title: T-cell regulation by casitas B-lineage lymphoma (Cblb) is a critical failsafe against autoimmune disease due to autoimmune regulator (Aire) deficiency.
abstract: Autoimmune polyendocrinopathy syndrome type 1 (APS1) results from homozygous Aire mutations that cripple thymic deletion of organ-specific T cells. The clinical course in man and mouse is characterized by high variability both in the latent period before onset of autoimmune disease and in the specific organs affected, but the reasons for this are unknown. Here we test the hypothesis that the latent period reflects the failsafe action of discrete postthymic mechanisms for imposing self-tolerance in peripheral T cells. Aire-deficient mice were crossed with mice of a uniform major histocompatibility complex (MHC) haplotype and genetic background carrying specific genetic defects in one of four distinct peripheral tolerance mechanisms: activation-induced cell death (Fasl(gld/gld)), anergy and requirement for CD28 costimulation (Cblb(-/-)), inhibition of ICOS and T(FH) cells (Rc3h1(san/san)), or decreased numbers of Foxp3(+) T regulatory cells (Card11(unm/unm)). Cblb-deficiency was unique among these four in precipitating rapid clinical autoimmune disease when combined with Aire-deficiency, resulting in autoimmune exocrine pancreatitis with median age of survival of only 25 d. Massive lymphocytic infiltration selectively destroyed most of the exocrine acinar cells of the pancreas and submandibular salivary gland, and CD4(+) and CD8(+) subsets were necessary and sufficient to transfer the disease. Intrinsic regulation of peripheral T cells by CBL-B thus serves a uniquely critical role as a failsafe against clinical onset of autoimmune disease in AIRE deficiency, and multiple peripheral tolerance mechanisms may need to fail before onset of clinical autoimmunity to many organs.
authors.affiliation: Immune Tolerance and Signalling Laboratory, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra 0200, Australia.
authors.forename: Charis E
authors.initials: CE
authors.lastname: Teh
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Daley
authors.forename: Anselm
authors.initials: A
authors.lastname: Enders
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012469:Salivary Glands / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013270:Stomach / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D018183:Transplantation Chimera / Q000276:immunology; D000096927:AIRE Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050721:Proto-Oncogene Proteins c-cbl; D014157:Transcription Factors; D000096927:AIRE Protein; C118387:Cblb protein, mouse