title: The T Cell Repertoire-Diversifying Enzyme TSSP Contributes to Thymic Selection of Diabetogenic CD4 T Cell Specificities Reactive to ChgA and IAPP Autoantigens.
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.
authors.affiliation: 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.
authors.forename: Christophe
authors.initials: C
authors.lastname: Viret
authors.affiliation: 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.
authors.forename: Karim
authors.initials: K
authors.lastname: Mahiddine
authors.affiliation: Integrated Department of Immunology, University of Colorado Denver School of Medicine and National Jewish Health, Denver, CO 80206.
authors.forename: Rocky Lee
authors.initials: RL
authors.lastname: Baker
authors.affiliation: Integrated Department of Immunology, University of Colorado Denver School of Medicine and National Jewish Health, Denver, CO 80206.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Haskins
authors.affiliation: 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.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Guerder
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D053379:Chromogranin A / Q000276:immunology*; D005434:Flow Cytometry; D058228:Islet Amyloid Polypeptide / Q000276:immunology*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; D053379:Chromogranin A; D058228:Islet Amyloid Polypeptide; D011948:Receptors, Antigen, T-Cell; C506155:chromogranin A, mouse; C472501:Prss16 protein, mouse; D012697:Serine Endopeptidases