Exposure to sequestered self-antigens in vivo is not sufficient for the induction of autoimmune diabetes

• Published in: PloS one Vol. 12; no. 3; p. e0173176
• Main Authors: Ono, Nobuyuki, Murakami, Kiichi, Chan, Olivia, Hall, Håkan, Elford, Alisha R, Yen, Patty, Calzascia, Thomas, Spencer, David M, Ohashi, Pamela S, Dhanji, Salim
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.03.2017; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Antigen presentation; Antigen Presentation - genetics; Antigen Presentation - immunology; Antigens; Apoptosis; Apoptosis - genetics; Autoantigens; Autoantigens - administration & dosage; Autoantigens - immunology; Autoimmune diseases; Autoimmunity; Autoimmunity - genetics; Biology and Life Sciences; Caspase; CD11c antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell death; Cell proliferation; Clonal deletion; Dendritic cells; Dendritic Cells - immunology; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - etiology; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Disease Models, Animal; Humans; Immune Tolerance; Immunity; Interferon; Interferon-gamma - genetics; Kinases; Lymph nodes; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Mice; Mice, Transgenic - immunology; Priming; Research and Analysis Methods; Rodents; T cell receptors; T cells; T-Lymphocytes, Regulatory - immunology; Transgenic mice; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0173176

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.