The T Cell Repertoire-Diversifying Enzyme TSSP Contributes to Thymic Selection of Diabetogenic CD4 T Cell Specificities Reactive to ChgA and IAPP Autoantigens

J Immunol. 2015 Sep 1;195(5):1964-73. doi: 10.4049/jimmunol.1401683. Epub 2015 Jul 24.


Multiple studies highlighted the overtly self-reactive T cell repertoire in the diabetes-prone NOD mouse. This autoreactivity has primarily been linked to defects in apoptosis induction during central tolerance. Previous studies suggested that thymus-specific serine protease (TSSP), a putative serine protease expressed by cortical thymic epithelial cells and thymic dendritic cells, may edit the repertoire of self-peptides presented by MHC class II molecules and shapes the self-reactive CD4 T cell repertoire. To gain further insight into the role of TSSP in the selection of self-reactive CD4 T cells by endogenous self-Ags, we examined the development of thymocytes expressing distinct diabetogenic TCRs sharing common specificity in a thymic environment lacking TSSP. Using mixed bone marrow chimeras, we evaluated the effect of TSSP deficiency confined to different thymic stromal cells on the differentiation of thymocytes expressing the chromogranin A-reactive BDC-2.5 and BDC-10.1 TCRs or the islet amyloid polypeptide-reactive TCR BDC-6.9 and BDC-5.2.9. We found that TSSP deficiency resulted in deficient positive selection and induced deletion of the BDC-6.9 and BDC-10.1 TCRs, but it did not affect the differentiation of the BDC-2.5 and BDC-5.2.9 TCRs. Hence, TSSP has a subtle role in the generation of self-peptide ligands directing diabetogenic CD4 T cell development. These results provide additional evidence for TSSP activity as a novel mechanism promoting autoreactive CD4 T cell development/accumulation in the NOD mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Chromogranin A / immunology*
  • Flow Cytometry
  • Islet Amyloid Polypeptide / immunology*
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / immunology*
  • Serine Endopeptidases / metabolism
  • Stromal Cells / immunology
  • Stromal Cells / metabolism
  • Thymocytes / immunology
  • Thymocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Thymus Gland / metabolism


  • Autoantigens
  • Chromogranin A
  • Islet Amyloid Polypeptide
  • Receptors, Antigen, T-Cell
  • chromogranin A, mouse
  • Prss16 protein, mouse
  • Serine Endopeptidases