Expression of CD40 identifies a unique pathogenic T cell population in type 1 diabetes

Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3782-7. doi: 10.1073/pnas.052247099. Epub 2002 Mar 12.

Abstract

Juvenile diabetes (type 1) is an autoimmune disease in which CD4(+) T cells play a major role in pathogenesis characterized by insulitis and beta cell destruction leading to clinical hyperglycemia. To date, no marker for autoimmune T cells has been described, although it was previously demonstrated that autoimmune mice have a large population of CD4(+) cells that express CD40. We show here that established, diabetogenic T cell clones of either the Th1 or Th2 phenotype are CD40-positive, whereas nondiabetogenic clones are CD40-negative. CD40 functionally signals T cell clones, inducing rapid activation of the transcription factor NFkappaB. We show that autoimmune diabetes-prone nonobese diabetic mice have high levels of CD40(+)CD4(+) T cells in the thymus, spleen, and importantly, in the pancreas. Finally, as demonstrated by adoptive transfers, CD4(+)CD40(+) cells infiltrate the pancreatic islets causing beta-cell degranulation and ultimately diabetes.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • CD4 Antigens / analysis
  • CD4 Antigens / metabolism
  • CD40 Antigens / analysis
  • CD40 Antigens / genetics
  • CD40 Antigens / metabolism*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology*
  • Flow Cytometry
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology*
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th1 Cells / pathology
  • Thymus Gland / cytology
  • Thymus Gland / immunology

Substances

  • CD4 Antigens
  • CD40 Antigens
  • NF-kappa B