Thymic Positive Selection and Peripheral Activation of Islet Antigen-Specific T Cells: Separation of Two Diabetogenic Steps by an I-A(g7) Class II MHC Beta-Chain Mutant

J Immunol. 1998 Nov 1;161(9):4489-92.

Abstract

The diabetes-susceptible class II MHC genes (in human and mouse) share unique nonaspartic acid residues at position 57 of the class II beta-chain. Transgenic expression of a mutant I-A(g7), substituting histidine and serine at position 56 and 57 of beta-chain with proline and aspartic acid (I-A(g7)PD), respectively, inhibits diabetes development in the nonobese diabetic mouse model. Here, we demonstrate that immature thymocytes expressing a diabetogenic islet Ag-specific transgenic TCR are positively selected by I-A(g7)PD class II MHC to give rise to mature CD4+ T cells. However, splenic APCs expressing the same I-A(g7)PD fail to present pancreatic islet Ag to mature T cells bearing this diabetogenic TCR. These results indicate that nonaspartic acid residues at position 57 of class II MHC beta-chain is important for diabetogenic CD4+ T cell activation in the periphery but is not essential for the formation of a diabetogenic T cell repertoire in the thymus.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antigen Presentation
  • Autoimmune Diseases / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Clonal Deletion*
  • Codon / genetics
  • DNA, Complementary / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Histocompatibility Antigens Class II / genetics*
  • Histocompatibility Antigens Class II / immunology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Point Mutation
  • Promoter Regions, Genetic
  • Radiation Chimera
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Specific Pathogen-Free Organisms
  • Spleen / pathology
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / pathology
  • Thymus Gland / immunology*
  • Thymus Gland / pathology

Substances

  • Codon
  • DNA, Complementary
  • Histocompatibility Antigens Class II
  • I-E-antigen
  • Receptors, Antigen, T-Cell