The diabetogenic, insulin-specific CD8 T cell response primed in the experimental autoimmune diabetes model in RIP-B7.1 mice

Eur J Immunol. 2007 Aug;37(8):2097-103. doi: 10.1002/eji.200737222.

Abstract

Type 1 diabetes mellitus can result from the specific destruction of pancreatic beta cells by autoreactive T cells. As shown here, experimental autoimmune diabetes (EAD) is efficiently induced in RIP-B7.1 mice by preproinsulin (ppins)-encoding DNA vaccines. EAD develops in RIP-B7.1 mice within 3-4 wk after a single immunization with ppins-encoding plasmid DNA. RIP-B7.1 mice develop insulitis, insulin deficiency and hyperglycemia after vaccination with plasmids encoding murine ppins-I or murine ppins-II or human hu-ppins. EAD induction critically depends on CD8 T cells and is independent of CD4 T cells. To be diabetogenic, ppins-specific CD8 T cells had to express IFN-gamma. Neither expression of perforin nor signaling through the type I IFN receptor is an essential component of this pathogenic CD8 T cell phenotype. Using plasmids encoding truncated ppins variants, we show that EAD is only induced by DNA vaccines encoding the insulin A-chain. Diabetogenic CD8 T cells specifically recognize the Kb-restricted A12-21 epitope of the insulin A-chain. The RIP-B7.1 model hence represents an attractive model for the characterization of cellular and molecular events involved in the CD8 T cell-mediated immune pathogenesis of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Diabetes Mellitus, Experimental / immunology*
  • Diabetes Mellitus, Experimental / pathology
  • Disease Models, Animal
  • Female
  • Humans
  • Insulin / immunology*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Male
  • Mice
  • Molecular Sequence Data
  • Plasmids / genetics
  • Proinsulin / genetics
  • Proinsulin / immunology*
  • Protein Precursors / genetics
  • Protein Precursors / immunology*
  • Vaccines, DNA / immunology

Substances

  • Insulin
  • Protein Precursors
  • Vaccines, DNA
  • preproinsulin
  • Interferon-gamma
  • Proinsulin