Cathepsin S dominates autoantigen processing in human thymic dendritic cells

Christina Stoeckle, Paula Quecke, Thomas Rückrich, Timo Burster, Michael Reich, Ekkehard Weber, Hubert Kalbacher, Christoph Driessen, Arthur Melms, Eva Tolosa

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)332-43
Number of pages12
JournalJournal of Autoimmunity
Volume38
Issue number4
DOIs
Publication statusPublished - Jun 2012

Fingerprint

cathepsin S
Autoantigens
Dendritic Cells
Antigen-Presenting Cells
T-Lymphocyte Epitopes
T-Lymphocytes
Thymocytes
Peptide Hydrolases
Peptides
Epitopes
Cathepsins
Proinsulin
Myelin Basic Protein
Antigen Presentation
Myeloid Cells
Autoimmunity
Thymus Gland

Keywords

  • Amino Acid Sequence
  • Antigen Presentation
  • Autoantigens
  • Cathepsins
  • Dendritic Cells
  • Humans
  • Molecular Sequence Data
  • Myelin Basic Protein
  • Proinsulin
  • Thymus Gland
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Stoeckle, C., Quecke, P., Rückrich, T., Burster, T., Reich, M., Weber, E., ... Tolosa, E. (2012). Cathepsin S dominates autoantigen processing in human thymic dendritic cells. Journal of Autoimmunity, 38(4), 332-43. https://doi.org/10.1016/j.jaut.2012.02.003

Cathepsin S dominates autoantigen processing in human thymic dendritic cells. / Stoeckle, Christina; Quecke, Paula; Rückrich, Thomas; Burster, Timo; Reich, Michael; Weber, Ekkehard; Kalbacher, Hubert; Driessen, Christoph; Melms, Arthur; Tolosa, Eva.

In: Journal of Autoimmunity, Vol. 38, No. 4, 06.2012, p. 332-43.

Research output: Contribution to journalArticle

Stoeckle, C, Quecke, P, Rückrich, T, Burster, T, Reich, M, Weber, E, Kalbacher, H, Driessen, C, Melms, A & Tolosa, E 2012, 'Cathepsin S dominates autoantigen processing in human thymic dendritic cells', Journal of Autoimmunity, vol. 38, no. 4, pp. 332-43. https://doi.org/10.1016/j.jaut.2012.02.003
Stoeckle, Christina ; Quecke, Paula ; Rückrich, Thomas ; Burster, Timo ; Reich, Michael ; Weber, Ekkehard ; Kalbacher, Hubert ; Driessen, Christoph ; Melms, Arthur ; Tolosa, Eva. / Cathepsin S dominates autoantigen processing in human thymic dendritic cells. In: Journal of Autoimmunity. 2012 ; Vol. 38, No. 4. pp. 332-43.
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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

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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.

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KW - Proinsulin

KW - Thymus Gland

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