title: Exposure to sequestered self-antigens in vivo is not sufficient for the induction of autoimmune diabetes.
abstract: Although the role of T cells in autoimmunity has been explored for many years, the mechanisms leading to the initial priming of an autoimmune T cell response remain enigmatic. The 'hit and run' model suggests that self-antigens released upon cell death can provide the initial signal for a self-sustaining autoimmune response. Using a novel transgenic mouse model where we could induce the release of self-antigens via caspase-dependent apoptosis. We tracked the fate of CD8+ T cells specific for the self-antigen. Our studies demonstrated that antigens released from apoptotic cells were cross-presented by CD11c+ cells in the draining lymph node. This cross-presentation led to proliferation of self-antigen specific T cells, followed by a transient ability to produce IFN-γ, but did not lead to the development of autoimmune diabetes. Using this model we examined the consequences on T cell immunity when apoptosis was combined with dendritic cell maturation signals, an autoimmune susceptible genetic background, and the deletion of Tregs. The results of our study demonstrate that autoimmune diabetes cannot be initiated by the presentation of antigens released from apoptotic cells in vivo even in the presence of factors known to promote autoimmunity.
authors.affiliation: Department of Rheumatology, Faculty of Medicine, Saga University, Saga, Japan.|Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ono
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada.
authors.forename: Olivia
authors.initials: O
authors.lastname: Chan
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada.
authors.forename: Håkan
authors.initials: H
authors.lastname: Hall
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada.
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada.
authors.forename: Patty
authors.initials: P
authors.lastname: Yen
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Calzascia
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Texas Medical Center, Houston, Texas, United States of America.|Bellicum Pharmaceuticals, Inc. Houston, Texas, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Departments of Medical Biophysics and Immunology, Toronto, Ontario, Canada.
authors.forename: Salim
authors.initials: S
authors.lastname: Dhanji
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000235:genetics; D001324:Autoantigens / Q000008:administration & dosage* / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D001324:Autoantigens; D007371:Interferon-gamma