Deficiency in expression of the signaling protein Sin/Efs leads to T-lymphocyte activation and mucosal inflammation

Mol Cell Biol. 2005 Dec;25(24):11035-46. doi: 10.1128/MCB.25.24.11035-11046.2005.

Abstract

Our studies have concentrated on elucidating the role of the signaling protein Sin in T-lymphocyte function. We have previously shown that Sin overexpression inhibits T-lymphocyte development and activation. Here we show that Sin-deficient mice exhibit exaggerated immune responses characterized by enhanced cytokine secretion and T-cell-dependent antibody production. Excessive T-cell responses in young mice correlate with spontaneous development of inflammatory lesions in different organs of aged Sin(-/-) mice, particularly the small intestine. The intestinal inflammation is characterized by T- and B-cell infiltrates in the lamina propria, which correlate with crypt enlargement and marked villus expansion and/or damage. Similar to the human intestinal inflammatory disorder Crohn's disease (CD), and in contrast to most mouse models of mucosal inflammation, inflammatory lesions in the gastrointestinal tract of Sin(-/-) mice are restricted to the small bowel. Taken together, these results suggest that Sin regulates immune system and T-lymphocyte function and that immune system dysfunction in the absence of Sin may underlie the pathogenesis of tissue-specific inflammation and enteropathies such as CD.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • Enterocolitis / genetics
  • Enterocolitis / immunology*
  • Granuloma / genetics
  • Intestinal Mucosa / pathology
  • Liver / pathology
  • Lymphocyte Activation*
  • Male
  • Mice
  • Mice, Knockout
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Receptors, Interleukin-2 / analysis
  • Signal Transduction
  • T-Lymphocytes / immunology*

Substances

  • Efs protein, mouse
  • Phosphoproteins
  • Receptors, Interleukin-2