A defect in central tolerance in NOD mice

Nat Immunol. 2001 Nov;2(11):1025-31. doi: 10.1038/ni726.

Abstract

The predisposition of nonobese diabetic (NOD) mice to develop autoimmune disease is usually attributed to defects in peripheral tolerance mechanisms. Here, evidence is presented that NOD mice display a defect in central tolerance (negative selection) of thymocytes. Impaired central tolerance in NOD mice was most prominent in a population of semi-mature thymocytes found in the medulla. The defect was apparent in vivo as well as in vitro, was independent of IAbetag7 expression and affected both Fas-dependent and Fas-independent pathways of apoptosis; for Fas-dependent apoptosis, the defective tolerance of NOD thymocytes correlated with the strong T cell receptor-mediated up-regulation of caspase 8-homologous FLICE (Fas-associated death-domain-like interleukin 1beta-converting enzyme)-inhibitory protein. In light of these findings, disease onset in NOD mice may reflect defects in central as well as peripheral tolerance.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, CD / genetics
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Apoptosis
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CD28 Antigens / physiology
  • CD4 Antigens / analysis
  • CD8 Antigens / analysis
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / genetics
  • Clonal Deletion / immunology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Fas Ligand Protein
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Immune Tolerance / immunology*
  • Interleukin-4 / pharmacology
  • Interleukin-7 / pharmacology
  • Intracellular Signaling Peptides and Proteins*
  • Lectins, C-Type
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Inbred NOD / genetics
  • Mice, Inbred NOD / immunology*
  • Mice, Inbred NZB
  • RNA, Messenger / biosynthesis
  • Receptors, Antigen, T-Cell / physiology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / pathology
  • Thymus Gland / pathology*
  • fas Receptor / physiology

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CD28 Antigens
  • CD4 Antigens
  • CD69 antigen
  • CD8 Antigens
  • Carrier Proteins
  • Cflar protein, mouse
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Interleukin-7
  • Intracellular Signaling Peptides and Proteins
  • Lectins, C-Type
  • Membrane Glycoproteins
  • RNA, Messenger
  • Receptors, Antigen, T-Cell
  • fas Receptor
  • Interleukin-4