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Molecular and Cellular Biology, December 2005, p. 11035-11046, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.11035-11046.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Deficiency in Expression of the Signaling Protein Sin/Efs Leads to T-Lymphocyte Activation and Mucosal Inflammation

Laura T. Donlin ,{dagger},{ddagger} Nichole M. Danzl,{dagger} Celestine Wanjalla, and Konstantina Alexandropoulos*

Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032

Received 25 April 2005/ Returned for modification 3 June 2005/ Accepted 30 September 2005

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.

* Corresponding author. Mailing address: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032. Phone: (212) 305-2705. Fax: (212) 305-8780. E-mail: ka141{at}columbia.edu.

{dagger} L.T.D. and N.M.D. made equal contributions to this work.

{ddagger} Present address: Laboratory of Lymphocyte Signaling, The Rockefeller University, 1230 York Ave., New York, NY 10021.

Molecular and Cellular Biology, December 2005, p. 11035-11046, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.11035-11046.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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