TY - JOUR
T1 - DLGH1 is a negative regulator of T-lymphocyte proliferation
AU - Stephenson, Linda M.
AU - Sammut, Bénédicte
AU - Graham, Daniel B.
AU - Chan-Wang, Joaquim
AU - Brim, Karry L.
AU - Huett, Alan S.
AU - Miletic, Ana V.
AU - Kloeppel, Tracie
AU - Landry, Aimee
AU - Xavier, Ramnik
AU - Swat, Wojciech
PY - 2007/11
Y1 - 2007/11
N2 - 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 hyperproliferative 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.
AB - 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 hyperproliferative 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.
UR - http://www.scopus.com/inward/record.url?scp=35649008864&partnerID=8YFLogxK
U2 - 10.1128/MCB.00439-07
DO - 10.1128/MCB.00439-07
M3 - Article
C2 - 17724087
AN - SCOPUS:35649008864
VL - 27
SP - 7574
EP - 7581
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 21
ER -