title: Defective central tolerance induction in NOD mice: genomics and genetics.
abstract: The genetic determinism of type-1 diabetes in NOD mice likely involves complementary defects in central T cell tolerance induction and peripheral immunoregulation. To study the contribution of the NOD genetic background to central tolerance, we followed the behavior of BDC2.5 clonotype thymocytes in fetal thymic organ cultures (FTOC). The NOD genetic background encodes a quantitative deficiency in the ability to delete these self-reactive thymocytes and to divert them to the CD8alphaalpha lineage. In genetic analyses, comparing NOD and B6.H2g7 FTOCs, the NOD defect incorporated the influence of several loci (notably ones on chr1 and 3). Microarray analyses assessing FTOCs from the same two strains argued that the NOD abnormality reflects the combined effects of turning down the gene expression program that provokes apoptosis and turning on a new program promoting cell survival. Intersection of the data from the two approaches points to a small set of attractive candidate genes.
authors.affiliation: Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zucchelli
authors.forename: Phil
authors.initials: P
authors.lastname: Holler
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamagata
authors.forename: Matthew
authors.initials: M
authors.lastname: Roy
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000276:immunology; D002874:Chromosome Mapping; D017637:Clonal Deletion / Q000276:immunology; D005333:Fetus; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics* / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D017634:Self Tolerance / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*