title: Presentation of Autoantigen in Peripheral Lymph Nodes Is Sufficient for Priming Autoreactive CD8+T Cells.
abstract: Peripheral tolerance is an important mechanism by which the immune system can guarantee a second line of defense against autoreactive T and B cells. One autoimmune disease that is related to a break of peripheral tolerance is diabetes mellitus type 1. Using the RIP-GP mouse model, we analyzed the role of the spleen and lymph nodes (LNs) in priming CD8+T cells and breaking peripheral tolerance. We found that diabetes developed in splenectomized mice infected with the lymphocytic choriomeningitis virus (LCMV), a finding showing that the spleen was not necessary in generating autoimmunity. By contrast, the absence of LNs prevented the priming of LCMV-specific CD8+T cells, and diabetes did not develop in these mice. Additionally, we found that dendritic cells are responsible for the distribution of virus in secondary lymphoid organs, when LCMV was administered intravenously. Preventing this distribution with the sphingosine-1-phosphate receptor antagonist FTY720 inhibits the transport of antigen to peripheral LNs and consequently prevented the onset of diabetes. However, in case of subcutaneous infection, administration of FTY720 could not inhibit the onset of diabetes because the viral antigen is already presented in the peripheral LNs. These findings demonstrate the importance of preventing the presence of antigen in LNs for maintaining tolerance.
authors.affiliation: Medical Faculty, Institute of Immunology, University of Duisburg-Essen, Essen, Germany; Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Honke
authors.affiliation: Medical Faculty, Institute of Immunology, University of Duisburg-Essen, Essen, Germany; Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Namir
authors.initials: N
authors.lastname: Shaabani
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute , La Jolla, CA , USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Teijaro
authors.affiliation: Pharmazentrum Frankfurt, Goethe University Hospital Frankfurt , Frankfurt am Main , Germany.
authors.forename: Urs
authors.initials: U
authors.lastname: Christen
authors.affiliation: Medical Faculty, Institute of Immunology, University of Duisburg-Essen , Essen , Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hardt
authors.affiliation: Medical Faculty, Institute of Immunology, University of Duisburg-Essen , Essen , Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Bezgovsek
authors.affiliation: Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany; Medical Faculty, Department of Molecular Medicine II, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.affiliation: Medical Faculty, Institute of Immunology, University of Duisburg-Essen, Essen, Germany; Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
keywords: LCMV; autoimmune diabetes; enforced viral replication; lymph nodes; sphingosine-1-phosphate receptor