Enhanced T cell responses contribute to the genetic predisposition of CD8-mediated spontaneous autoimmunity

Eur J Immunol. 2002 Mar;32(3):885-94. doi: 10.1002/1521-4141(200203)32:3<885::AID-IMMU885>3.0.CO;2-E.

Abstract

A number of factors have been demonstrated to influence the induction of pathogenic autoimmune responses, including the loss of regulatory T cells. To assess the contribution of regulatory T cells in CD8(+) T cell-mediated autoimmunity, RIP-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic beta-islet cells, together with T cells expressing an LCMV-gp-specific T cell receptor (TCR), were crossed to RAG 2-deficient mice. The loss of potentially regulatory T cells, however, did not contribute to diabetes induction. Surprisingly, both RIP-gp/P14-RAG(+/-) and RIP-gp/P14-RAG(-/-) developed spontaneous disease, suggesting an influence of the 129 genetic background on disease susceptibility. Further studies demonstrated that disease susceptibility was not due to nonspecific T cell activation, nor to enhanced cross-presentation of LCMV-gp, nor to decreased expression levels of the negative regulatory molecule CD5. Disease susceptibility did associate, however, with enhanced T cell responses. Thus, T cell hyperactivity combined with various genetic factors may predispose an individual to autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Viral / genetics
  • Antigens, Viral / immunology
  • Autoantigens / immunology
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • Crosses, Genetic
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Glycoproteins / genetics
  • Glycoproteins / immunology
  • Insulin / genetics
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Lymphocyte Activation*
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Peptide Fragments / genetics
  • Peptide Fragments / immunology
  • Promoter Regions, Genetic
  • Rats
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • T-Lymphocyte Subsets / immunology*
  • Viral Proteins / genetics
  • Viral Proteins / immunology

Substances

  • Antigens, Viral
  • Autoantigens
  • DNA-Binding Proteins
  • Glycoproteins
  • Insulin
  • Peptide Fragments
  • Rag2 protein, mouse
  • Receptors, Antigen, T-Cell, alpha-beta
  • Recombinant Fusion Proteins
  • V(D)J recombination activating protein 2
  • Viral Proteins
  • glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus