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

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

Author information

1
Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France; INSERM, U1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, Unité Mixte Recherche 5282, Toulouse F-31300, France; Université Toulouse III Paul-Sabatier, Toulouse F-31300, France; and.
2
Integrated Department of Immunology, University of Colorado Denver School of Medicine and National Jewish Health, Denver, CO 80206.
3
Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France; INSERM, U1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, Unité Mixte Recherche 5282, Toulouse F-31300, France; Université Toulouse III Paul-Sabatier, Toulouse F-31300, France; and sylvie.guerder@inserm.fr.

Abstract

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.

PMID:
26209627
DOI:
10.4049/jimmunol.1401683
[Indexed for MEDLINE]
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