title: Cathepsin S dominates autoantigen processing in human thymic dendritic cells.
abstract: The interaction of developing thymocytes with peptide-MHC complexes on thymic antigen presenting cells (APC) is crucial for T cell development, both for positive selection of "useful" thymocytes as well as negative selection of autoreactive thymocytes to prevent autoimmunity. The peptides presented on MHC II molecules are generated by lysosomal proteases such as the cathepsins. At the same time, lysosomal proteases will also destroy other potential T cell epitopes from self-antigens. This will lead to a lack of presentation on negatively selecting thymic antigen presenting cells and consequently, escape of autoreactive T cells recognizing these epitopes. In order to understand the processes that govern generation or destruction of self-epitopes in thymic APC, we studied the antigen processing machinery and epitope processing in the human thymus. We find that each type of thymic APC expresses a different signature of lysosomal proteases, providing indirect evidence that positive and negative selection of CD4(+) T cells might occur on different sets of peptides, in analogy to what has been proposed for CD8(+) T cells. We also find that myeloid dendritic cells (DC) are more efficient in processing autoantigen than plasmacytoid DC. In addition, we observed that cathepsin S plays a central role in processing of the autoantigens myelin basic protein and proinsulin in thymic dendritic cells. Cathepsin S destroyed a number of known T cell epitopes, which would be expected to result in lack of presentation and consequently, escape of autoreactive T cells. Cathepsin S therefore appears to be an important factor that influences selection of autoreactive T cells.
authors.affiliation: Hertie Institute for Clinical Brain Research, University of Tuebingen, Germany. christina.stoeckle@web.de
authors.forename: Christina
authors.initials: C
authors.lastname: Stoeckle
authors.forename: Paula
authors.initials: P
authors.lastname: Quecke
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückrich
authors.forename: Timo
authors.initials: T
authors.lastname: Burster
authors.forename: Michael
authors.initials: M
authors.lastname: Reich
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Weber
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.forename: Christoph
authors.initials: C
authors.lastname: Driessen
authors.forename: Arthur
authors.initials: A
authors.lastname: Melms
authors.forename: Eva
authors.initials: E
authors.lastname: Tolosa
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism; D011384:Proinsulin / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; D004676:Myelin Basic Protein; D011384:Proinsulin; D002403:Cathepsins; C028217:cathepsin S