Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes

Nat Immunol. 2009 Sep;10(9):1026-33. doi: 10.1038/ni.1773. Epub 2009 Aug 9.

Abstract

Type 1 diabetes may result from a breakdown in peripheral tolerance that is partially controlled by the expression of peripheral tissue antigens (PTAs) in lymph nodes. Here we show that the transcriptional regulator Deaf1 controls the expression of genes encoding PTAs in the pancreatic lymph nodes (PLNs). The expression of canonical Deaf1 was lower, whereas that of an alternatively spliced variant was higher, during the onset of destructive insulitis in the PLNs of nonobese diabetic (NOD) mice. We identified an equivalent variant Deaf1 isoform in the PLNs of patients with type 1 diabetes. Both the NOD mouse and human Deaf1 variant isoforms suppressed PTA expression by inhibiting the transcriptional activity of canonical Deaf1. Lower PTA expression resulting from the alternative splicing of DEAF1 may contribute to the pathogenesis of type 1 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Antigens / genetics*
  • Base Sequence
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Gene Expression Regulation
  • Humans
  • Lymph Nodes / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Molecular Sequence Data
  • Nuclear Proteins / physiology*
  • Pancreas / immunology*
  • Protein Isoforms

Substances

  • Antigens
  • DEAF1 protein, human
  • Nuclear Proteins
  • Protein Isoforms

Associated data

  • GENBANK/FJ377318
  • GENBANK/FJ377319
  • GENBANK/FJ985253