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.
ACKNOWLEDGMENTS
We thank Alessandra Pernis, Jessica Fanzo, and So Young Jang for technical advice and reagents; Raphael Clynes and Ramon Parsons for providing fluorescent microscopes; Kevan Herold and Qiong-Fen Guo for assistance with the cytokine assays; and Mathias Szabolcs for evaluating histology sections.
This work was supported in part by the American Cancer Society grant RPG99-09-01MGO, by the Department of Defense grants DAMD17-99-1-9151 and DAMD17-99-1-915, and by the National Institute of Allergy and Infectious Disease grant RO1 AI49387-01.