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Molecular and Cellular Biology, November 2007, p. 7574-7581, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00439-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

DLGH1 Is a Negative Regulator of T-Lymphocyte Proliferation ^,

Linda M. Stephenson ,^1, Bénédicte Sammut,^1, Daniel B. Graham,¹ Joaquim Chan-Wang,¹ Karry L. Brim,¹ Alan S. Huett,² Ana V. Miletic,¹ Tracie Kloeppel,¹ Aimee Landry,² Ramnik Xavier,^2* and Wojciech Swat^1*

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110,¹ Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115²

Received 14 March 2007/ Returned for modification 24 April 2007/ Accepted 10 August 2007

Discs large homolog 1 (DLGH1), a founding member of the membrane-associated guanylate kinase family of proteins containing PostSynaptic Density-95/Discs large/Zona Occludens-1 domains, is an ortholog of the Drosophila tumor suppressor gene Discs large. In the mammalian embryo, DLGH1 is essential for normal urogenital morphogenesis and the development of skeletal and epithelial structures. Recent reports also indicate that DLGH1 may be a critical mediator of signals triggered by the antigen receptor complex in T lymphocytes by functioning as a scaffold coordinating the activities of T-cell receptor (TCR) signaling proteins at the immune synapse. However, it remains unclear if DLGH1 functions to enhance or attenuate signals emanating from the TCR. Here, we used Dlgh1 gene-targeted mice to determine the requirement for DLGH1 in T-cell development and activation. Strikingly, while all major subsets of T cells appear to undergo normal thymic development in the absence of DLGH1, peripheral lymph node Dlgh1^–/– T cells show a hyper-proliferative response to TCR-induced stimulation. These data indicate that, consistent with the known function of Discs large proteins as tumor suppressors and attenuators of cell division, in T lymphocytes, DLGH1 functions as a negative regulator of TCR-induced proliferative responses.

Published ahead of print on 27 August 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

L.M.S. and B.S. contributed equally to this work.