Cathepsin S dominates autoantigen processing in human thymic dendritic cells.

TY - JOUR

T1 - Cathepsin S dominates autoantigen processing in human thymic dendritic cells.

AU - Stoeckle, Christina

AU - Quecke, Paula

AU - Rückrich, Thomas

AU - Burster, Timo

AU - Reich, Michael

AU - Weber, Ekkehard

AU - Kalbacher, Hubert

AU - Driessen, Christoph

AU - Melms, Arthur

AU - Tolosa, Eva

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Humans

KW - Amino Acid Sequence

KW - Molecular Sequence Data

KW - Antigen Presentation/immunology

KW - Autoantigens/immunology/metabolism

KW - Cathepsins/metabolism

KW - Dendritic Cells/immunology/metabolism

KW - Myelin Basic Protein/immunology/metabolism

KW - Proinsulin/immunology/metabolism

KW - Thymus Gland/immunology/metabolism

KW - Humans

KW - Amino Acid Sequence

KW - Molecular Sequence Data

KW - Antigen Presentation/immunology

KW - Autoantigens/immunology/metabolism

KW - Cathepsins/metabolism

KW - Dendritic Cells/immunology/metabolism

KW - Myelin Basic Protein/immunology/metabolism

KW - Proinsulin/immunology/metabolism

KW - Thymus Gland/immunology/metabolism

M3 - SCORING: Journal article

VL - 38

SP - 332

EP - 343

JO - J AUTOIMMUN

JF - J AUTOIMMUN

SN - 0896-8411

IS - 4

M1 - 4

ER -