title: How defects in central tolerance impinge on a deficiency in regulatory T cells.
abstract: Both central (thymic) and peripheral (nonthymic) mechanisms are important for the induction and maintenance of T cell tolerance. Mice with a defect in Foxp3, required for the generation and activity of CD4(+)CD25(+) regulatory T cells, exhibit massive lymphoproliferation and severe inflammatory infiltration of multiple organs, in particular the lungs, liver, and skin. We have explored how this phenotype is influenced by an additional defect in central tolerance induction, generated by either crossing in a null mutation of the Aire gene or substituting the nonobese diabetic (NOD) genetic background. The double-deficient mice had fulminant autoimmunity in very early life and a gravely shortened lifespan vis-à-vis single-deficient littermates. They showed massive lymphoproliferation and exacerbated inflammatory damage, particularly in the lungs and liver. Yet, the range of affected sites was not noticeably extended, and, surprisingly, many organs, or regions of organs, remained untouched, suggesting additional important mechanisms to enforce immunological self-tolerance.
authors.affiliation: Section on Immunology and Immunogenetics, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Chen
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics; D006652:Histological Techniques; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics; D000096927:AIRE Protein
chemical_list: D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D000096927:AIRE Protein; C498833:Foxp3 protein, mouse