+) T cells.
authors.affiliation: Inserm, U905, Rouen, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Franck
authors.forename: Carole
authors.initials: C
authors.lastname: Bonneau
authors.forename: Laetitia
authors.initials: L
authors.lastname: Jean
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Henry
authors.forename: Yann
authors.initials: Y
authors.lastname: Lacoume
authors.forename: Anna
authors.initials: A
authors.lastname: Salvetti
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.forename: Sahil
authors.initials: S
authors.lastname: Adriouch
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D007108:Immune Tolerance; D008198:Lymph Nodes / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009132:Muscles / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013934:Thymectomy; D018183:Transplantation Chimera
chemical_list: D001324:Autoantigens