title: The Autoimmunity-Associated Gene CLEC16A Modulates Thymic Epithelial Cell Autophagy and Alters T Cell Selection.
abstract: CLEC16A variation has been associated with multiple immune-mediated diseases, including type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, celiac disease, Crohn's disease, Addison's disease, primary biliary cirrhosis, rheumatoid arthritis, juvenile idiopathic arthritis, and alopecia areata. Despite strong genetic evidence implicating CLEC16A in autoimmunity, this gene's broad association with disease remains unexplained. We generated Clec16a knock-down (KD) mice in the nonobese diabetic (NOD) model for type 1 diabetes and found that Clec16a silencing protected against autoimmunity. Disease protection was attributable to T cell hyporeactivity, which was secondary to changes in thymic epithelial cell (TEC) stimuli that drive thymocyte selection. Our data indicate that T cell selection and reactivity were impacted by Clec16a variation in thymic epithelium owing to Clec16a's role in TEC autophagy. These findings provide a functional link between human CLEC16A variation and the immune dysregulation that underlies the risk of autoimmunity.
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schuster
authors.affiliation: Rudolf Virchow Center/DFG Research Center for Experimental Biomedicine, University of Wurzburg, Josef-Schneider Strasse 2, 97080 Wurzburg, Germany.
authors.forename: Kay D
authors.initials: KD
authors.lastname: Gerold
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.
authors.forename: Kilian
authors.initials: K
authors.lastname: Schober
authors.affiliation: Rudolf Virchow Center/DFG Research Center for Experimental Biomedicine, University of Wurzburg, Josef-Schneider Strasse 2, 97080 Wurzburg, Germany.
authors.forename: Lilli
authors.initials: L
authors.lastname: Probst
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Boerner
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Ruckdeschel
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Serwold
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02215, USA; Rudolf Virchow Center/DFG Research Center for Experimental Biomedicine, University of Wurzburg, Josef-Schneider Strasse 2, 97080 Wurzburg, Germany. Electronic address: stephan.kissler@joslin.harvard.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kissler
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D001343:Autophagy / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: C000591253:CLEC16A protein, mouse; D037181:Lectins, C-Type; D009004:Monosaccharide Transport Proteins